WO2011116123A1 - Tafamidis for the treatment of ophthalmic diseases - Google Patents

Abstract

Provided herein are methods of using 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) to treat ophthalmic diseases.

Description

METHODS FOR TREATING OPHTHALMIC DISEASES

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. provisional application serial number 61/315,466, filed March 19, 2010, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

[0002] The invention relates to compounds, compositions and methods for the treatment of ophthalmic diseases and disorders.

BACKGROUND OF THE INVENTION

[0003] Vitamin A and its various metabolites play diverse roles in physiology. For example, vitamin A deficiency is the major cause of blindness in children. Excess vitamin-A levels in organs and tissues, such as the eye, may also cause blindness in a variety of retinal diseases, including macular degeneration. Age-related macular degeneration (AMD) or dystrophy leads to gradual loss of vision, and eventually severe damage to the central vision. Over ten million individuals are estimated to suffer from AMD, and this number is expected to triple over the next decade.

[0004] Abnormal levels of vitamin A, and/or its associated transport proteins, retinol binding protein (RBP) and transthyretin (TTR) are also correlated with the manifestation of other diseases, including metabolic disorders. Abnormal levels of retinol were seen in type I and type II diabetic patients, but not in normal patients. Other diseases include idiopathic intracranial hypertension (IIH), and bone -related disorders, including cervical spondylosis, spinal hyperostosis, and diffuse idiopathic skeletal hyperostosis (DISH). In addition, vitamin A and/or its associated transport proteins, particularly TTR, may play a role in protein misfolding and aggregation disease, including Alzheimer's disease and systemic amyloidosis.

SUMMARY OF THE INVENTION

[0005] Provided herein are methods of using 2-(3,5-dichlorophenyl)benzo[d]oxazole-6- carboxylic acid (Tafamidis) for treating ophthalmic diseases comprising administering to a subject in need thereof, a therapeutically effective amount of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6- carboxylic acid (Tafamidis) or a physiologically acceptable salt thereof. In certain embodiments, such diseases are mediated by the binding of retinol binding protein 4 (RBP4) to transthyretin (TTR).

[0006] In certain embodiments of such methods the ophthalmic disease is a macular degenearation disease or any retinol or retinol binding protein 4 (RBP4) mediated disease. In certain embodiments of such methods, the macular degeneration disease is selected from age related macular degeneration (AMD) Stargardt' s Disease, Cone-Rod Dystrophy, Corneal Dystrophy, Fuch's Dystrophy, Sorsby's Macular Dystrophy, Best Disease, and Juvenile

Retinoschisis, dry macular degeneration and wet macular degeneration.

[0007] In certain embodiments of such methods, the subject is a human subject, while in other embodiments the subject is an animal subject.

[0008] In the above methods for treating ophthalmic diseases or conditions, 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) is administered to a subject, wherein the subject is a human.

[0009] In the above methods for treating ophthalmic diseases or conditions, 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) is administered to a subject, wherein the subject is an animal.

[00010] In certain embodiments of the above methods for treating ophthalmic diseases, 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) is used alone or in combination with a second therapeutic agent. In certain embodiments, such second therapeutic agents further mediated retinol binding protein 4 (RBP4) to transthyretin (TTR). In other embodiments of such methods, the method further comprises the administration a second compound selected from the group consisting of fenretinide, an inducer of nitric oxide production, an antioxidant, an antiinflammatory agent, a mineral, an anti-oxidant, a carotenoid, a negatively charged phospholipid and a statin.

[00011] In another aspect provided herein is the use of 2-(3,5-dichlorophenyl)benzo[d]oxazole- 6-carboxylic acid (Tafamidis) or a physiologically acceptable salt or a pharmaceutical composition thereof, for modulating the binding to retinol binding protein 4 (RBP4) to transthyretin (TTR).

[00012] Another aspect provided herein are methods for modulating the binding of retinol binding protein 4 (RBP4) to transthyretin (TTR) in a cell, wherein such methods comprise contacting the cell with an effective amount of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6- carboxylic acid (Tafamidis) or a physiologically acceptable salt thereof, thereby modulating the binding of retinol binding protein 4 (RBP4) to transthyretin (TTR).

[00013] Also provided herein are methods for effecting the rate of N-retinylidene-N- retinylethanolamine (A2E) progression, wherein such methods comprises administering to subject an effective amount of of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or a pharmaceutical composition containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis). In certain embodiments of such methods, the administration of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) modulates the binding of retinol binding protein 4 (RBP4) to transthyretin (TTR), thereby modulating the serum concentration of RBP which has an effect on A2E progression.

[00014] Also provided herein are methods for reducing the concentration of N-retinylidene-N- retinylethanolamine (A2E), wherein such methods comprises administering to subject an effective amount of of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or a pharmaceutical composition containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis).

[00015] Also provided herein are methods for effecting the rate of transport of retinol to the eye, comprising administering to subject in need thereof a therapeutically effective amount of 2- (3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid or a physiologically acceptable salt thereof.

[00016] Another aspect provided herein are methods for treating dry form age-related macular degeneration in an eye of a mammal comprising administering to the mammal an effective amount of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis).

[00017] In certain embodiments of such methods, wherein the method comprises multiple administrations of the effective amount of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), and the time between multiple administrations is at least one day.

[00018] In certain embodiments of such methods, the method further comprising a drug holiday, wherein the administration of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) is temporarily suspended or the dose of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6- carboxylic acid (Tafamidis) administered is temporarily reduced. In certain embodiments, the drug holiday lasts at least seven days.

[00019] In certain embodiments of such methods, the effective amount of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) is administered orally to the mammal. In certain embodiments of such methods, the effective amount of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) is administered ophthalmically to the mammal.

[00020] In certain embodiments of such methods, the mammal is a human having a macular degeneration disease. In certain embodiments of such methods, the macular degeneration disease is selected from Stargardt' s Disease, Cone-Rod Dystrophy, Corneal Dystrophy, Fuch's Dystrophy, Sorsby's Macular Dystrophy, Best Disease, and Juvenile Retinoschisis, dry macular degeneration and wet macular degeneration.

[00021] In another aspect provided herein is the use of 2-(3,5-dichlorophenyl)benzo[d]oxazole- 6-carboxylic acid (Tafamidis) or a physiologically acceptable salt thereof or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of ophthalmic diseases or conditions. In certain embodiments such disease or conditions include age related macular degeneration, Stargardt' s disease or any retinol or retinol binding protein 4 (RBP4) mediated disease.

[00022] In another aspect provided herein are pharmaceutical compositions for treating ophthalmic diseases, wherein such compositions comprise 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) and a physiologically acceptable carrier.

[00023] In another aspect provided herein is a compound for use in a method of medical treatment, wherein the method of medical treatment is for treating an ophthalmic disease, wherein the disease is selected from age related macular degeneration, Stargardt' s Disease, Cone-Rod Dystrophy, Corneal Dystrophy, Fuch's Dystrophy, Sorsby's Macular Dystrophy, Best Disease, and Juvenile Retinoschisis, dry macular degeneration and wet macular degeneration, and wherein the compound is 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid or a physiologically acceptable salt thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

[00024] The novel features of the methods and compositions disclosed herein are set forth with particularity in the appended claims. A better understanding of the features and advantages will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles disclosed herein are utilized, and the accompanying drawings.

[00025] FIG. 1 shows the serum RBP4 levels in a female RBP4-abcr-83 mice as a function of time after administration of vehicle, fenretinide and 2-(3,5-dichlorophenyl)benzo[d]oxazole-6- carboxylic acid (Tafamidis).

[00026] FIG. 2 shows the serum RBP4 levels in a male RBP4-abcr-85 mice as a function of time after administration of vehicle, 100 mg/kg of fenretinide, 50 mg/kg of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) and 30 mg/kg of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis).

[00027] FIG. 3 shows the serum RBP4 levels in a male RBP4-abcr-82 mice as a function of time after administration of vehicle, 100 mg/kg of fenretinide and 100 mg kg of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis).

[00028] FIG. 4 shows the change in accumulation of A2E in the eye with and without the administration of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis). DETAILED DESCRIPTION OF THE INVENTION

Definitions

[00029] The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[00030] The term "administration" or "administering" of the subject compound means providing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), a

pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or prodrug thereof to a subject in need of treatment.

[00031] The term "carrier," as used herein, refers to chemical compounds or agents that facilitate the incorporation of a compound described herein into cells or tissues.

[00032] The terms "co-administration" or "combined administration" or the like as used herein are meant to encompass administration of the selected therapeutic agents to a single subject or patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.

[00033] The term "diluent," as used herein, refers to chemical compounds that are used to dilute a compound described herein prior to delivery. Diluents can also be used to stabilize compounds described herein.

[00034] The terms "effective amount" or "therapeutically effective amount," as used herein, refer to an amount of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or prodrug thereof that will elicit a biological or medical response in a cell, tissue, organ, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. The terms refers to an amount of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), a

pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or prodrug thereof which, as compared to a corresponding subject who has not received such an amount, results in improved treatment, healing, prevention, or amelioration of an ophthalmic disease, or a decrease in the rate of advancement of such a disease. The term also includes within its scope amounts effective to enhance normal physiological function.

[00035] The terms "enhance" or "enhancing," as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term "enhancing" refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An "enhancing-effective amount," as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.

[00036] The term "iatrogenic," as used herein, means a condition, disorder, or disease created or worsened by medical or surgical therapy.

[00037] The term "mammal", as used herein, means all mammals including humans. Mammals include, by way of example only, humans, non-human primates, cows, dogs, cats, goats, sheep, pigs, rats, mice and rabbits.

[00038] The term "ophthalmically acceptable", as used herein, means having no persistent detrimental effect on the treated eye or the functioning thereof, or on the general health of the subject being treated. Transient effects such as minor irritation or a "stinging" sensation are common with topical ophthalmic administration of agents and consistent with the formulation, composition or ingredient in question being "ophthalmically acceptable."

[00039] The term "pharmaceutically acceptable," as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compounds described herein. Such materials are administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[00040] The term "pharmaceutically acceptable salt," as used herein, refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compounds described herein.

[00041] The terms "combination" or "pharmaceutical combination," as used herein mean a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, by way of example, 2-(3,5-dichlorophenyl)benzo[d]oxazole-6- carboxylic acid (Tafamidis) and an additional therapeutic agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, by way of example, 2-(3,5-dichlorophenyl)benzo[d]oxazole-6- carboxylic acid (Tafamidis) and an additional therapeutic agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the 2 compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of 3 or more active ingredients.

[00042] The terms "composition" or "pharmaceutical composition," as used herein, refers to a mixture of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.

[00043] The term "subject" or "patient," as used herein, encompasses mammals. Examples of mammals include, but are not limited to, humans, chimpanzees, apes monkeys, cattle, horses, sheep, goats, swine; rabbits, dogs, cats, rats, mice, guinea pigs, and the like.

[00044] The terms "treat," "treating" or "treatment," as used herein, refers to methods of alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactic ally and/or therapeutically.

[00045] Other objects, features and advantages of the methods, compositions and combinations described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only.

Modes of Carrying Out the Invention

[00046] Provided herein are methods, compounds and pharmaceutical compositions thereof for the treatment of ophthalmic diseases, wherein such methods of treatment is the administration of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or a pharmaceutical composition containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), to a patient in need thereof. The ophthalmic diseases treated using such methods include, but are not limited to, a macular degenearation disease or any retinol or retinol binding protein 4 (RBP4) mediated disease. In certain embodiments the macular degeneration disease is age related macular degeneration (AMD), Stargardt's Disease, Cone-Rod Dystrophy, Corneal Dystrophy, Fuch's Dystrophy, Sorsby's Macular Dystrophy, Best Disease, and Juvenile Retinoschisis, dry macular degeneration or wet macular degeneration.

[00047] Also provided herein are methods for modulating the binding of retinol binding protein 4 (RBP4) to transthyretin (TTR), wherein the methods include administration of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or a pharmaceutical composition containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), to a patient in need thereof, thereby treating an ophthalmic diseases. Such ophthalmic diseases include but are not limited to a macular degenearation disease or any retinol or retinol binding protein 4 (RBP4) mediated disease. In certain embodiments the macular degeneration disease is age related macular degeneration (AMD), Stargardt's Disease, Cone-Rod Dystrophy, Corneal Dystrophy, Fuch's Dystrophy, Sorsby's Macular Dystrophy, Best Disease, and Juvenile Retinoschisis, dry macular degeneration or wet macular degeneration. .

[00048] Also provided herein are methods for effecting the rate of N-retinylidene-N- retinylethanolamine (A2E) progression, wherein such methods comprises administering to subject an effective amount of of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or a pharmaceutical composition containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis). In certain embodiments of such methods, the administration of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) modulates the binding of retinol binding protein 4 (RBP4) to transthyretin (TTR), thereby modulating the serum concentration of RBP which has an effect on A2E progression.

[00049] Also provided herein are methods for reducing the concentration of N-retinylidene-N- retinylethanolamine (A2E), wherein such methods comprises administering to subject an effective amount of of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or a pharmaceutical composition containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis).

[00050] In other embodiments, of such treatment methods, the method further comprises administration of a second compound selected from the group consisting of fenretinide, an inducer of nitric oxide production, an antioxidant, an anti-inflammatory agent, a mineral, an anti-oxidant, a carotenoid, a negatively charged phospholipid, a complement inhibitor, a fish oil, and a statin.

[00051] In certain embodiments, 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid used in the methods provided herein is an isotopically labeled form, wherein one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid include isotopes of hydrogen, carbon, nitrogen, oxygen and chlorine, such as ²H, ³H, ⁿC, ¹³C, ¹⁴C, ¹⁵N and ³⁶C1. Isotopic variations of the compounds have the potential to change a compound' s metabolic fate and/or create small changes in physical properties such as hydrophobicity, and the like. Isotopic variations also have the potential to enhance efficacy and safety, enhance bioavailability and half- life, alter protein binding, change biodistribution, increase the proportion of active metabolites and/or decrease the formation of reactive or toxic metabolites.

Pharmacology and Utility

[00052] Retinol binding protein 4 (RBP4) is a circulatory protein that is part of an extracellular transport system for retinol. RBP4 is synthesized in an apo form in the rough endoplasmic reticulum, but is not efficiently transferred out of the endoplasmic reticulum until it is complexed with retinol. Furthermore, RBP4 is predominately found in the serum bound to transthyretin (TTR). TTR itself can bind two molecules of thyroid protein, but in the context of retinal homeostasis, is thought to prevent RBP4 from being excreted during plasma filtration in the kidney. Therefore, the activity level of RBP4 can be altered by changing the level of RBP4 produced or maintained in the body, which in turn can be altered by changing 1) the rate of production of nascent RBP4, 2) the ability of RBP4 to interact with retinol, 3) the ability of RBP4 to interact with TTR and 4) the half life of RBP4 in the body. In addition, RBP4 activity can be altered by changing the ability of RBP4 to deliver retinol to the cells such that, for example, retinal dependent signaling is affected.

[00053] Provided herein are methods for modulating the binding of retinol binding protein 4 (RBP4) to transthyretin (TTR), by the administration of an effective amount of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid. Also provided herein are compositions and methods for effecting A2E progression by modulating the binding of retinol binding protein 4 (RBP4) to transthyretin (TTR) upon the administration of an effective amount of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid.

[00054] Further provided herein methods for the treatment of ophthalmic diseases which are mediated by binding of retinol binding protein 4 (RBP4) to transthyretin (TTR), wherein such methods involve the administration of an effective amount of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid. In particular embodiments, such methods are used for the treatment of macular degeneration and dystrophies, or any retinol or retinol binding protein 4 (RBP4) mediated disease.

Phototransduction

[00055] Phototransduction is the biological conversion of a photon into an electrochemical signal in the retina. The vertebrate retina contains two types of photoreceptor cells: rods and cones. Rods are specialized for vision under low light conditions, whereas cones are less sensitive, provide vision at high temporal and spatial resolutions, and provide color perception. During daylight the rod response is saturated and vision is mediated entirely by cones. Both rods and cones contain a structure called the outer segment which comprises a stack of membranous discs. The reactions of phototransduction take place on the surfaces of these discs. Part of the cycle occurs within the outer segment of the rods and part of the cycle occurs in the retinal pigment epithelium (RPE).

[00056] The first step in the phototransduction cascade is mediated by light sensitive G-protein coupled receptors (GPCRs) called opsins located in the photoreceptor cells of the retina.

Rhodopsin is found in the rod cells of the eye and is the active visual chromophore of the phototransduction pathway. Specifically, rhodopsin is a retinylidene protein that consists of 11-cis retinal covalently linked via a Schiff base to the opsin receptor (GPCR). Rhodopsin, G protein- coupled receptor, has two physiological pathways: phototransduction and/or recovery from bleaching (return of activated components to the dark state) and the retinoid cycle (production of 11-cis-retinal). Absorption of a photon by an opsin-pigment molecule causes the 11-cis retinal to undergo photoisomerization to all-trans retinal, which subsequently changes the conformation of the opsin GPCR. This leads to signal a transduction cascade which causes closure of a cyclic GMP-gated cation channel, and hyperpolarization of the photoreceptor cell.

The Retinoid Cycle

[00057] In vertebrates, restoration of a photosensitive receptor conformation (return to the dark state) requires the formation of 11-cis-retinal from all-trans-retinal via the retinoid cycle. The entire cycle of isomerization and pigment regeneration in humans occurs on a time scale of minutes for rhodopsin, and significantly faster for cone pigments. Thus, before light sensitivity can be regained, the all-trans-retinylidene Schiff base hydrolyzes and all-trans-retinal dissociates from the binding pocket of the opsin apoprotein. This all-trans-retinal is then reduced to all-trans retinol by NADPH-dependent all-trans-retinol dehydrogenase, a membrane-associated enzyme that belongs to large gene family of short-chain alcohol dehydrogenases (SCAD), before returning to the retinal pigment epithelium to regenerate 11-cis retinal. The process by which all-trans-retinol translocates to the RPE is poorly defined but it may involve components like IRBP (a protein that transports Vitamin A within the retina) and retinol binding protein (RBP) present in the interphotoreceptor matrix (IPM), or passive diffusion driven by trapping retinoids (e.g., insoluble fatty acid retinyl esters) in RPE.

[00058] The regeneration of 11-cis retinal involves esterification of all-trans retinol and conversion of the resulting product to 11-cis retinol by the isomerohydrolase RPE65. Esterification occurs in the retinal pigment epithelial cell (RPE) and involves the catalyzed transfer of an acyl group from lecithin to retinol by lecithin:retinol acyltransferase (LRAT). The 11-cis retinol is then oxidized to 11-cis-retinal in a reaction catalyzed by NAD- and NADP-dependent 11-cis-retinol dehydrogenases, which are other short chain dehydrogenase family members. Finally 11-cis-retinal moves back to the rod photoreceptors, either in IRBP-dependent or -independent fashion, where it joins with opsin to regenerate a new, functional visual pigment (rhodopsin). Reduction of all trans- retinal to all-trans-retinol takes place in photoreceptor outer segments whereas all other reactions, including isomerization, occur within the RPE.

[00059] Retinal photoreceptors and associated RPE cells also regenerate photochemically altered chromophores. However, photochemically activated chromophores can also chemically react with other molecules in the retina, especially lipids, to form toxic by-products. The most common by-products of phototransduction comprise the lipofuscins, which are very stable toxic substances, and not readily eliminated from the eye. Lipofuscin is the name given to finely granular yellow brown pigment granules composed of lipid-containing residues of lysosomal digestion. Lipofuscin is primarily responsible for the intrinsic fluorescence of the human ocular fundus, and by the ninth decade of life, lipofuscin granules occupy approximately 19% of the area of a macular RPE cell. One important constituent of lipofuscin is derived from the inability of the retinal pigment epithelium (RPE) to convert all all-irans-retinol into 11-cz^'s-retinal. This component is the compound 2-[2,6-dimethyl-8-(2,6,6-trimethyl- l-cyclohexen-l-yl)- lE,3E,5E,7E- octatetraenyl]-l-(2-hydroxyethyl)-4-[4-methyl-6-(2,6,6-trimethyl-l-cyclohexen-l-yl)-lE,3E,5E- hexatrienyl]-pyridinium, also referred to as N-retinyl-N-retinylidene ethanolamine or A2E. A2E is a major fluorophore of lipofuscin that increases the sensitivity of the RPE to blue light and has several toxic effects on RPE cells.

[00060] A2E formation begins in photoreceptor outer segments from condensation reactions between phosphatidylethanolamine (PE) and all-trans-retmal (atRAL) (1 :2 stoichiometry) that generate A2-PE, the immediate precursor of A2E. Photoreceptor outer segments are shed from the photoreceptors in a circadian regulated process and are phagocytosed by the RPE. Thus, A2-PE is deposited in RPE cells during the normal process of outer-segment phagocytosis. Subsequent phosphate cleavage of A2-PE generates A2E. Since the eye is exposed to light, photoisomers of A2E are also generated, including iso-A2E.

[00061] Other products of reactions of all-trans-retma\ are cill-trans-retmal dimer- phosphatidylethanolamine (atRAL d-PE) and its cleavage product atRAL dimer-ethanolamine. Besides having structures that are distinct from A2E, atRAL d-PE and atRAL dimer-ethanolamine have UV- visible absorbance spectra that are red-shifted relative to A2E (atRAL d-PE: hma_X 265, 510; A2E: 335, 439).

Macular Degeneration

[00062] Macular degeneration (also referred to as retinal degeneration) is a disease of the eye that involves deterioration of the central portion of the retina, known as the macula, which is a portion of the retina that is responsible for sharp central vision. Such deterioration involves thinning, atrophy, and in some cases, bleeding and/or scarring. Macular degeneration results in loss of central vision, which entails inability to see fine details, to read, or to recognize faces. According to the American Academy of Ophthalmology, it is the leading cause of central vision loss (blindness) in the United States today for those over the age of fifty years. Macular degeneration is used to refer to macular dystrophies affecting younger individuals, however macular degeneration is predominantly found in elderly adults and the term generally refers to age- related macular degeneration (AMD or ARMD).

[00063] There are two general categories of age-related macular degeneration: "dry" (also known as atrophic, nonexudative, drusenoid or non-neovascular) macular degeneration and "wet" (also known as choroidal neovascularization, subretinal neovascularization, exudative, or disciform degeneration) macular degeneration. Approximately 85% to 90% of the cases of macular degeneration are "dry" macular degeneration, while about 10% to 15% of the cases of macular degeneration are "wet" macular degeneration. However, "wet" macular degeneration cases account for approximately 90% of macular degeneration-related blindness.

[00064] In "dry" macular degeneration, the deterioration of the retina is associated with the formation of small yellow deposits, known as drusen, under the macula, and with the accumulation of lipofuscin in the RPE. Drusen are extracellular deposits that accumulate below the RPE. This phenomena leads to a thinning and drying out of the macula, and the location and amount of thinning in the retina caused by the drusen directly correlates to the amount of central vision loss. Degeneration of the pigmented layer of the retina and photoreceptors overlying drusen become atrophic and can cause a slow loss of central vision.

[00065] In "wet" macular degeneration new blood vessels form to improve the blood supply to retinal tissue, specifically beneath the macula. The new vessels are leaky and sometimes rupture, causing leakage of blood and fluid into the macula resulting in damage to photoreceptor cells and the surrounding tissue. Studies have shown that the dry form of macular degeneration can lead to the wet form of macular degeneration, wherein the presence of drusen under the macula can cause damage to such blood vessels. Neovascularization can lead to rapid loss of vision and eventual scarring of the retinal tissues and bleeding in the eye. This scar tissue and blood produces a dark, distorted area in the vision, often rendering the eye legally blind.

[00066] Stargardt' s Disease, also known as Stargardt' s Macular Dystrophy or Fundus

Flavimaculatus, is a macular dystrophy that manifests as a recessive form of macular degeneration with an onset typically during childhood, and is characterized clinically by progressive loss of central vision and progressive atrophy of the RPE overlying the macula. Mutations in the human ABCA4 gene (also known as the ABCR gene) for Rim Protein (RmP) are responsible for

Stargardt' s Disease. Early in the disease course, patients show delayed dark adaptation but otherwise normal rod function. Histologically, Stargardt' s Disease is associated with deposition of lipofuscin pigment granules in RPE cells. In the case of Stargardt' s disease, the RPE is confronted with photoreceptor outer segments that contain abnormally high levels of all-irans-retinal and N- retinylidine-PE. As a consequence, during enzymatic digestion within phagosomes N-retinylidine- N-retinylethanolamine (A2E) is generated. A2E is a major fluorophore of lipofuscin and has several toxic effects on the RPE. Removal of N-retinylidine-PE from the disks may be facilitated by an ATP-binding cassette transporter (ABCA4). Mutations in ABCA4 have been implicated in recessive retinitis pigmentosa, recessive cone -rod dystrophy, and non-exudative age-related macular degeneration, although the prevalence of ABCA4 mutations in AMD is still uncertain. However, with reduced function of ABCR, the RPE is poisoned by A2E. The resulting loss of function of the RPE and the possible loss of RPE cells is thought to result in photoreceptor degeneration and subsequent loss of vision.

[00067] In addition, there are several types of macular degenerations that affect children, teenagers or adults that are commonly known as early onset or juvenile macular degeneration. Many of these types are hereditary and are looked upon as macular dystrophies instead of degeneration. Some examples of macular dystrophies include: Cone-Rod Dystrophy, Corneal Dystrophy, Fuch's Dystrophy, Sorsby's Macular Dystrophy, Best Disease, and Juvenile

Retinoschisis, as well as Stargardt's Disease.

[00068] One of the hallmarks of aging and of some inherited retinal disorders is the progressive accumulation of autofluorescent membrane -bound lipofuscin in the retinal pigmented epithelium (RPE). A2E, a major fluorophore of lipofuscin, accumulates abnormally in some types of macular or retinal degeneration or dystrophy, including Stargardt' s Disease and probably age-related macular degeneration, presumably due to excess production of the photo transduction retinoid, all- trans-retinaldehyde; a precursor of A2E. As described above, lipofuscin is amassed by the RPE cells by phagocytosis of the large number of outer segment disc membranes that are shed daily by the photoreceptor cells. The greatest accumulation of lipofuscin by RPE cells occurs in the macula, due to the high concentration of photoreceptors in this area. Similar to Stargardt' s Disease, lipofuscin deposition in RPE cells is also seen prominently in AMD, and some cases of retinitis pigmentosa.

[00069] The production of lipofuscin, and potentially drusen (extracellular deposits that accumulate below the RPE) under the macula are risk factors for developing age-related macular degeneration. The presence of excessive lipofuscin is detected by fundus autofluorescence, wherein the fluorescence is associated with A2E, an orange-emitting fluorophore, and A2E-related compounds. As presented above, lipofuscin accumulates progressively in a number or retinal diseases, such as recessive and dominant Stargardt's disease, age-related macular degeneration (AMD), ABCA4-mediated autosomal recessive cone-rod dystrophy, and a form of autosomal recessive retinitis pigmentosa (RP19). In addition, strong fundus autofluorescence, indicating the presence of excessive lipofuscin, is also seen in patients with Best vitelliform macular dystrophy and a subset of patients with cone-rod dystrophy.

[00070] Lipofuscin accumulation has been reported in several animal models of inherited retinal and macular degeneration. The Abca4-/- mouse (also called Abcr-/-), a model for recessive Stargardt' s disease, exhibits an accumulation of lipofuscin granules and A2E in the RPE cells. Also, mice with deficiency in all-trans-RDH in photoreceptors, contain several-fold higher levels of A2E compared with WT eyes. Transgenic mice with a mutation in the elovl4 gene, the gene involved in dominant Stargardt' s macular degeneration, contain elevated levels of A2E in the RPE. Transgenic mice that express a mutant form of cathepsin D (mcd) in RPE cells manifest many features of AMD including autofluorescent lipofuscin pigments in the RPE. Mice with knockout mutations in the genes for monocyte chemoattractant protein- 1 (Ccl-2), or its cognate chemokine receptor-2 (Ccr-2), show clinical features of AMD and A2E accumulation in RPE cells. In addition, Sodl-/-, reported to be a good animal model for AMD, also have elevated A2E levels compared to WT controls.

[00071] Non-diseased eyes contain low concentrations A2E, indicating that certain levels of A2E are tolerated by the photoreceptors and the RPE. However, diseased eyes have elevated concentrations of A2E, and at high concentrations A2E sensitizes the RPE to light-induced damage, including lysosomal rupture which leads to cell death. In addition, high concentrations of A2E are cytotoxic to the RPE, which leads to retinal damage and destruction. Furthermore, A2E has many toxic properties in vitro, such as inhibition of lysosomal function. For example, in Stargardt' s Disease A2E levels can be over lOx higher than that in normal eyes.

[00072] Currently, treatment options for the macular degenerations and macular dystrophies are limited and unsatisfactory. Some patients with dry form AMD have responded to high doses of vitamins and minerals. In addition, a few studies have indicated that laser photocoagulation of drusen prevents or delays the development of drusen that can lead to the more severe symptoms of dry form AMD. Finally, certain studies have shown that extracorporeal rheopheresis benefits patients with dry form AMD. However, successes have been limited and there continues to be a strong desire for new methods and treatments to manage and limit vision loss associated with the macular degenerations and dystrophies.

[00073] The reduction of the amount of A2E in the RPE would be beneficial in reducing lipofuscin build-up, and afford a treatment of Stargardt' s and age-related macular degeneration. Because A2E excess typically takes decades to build up, removing/clearing out even a small fraction of A2E has therapeutic benefit in prolonging the patient's visual longevity and is applicable in treating the retinal diseases listed herein, as well as those represented by animal models. [00074] Current therapeutic approaches to treating A2E-mediated diseases involve the slowing down or arrest of A2E biosynthesis, and are not designed to affect the existing pool of A2E in the eye. For example, fenretinide is reported to reduce vitamin A delivery to the eye, thereby reducing the flow of retinoids in the retinoid cycle. The latter reduces the rate of phototransduction and therefore, the rate of A2E biosynthesis.

[00075] The methods provided herein use 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis)or pharmaceutical compositions containing 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) to modulate the binding of retinol binding protein 4 (RBP4) to transthyretin (TTR), which effects the amount of A2E in the RPE and thereby treats ophthalmic diseases, such as the macular degeneration diseases listed herein.

[00076] In addition, the methods provided herein use 2-(3,5-dichlorophenyl)benzo[d]oxazole-6- carboxylic acid (Tafamidis)or pharmaceutical compositions containing 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) to modulate the binding of retinol binding protein 4 (RBP4) to transthyretin (TTR), which reduces vitamin A delivery to the eye, thereby reducing the flow of retinoids in the retinoid cycle and effects the amount of A2E in the RPE. Such methods are thereby used to treat ophthalmic diseases, such as the macular degeneration diseases listed herein.

[00077] In certain embodiments of the methods provided herein, 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis)is administered either alone, included in a pharmaceutical composition, or as part of a combination therapy.

[00078] In certain embodiments of the methods provided herein that use 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) are therapeutic for all retinal diseases that exhibit above-normal accumulation of lipofuscin, A2E, A2E-related metabolites (such as, by way of example only, A2E isomers like iso-A2E), and other toxic vitamin A-related byproducts phototransduction or the retinoid cycle (such as, by way of example only, all-trans retinal dimer). In other embodiments, such retinal disease are retinal diseases that involve genetic variations in the ABCA4 gene including, but not limited to, recessive Stargardt's macular degeneration, age-related macular degeneration, recessive retinitis pigmentosa, and cone-rod dystrophy. In other embodiments, such retinal disease are retinal diseases where ABCR deficiency is not necessarily involved, such as, by way of example only, age-related macular degeneration associated with mutations in complement factors or other genes, Best vitelliform macular dystrophy (BMD), and dominant Stargardt' s macular degeneration.

[00079] In other embodiments, the methods and compositions described herein are useful for the modulation of vitamin A (all-trans retinol) levels in a mammalian subject. In particular, modulation of vitamin A levels can occur through the regulation of retinol binding protein (RBP) and transthyretin (TTR) availability or activity in a mammal. The methods and compositions described herein provide for the modulation of RBP and TTR levels or activity in a mammalian subject, and subsequently modulation of vitamin A levels. Increases or decreases in vitamin A levels in a subject can have effects on retinol availability in target organs and tissues. Therefore, providing a means of modulating retinol or retinol derivative availability may correspondingly modulate disease conditions caused by a lack of or excess in local retinol or retinol derivative concentrations in the target organs and tissues.

[00080] Following digestion, retinol from food material is transported to the liver bound to lipid aggregates. Once in the liver, retinol forms a complex with retinol binding protein (RBP) and is then secreted into the blood circulation. Before the retinol-RBP holoprotein can be delivered to extra-hepatic target tissues, such as by way of example, the eye, it must bind with transthyretin (TTR). Zanotti and Berni, Vitam. Horm., 69:271-95 (2004). It is this secondary complex which allows retinol to remain in the circulation for prolonged periods. Association with TTR facilitates RBP release from hepatocytes, and prevents renal filtration of the RBP-retinol complex. The retinol-RBP-TTR complex is delivered to target tissues where retinol is taken up and utilized for various cellular processes. Delivery of retinol to cells through the circulation by the RBP-TTR complex is the major pathway through which cells and tissue acquire retinol. Retinol uptake from its complexed retinol-RBP-TTR form into cells occurs by binding of RBP to cellular receptors on target cells. This interaction leads to endocytosis of the RBP-receptor complex and subsequent release of retinol from the complex, or binding of retinol to cellular retinol binding proteins (CRBP), and subsequent release of apoRBP by the cells into the plasma. Other pathways contemplate alternative mechanisms for the entry of retinol into cells, including uptake of retinol alone into the cell.

[00081] By way of example, A2E, the major fluorophore of lipofuscin, is formed in macular or retinal degeneration or dystrophy, including age-related macular degeneration and Stargardt Disease, due to excess production of the visual-cycle retinoid, all-trans-retmaldehyde, a precursor of A2E. Reduction of vitamin A and all-trans retinaldehyde in the retina, therefore, would be beneficial in reducing A2E and lipofuscin build-up, and treatment of age-related macular degeneration. Studies have confirmed that reducing serum retinol may have a beneficial effect of reducing A2E and lipofuscin in RPE. For example, animals maintained on a vitamin A deficient diet have been shown to demonstrate significant reductions in lipofuscin accumulation. Katz et al., Mech. Ageing Dev., 35:291-305 (1986); Katz et al., Mech. Ageing Dev., 39:81-90 (1987); Katz et al., Biochim. Biophys. Acta, 924:432-41 (1987). Further evidence that reducing vitamin A levels may be beneficial in the progression of macular degeneration and dystrophy was shown by Radu and colleagues, where reduction in ocular vitamin A levels resulted in reductions in both lipofuscin and A2E. Radu et al, Proc. Natl. Acad. Sci. USA, 100:4742-7 (2003); Radu et al., Proc. Natl. Acad. Sci. USA, 101:5928-33 (2004).

[00082] Administration of the retinoic acid analog, N-4-(hydroxyphenyl)retinamide (HPR or fenretinide), has been shown to cause reductions in serum retinol and RBP. Formelli et al., Cancer Res. 49:6149-52 (1989); Formelli et al., J. Clin Oncol., 11:2036-42 (1993); Torrisi et al, Cancer Epidemiol. Biomarkers Prev., 3:507-10 (1994). In vitro studies have demonstrated that HPR interferes with the normal interaction of TTR with RBP. Malpeli et al., Biochim. Biophys. Acta 1294: 48-54 (1996); Holven et al., Int. J. Cancer 71:654-9 (1997). Therefore, modulators that inhibit delivery of retinol to cells either through interruption of binding of retinol to apo RBP or holo RBP (RBP + retinol) to its transport protein, TTR, or the increased renal excretion of RBP and TTR, would be useful in decreasing serum vitamin A levels, and buildup of retinol and its derivatives in target tissues such as the eye. Similarly, modulators that reduce the availability of the retinol transport proteins, retinol binding protein (RBP) and transthyretin (TTR), would also be useful in decreasing serum vitamin A levels, and buildup of retinol and its derivatives and physical manifestations in target tissues, such as the eye. TTR, for example, has been shown to be a component of Drusen constituents, suggesting a direct involvement of TTR in age-related macular degeneration. Mullins, RF, FASEB J. 14:835-846 (2000); Pfeffer BA, et al., Molecular Vision 10:23-30 (2004).

[00083] Another embodiment of the methods and compositions disclosed herein, therefore, provides for the modulation of RBP or TTR levels or activity in a mammal by administering to a mammal an effective amount of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis).

[00084] RBP binding to retinol is modulated by competitive binding of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis). Before retinol bound to RBP is transported in the blood stream for delivery to the eye, it must be complexed with TTR. It is this secondary complex which allows retinol to remain in the circulation for prolonged periods. In the absence of TTR, the retinol-RBP complex would be rapidly excreted in the urine. Similarly, in the absence of RBP, retinol transport in the blood stream and uptake by cells would be diminished. Therefore, one embodiment of the methods and compositions disclosed herein provides using 2- (3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) for modulation of RBP levels or activity in the blood stream. In addition, another embodiment provided herein, is to modulate availability of RBP or TTR for complexing to retinol or retinol-RBP in the blood stream by using 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) to modulate RBP or TTR binding characteristics or clearance rates. TTR binding to RBP holoprotein decreases the clearance rate of RBP and retinol, and therefore retinol levels are modulated in a subject in need thereof, by modulating either RBP or TTR availability or activity.

[00085] Figures 1-3 show that 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) has improved reduction of serum RBP4 compared with fenretinide. Specifically, Figures 1 and 2 demonstrate that a lower concentration of 2-(3,5-dichlorophenyl)benzo[d]oxazole- 6-carboxylic acid (Tafamidis) is able to achieve better or comparable serum RBP4 reduction as that obtained with fenretinide, whereas Figure 3 shows that, at the same concentration, 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) significantly decreases serum RBP4 in comparison to fenretinide.

Routes of Administration and Pharmaceutical Compositions

[00086] For the therapeutic uses of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis)described herein, 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid

(Tafamidis) is administered in a therapeutically effective amount either alone or as part of a pharmaceutical composition. Accordingly, provided herein are pharmaceutical compositions, which comprise 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) and one or more pharmaceutically acceptable carriers, diluents, or excipients. In addition, 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) and pharmaceutical compositions containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) are administered singly or in combination with one or more additional therapeutic agents. The routes of administration of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) and such pharmaceutical compositions include, but are not limited to, oral administration, intravitreal administration, rectal administration, parenteral, intravenous administration, intraperitoneal administration, intramuscular administration, inhalation, transmucosal administration, pulmonary administration, intestinal administration, subcutaneous administration, intramedullary

administration, intrathecal administration, direct intraventricular, intranasal administration, topical administration, ophthalmic administration or otic administration.

[00087] In certain embodiments, 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) or pharmaceutical compositions described herein are administered locally, while in other embodiments 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) or pharmaceutical composite described herein are administered systemically. Local administration includes, but is not limited to, injection into an organ, optionally in a depot or sustained release formulation. Systemic administration includes, but is not limited to, oral administration or intravenous administration. In other embodiments, 2-(3,5-dichlorophenyl)benzo[d]oxazole-6- carboxylic acid (Tafamidis) or pharmaceutical compositions described herein are administered in a targeted drug delivery system, such as, by way of example only, in a liposome coated with organ- specific antibody. The liposome is targeted to and taken up selectively by the organ. In other embodiments, 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) or pharmaceutical compositions described herein are administered in the form of a rapid release formulation, while in other embodiments, 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) or pharmaceutical compositions described herein are administered in the form of an extended release formulation . In other embodiments, 2-(3,5-dichlorophenyl)benzo[d]oxazole- 6-carboxylic acid (Tafamidis) or pharmaceutical compositions described herein are administered in the form of an intermediate release formulation.

[00088] Other aspects provided herein are processes for the preparation of pharmaceutical composition which comprise 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid

(Tafamidis). In certain embodiments, such processes include admixing 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) with one or more pharmaceutically acceptable carriers, diluents or excipients. In certain embodiments, the pharmaceutical

compositions comprise 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) in free form or in a pharmaceutically acceptable salt or solvate form. In certain embodiments, the pharmaceutical compositions comprising 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) in free form or in a pharmaceutically acceptable salt or solvate form, in association with at least one pharmaceutically acceptable carrier, diluent or excipient are manufactured by mixing, dissolving, granulating dragee -making, levigating, emulsifying, encapsulating, entrapping or compression processes and/or coating methods. In other

embodiments, such compositions are optionally contain excipients, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In other embodiments, such compositions are sterilized.

Ophthalmic Administration

[00089] In certain embodiments, the 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) or pharmaceutical composition described herein is ophthalmic ally administered to the eye. Administration to the eye generally results in direct contact of the agents with the cornea, through which at least a portion of the administered agents pass. In certain embodiments, 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) or pharmaceutical compositions have an effective residence time in the eye of about 2 to about 24 hours. In certain embodiments, 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) or pharmaceutical compositions have an effective residence time in the eye of about 4 to about 24 hours. In certain embodiments, 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) or pharmaceutical compositions have an effective residence time in the eye of about 6 to about 24 hours.

[00090] Ophthalmic administration, as used herein, includes, but is not limited to, topical administration, intraocular injection, subretinal injection, intravitreal injection, periocular administration, subconjuctival injections, retrobulbar injections, intracameral injections (including into the anterior or vitreous chamber), sub-Tenon's injections or implants, ophthalmic solutions, ophthalmic suspensions, ophthalmic ointments, ocular implants and ocular inserts, intraocular solutions, use of iontophoresis, incorporation in surgical irrigating solutions, and packs (by way of example only, a saturated cotton pledget inserted in the fornix). In certain embodiments, 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) or pharmaceutical composition described herein are formulated as an ophthalmic composition and are administered topically to the eye. Such topically administered ophthalmic compositions include, but are not limited to, solutions, suspensions, gels or ointments.

[00091] In certain embodiments the pharmaceutical compositions comprising 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) used for ophthalmic administration take the form of a liquid where the compositions are present in solution, in suspension or both. In some embodiments, a liquid composition includes a gel formulation. In other embodiments, the liquid composition is aqueous. In other embodiments, such liquid compositions take the form of an ointment. In certain embodiments, pharmaceutical compositions containing 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) are administered ophthamically as eye drops formulated as aqueous solutions that optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives. A desired dosage is administered via a known number of drops into the eye. By way of example only, for a drop volume of 25 μΐ, administration of 1-6 drops delivers 25-150 μΐ of the composition. In certain embodiments, the aqueous compositions contain from about 0.01% to about 50% weight/volume of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis). In other embodiments, the aqueous compositions contain from about 0.1% to about 20% weight/volume of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis). In still other embodiments, the aqueous compositions contain from about 0.2% to about 10% weight/volume of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis). In certain embodiments, the aqueous compositions contain from about 0.5% to about 5%, weight/volume of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis).

[00092] In certain embodiments the aqueous compositions have an ophthalmically acceptable pH and osmolality. In certain embodiments the aqueous compositions include one or more ophthalmically acceptable pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris- hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an ophthalmically acceptable range.

[00093] In certain embodiments the compositions also include also include one or more ophthalmically acceptable salts in an amount required to bring osmolality of the composition into an ophthalmically acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

[00094] In certain embodiments the aqueous compositions also contain one or more polymers as suspending agents. Such polymers include, but are not limited to, water-soluble polymers such as cellulosic polymers described herein, (for example only, hydroxypropyl methylcellulose), and water-insoluble polymers described herein (for example only, cross-linked carboxyl-containing polymers). In certain embodiments, the aqueous compositions also include an ophthalmically acceptable mucoadhesive polymer, selected for example from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.

[00095] In certain embodiments the compositions also include ophthalmically acceptable solubilizing agents to aid in the solubility of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis). The term "solubilizing agent" generally includes agents that result in formation of a micellar solution or a true solution of the agent. In certain embodiments, ophthalmically acceptable nonionic surfactants including, but not limited to, polysorbate 80 are used as solubilizing agents. In other embodiments, ophthalmically acceptable glycols including, but not limited to, polyglycols, polyethylene glycol 400, and glycol ethers are used as solubilizing agents.

[00096] In certain embodiments the compositions also include one or more ophthalmically acceptable surfactants to enhance physical stability or for other purposes. Such nonionic surfactants include, but are not limited to, polyoxyethylene fatty acid glycerides and vegetable oils (by way of example only, polyoxyethylene (60) hydrogenated castor oil) and polyoxyethylene alkylethers and alkylphenyl ethers (by way of example only, octoxynol 10 and octoxynol 40).

[00097] In certain embodiments the compositions also include one or more ophthalmically acceptable preservatives to inhibit microbial activity. Such preservatives include, but are not limited to mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride,

cetyltrimethylammonium bromide and cetylpyridinium chloride.

[00098] In certain embodiments the compositions also include one or more antioxidants to enhance chemical stability where required. Such antioxidants include, but are not limited to, ascorbic acid and sodium metabisulfite.

[00099] In certain embodiments, the aqueous compositions provided herein are packaged in single-dose non-reclosable containers, while in other embodiments the aqueous compositions provided herein are packaged in multiple-dose reclosable containers wherein a preservative is included in the composition.

[000100] In certain embodiments, the ophthalmic compositions containing 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) take the form of a solid article that can be inserted between the eye and eyelid or in the conjunctival sac, where it releases the 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis). Release is to the lacrimal fluid that bathes the surface of the cornea, or directly to the cornea itself, with which the solid article is generally in intimate contact. Solid articles suitable for implantation in the eye in such fashion are generally composed primarily of polymers and can be biodegradable or non-biodegradable.

Oral Dosage Forms

[000101] In certain embodiments, the pharmaceutical compositions containing 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) are administered orally as discrete dosage forms, wherein such dosage forms include, but are not limited to, capsules, gelatin capsules, caplets, tablets, chewable tablets, powders, pills, dragees, granules, liquids, gels, syrups, flavored syrups, elixirs, slurries, solutions or suspensions in aqueous or non-aqueous liquids, edible foams or whips, and oil-in-water liquid emulsions or water-in-oil liquid emulsions. The capsules, gelatin capsules, caplets, tablets, chewable tablets, powders or granules, used for the oral administration of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) are prepared by admixing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) (active ingredient) together with at least one excipient using conventional pharmaceutical compounding techniques. Non-limiting examples of excipients used in oral dosage forms described herein include, but are not limited to, binders, fillers, disinte grants, lubricants, absorbents, colorants, flavors, preservatives and sweeteners. [000102] Non-limiting examples of such binders include, but are not limited to, corn starch, potato starch, starch paste, pre- gelatinized starch, or other starches, sugars, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, tragacanth, guar gum, cellulose and its derivatives (by way of example only, ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose,

hydroxypropyl methylcellulose and microcrystalline cellulose), magnesium aluminum silicate, polyvinyl pyrrolidone and combinations thereof.

[000103] Non-limiting examples of such fillers include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof. In certain embodiments, the binder or filler in pharmaceutical compositions provided herein are present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.

[000104] Non-limiting examples of such disintegrants include, but are not limited to, agar-agar, alginic acid, sodium alginate, calcium carbonate, sodium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and combinations thereof. In certain embodiments, the amount of disintegrant used in the pharmaceutical compositions provided herein is from about 0.5 to about 15 weight percent of disintegrant, while in other embodiments the amount is from about 1 to about 5 weight percent of disintegrant.

[000105] Non-limiting examples of such lubricants include, but are not limited to, sodium stearate, calcium stearate, magnesium stearate, stearic acid, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, sodium lauryl sulfate, talc, hydrogenated vegetable oil (by way of example only, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, sodium oleate, ethyl oleate, ethyl laureate, agar, silica, a syloid silica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Piano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Mass.) and combinations thereof. In certain embodiments, the amount of lubricants used in the pharmaceutical compositions provided herein is in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms.

[000106] Non-limiting examples of such diluents include, but are not limited to, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine or combinations thereof. [000107] In certain embodiments, tablets and capsules are prepared by uniformly admixing 2- (3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) (active ingredients) with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary. In certain embodiments, tablets are prepared by compression. In other embodiments, tablets are prepared by molding.

[000108] In certain embodiments, 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) is orally administered as a controlled release dosage form. Such dosage forms are used to provide slow or controlled-release of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis). Controlled release is obtained using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof. In certain embodiments, controlled-release dosage forms are used to extend activity of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), reduce dosage frequency, and increase patient compliance.

[000109] Administration of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid

(Tafamidis) as oral fluids such as solution, syrups and elixirs are prepared in unit dosage forms such that a given quantity of solution, syrups or elixirs contains a predetermined amount of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis). Syrups are prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions are formulated by dispersing the compound in a nontoxic vehicle. Non-limiting examples of excipients used in as oral fluids for oral administration include, but are not limited to, solubilizers, emulsifiers, flavoring agents, preservatives, and coloring agents. Non-limiting examples of solubilizers and emulsifiers include, but are not limited to, water, glycols, oils, alcohols, ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers. Non-limiting examples of preservatives include, but are not limited to, sodium benzoate. Non-limiting examples of flavoring agents include, but are not limited to, peppermint oil or natural sweeteners or saccharin or other artificial sweeteners.

Parenteral Dosage Forms

[000110] In certain embodiments pharmaceutical compositions containing 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) are administered parenterally by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial.

[000111] Such parenteral dosage forms are administered in the form of sterile or sterilizable injectable solutions, suspensions, dry and/or lyophylized products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection (reconstitutable powders) and emulsions. Vehicles used in such dosage forms include, but are not limited to, Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, physiological saline buffer, Ringer's Injection solution, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection solution; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[000112] In certain embodiments, 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) or composition containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) is parenteral administration by bolus injection. In other embodiments, 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) or composition containing 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) is parenteral administration by continuous infusion. Formulations for injection are presented in unit dosage form, by way of example only, in ampoules or formulations for injection are presented in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.

Transdermal Administration

[000113] In certain embodiments pharmaceutical compositions containing 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) are administered transdermally. Such transdermal dosage forms include "reservoir type" or "matrix type" patches, which are applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis). By way of example only, such transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin. In other embodiments, matrix transdermal formulations are used. In certain embodiments transdermal administration is used to provide continuous, while in other embodiments transdermal administration is used to provide discontinuous infusion of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) in controlled amounts.

[000114] In certain embodiments, the rate of absorption is slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. In certain embodiments, transdermal delivery is via a transdermal patches placed over different portions of the patient's body, including over the eye.

[000115] Formulations for transdermal delivery of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6- carboxylic acid (Tafamidis) include an effective amount of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), a carrier and an optional diluent. A carrier includes, but is not limited to, absorbable pharmacologically acceptable solvents to assist passage through the skin of the host, such as water, acetone, ethanol, ethylene glycol, propylene glycol, butane- 1, 3 -diol, isopropyl myristate, isopropyl palmitate, mineral oil, and combinations thereof.

[000116] In certain embodiments, such transdermal delivery systems include penetration enhancers to assist in delivering 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) to the tissue. Such penetration enhancers include, but are not limited to, acetone; various alcohols such as ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; and various water-soluble or insoluble sugar esters such as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate).

[000117] In other embodiments, the pH of such a transdermal pharmaceutical composition or dosage form, or of the tissue to which the pharmaceutical composition or dosage form is applied, is adjusted to improve delivery of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis). In other embodiments, the polarity of a solvent carrier, its ionic strength, or tonicity are adjusted to improve delivery. In other embodiments, compounds such as stearates are added to improve delivery. In certain embodiments, such stearates serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery-enhancing or penetration- enhancing agent. In other embodiments, different salts, hydrates or solvates of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) are used to further adjust the properties of the resulting composition.

[000118] In other embodiments, transdermal delivery of 2-(3,5-dichlorophenyl)benzo[d]oxazole- 6-carboxylic acid (Tafamidis) is accomplished by means of iontophoretic patches and the like.

Topical Dosage Forms

[000119] In certain embodiments 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) is administered by topical application of pharmaceutical composition containing 2- (3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) in the form of lotions, gels, ointments solutions, emulsions, suspensions or creams. Suitable formulations for topical application to the skin are aqueous solutions, ointments, creams or gels, while formulations for ophthalmic administration are aqueous solutions. Such formulations optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

[000120] Such topical formulations include at least one carrier, and optionally at least one diluent. Such carriers and diluents include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane- 1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and combinations thereof.

[000121] In certain embodiments, such topical formulations include penetration enhancers to assist in delivering 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) to the tissue. Such penetration enhancers include, but are not limited to, acetone; various alcohols such as ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; KoUidon grades (Povidone, Polyvidone); urea; and various water-soluble or insoluble sugar esters such as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate).

Pulmonary Administration

[000122] In certain embodiments pharmaceutical compositions containing 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) are administered by inhalation. Dosage forms for inhaled administration are formulated as aerosols or dry powders. Aerosol formulations for inhalation administration comprise a solution or fine suspension of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) in a pharmaceutically acceptable aqueous or non-aqueous solvent. In addition, such pharmaceutical compositions optionally comprise a powder base such as lactose, glucose, trehalose, mannitol or starch, and optionally a performance modifier such as L-leucine or another amino acid, and/or metals salts of stearic acid such as magnesium or calcium stearate.

[000123] In certain embodiments, 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) is administered directly to the lung by inhalation using a Metered Dose Inhaler ("MDI"), which utilizes canisters that contain a suitable low boiling propellant, e.g.,

dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas, or a Dry Powder Inhaler (DPI) device which uses a burst of gas to create a cloud of dry powder inside a container, which is then be inhaled by the patient. In certain embodiments, capsules and cartridges of gelatin for use in an inhaler or insufflator are formulated containing a powder mixture of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid

(Tafamidis) and a powder base such as lactose or starch. In certain embodiments, 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) is delivered to the lung using a liquid spray device, wherein such devices use extremely small nozzle holes to aerosolize liquid drug formulations that can then be directly inhaled into the lung. In other embodiments, 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) is delivered to the lung using a nebulizer device, wherein a nebulizers creates an aerosols of liquid drug formulations by using ultrasonic energy to form fine particles that can be readily inhaled. In other embodiments 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) is delivered to the lung using an electrohydrodynamic ("EHD") aerosol device wherein such EHD aerosol devices use electrical energy to aerosolize liquid drug solutions or suspensions.

[000124] In certain embodiments, the pharmaceutical composition containing 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or pharmaceutically acceptable salts and solvates thereof, also contain one or more absorption enhancers. In certain embodiments, such absorption enhancers include, but are not limited to, sodium glycocholate, sodium caprate, N- lauryl- -D-maltopyranoside, EDTA, and mixed micelles.

[000125] In certain embodiments pharmaceutical compositions containing 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) are administered nasally. The dosage forms for nasal administration are formulated as aerosols, solutions, drops, gels or dry powders.

Rectal Administration

[000126] In certain embodiments pharmaceutical compositions containing 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) are administered rectally in the form of suppositories, enemas, retention enemas ointment, creams rectal foams or rectal gels. In certain embodiments such suppositories are prepared from fatty emulsions or suspensions, cocoa butter or other glycerides.

Depot Administration

[000127] In certain embodiments pharmaceutical compositions containing 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) are formulated as a depot preparation. Such long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. In certain embodiments, such formulations include polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[000128] In certain embodiments injectable depot forms are made by forming microencapsulated matrices of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) in

biodegradable polymers. The rate of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) release is controlled by varying the ratio of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6- carboxylic acid (Tafamidis) to polymer and the nature of the particular polymer employed. In other embodiments, depot injectable formulations are prepared by entrapping 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) in liposomes or microemulsions. In certain embodiments, posterior juxtascleral depots are used as a mode of administration of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis). In other embodiments, 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) is administered as a depot into the scleral layer of the eye by injection through a cannula with small diameter suitable for injection into the scleral layer. The sclera is a thin avascular layer, comprised of highly ordered collagen network surrounding most of vertebrate eye. Since the sclera is avascular it can be utilized as a natural storage depot from which injected material cannot rapidly removed or cleared from the eye.

Otic Administration

[000129] In certain embodiments pharmaceutical compositions containing 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) are administered otically as ear drops. Such formulations are aqueous solutions that optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

Treatment of Ophthalmic Diseases

[000130] Provided herein is the method of using 2-(3,5-dichlorophenyl)benzo[d]oxazole-6- carboxylic acid (Tafamidis) and pharmaceutical compositions containing 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) for the modulation of the binding of retinol binding protein 4 (RBP4) to transthyretin (TTR), and thereby prevent and/or treat ophthalmic diseases described herein by lowereing the delivery of retinal to the eye via formation of the RBP4/TTR/Retinal complex. In certain embodiments, the ophthalmic disease is a macular degeneration disease, while in other embodiments the ophthalmic diseases is any retinol or retinol binding protein 4 (RBP4) mediated disease. In certain embodiments, such modulation of binding of retinol binding protein 4 (RBP4) to transthyretin (TTR), affects A2E progression, thereby preventing or treating macular degeneration diseases. In certain embodiments of such methods, the macular degeneration disease is selected from age related macular degeneration (AMD)

Stargardt' s Disease, Cone- Rod Dystrophy, Corneal Dystrophy, Fuch's Dystrophy, Sorsby's Macular Dystrophy, Best Disease, and uvenile Retinoschisis, dry macular degeneration and wet macular degeneration.

[000131] Also provided herein are methods for the treatment of a subject suffering from an ophthalmic disease, wherein the methods include administering to the subject an effective amount of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) or a pharmaceutically acceptable salt, solvate, either alone or as part of a pharmaceutical composition as described herein.

[000132] Provided herein is the use of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for the treatment of an ophthalmic disease. In certain embodiments, the ophthalmic disease is a macular degeneration disease, while in other embodiments the ophthalmic diseases is any retinol or retinol binding protein 4 (RBP4) mediated disease. In certain embodiments the macular degeneration disease is selected from age related macular degeneration (AMD)

Stargardt' s Disease, Cone- Rod Dystrophy, Corneal Dystrophy, Fuch's Dystrophy, Sorsby's Macular Dystrophy, Best Disease, and Juvenile Retinoschisis, dry macular degeneration and wet macular degeneration.

[0001] Combination Therapies

[000133] In certain embodiments, 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical composition containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), are administered alone (without an additional therapeutic agent) for the treatment of one or more opthalmic diseases described herein.

[000134] In other embodiments, 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or a pharmaceutically acceptable salts or solvates thereof, or pharmaceutical composition containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), are administered in combination with one or more additional therapeutic agents or methods for the treatment of one or more opthalmic diseases described herein.

[000135] In other embodiments, 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or a pharmaceutically acceptable salts or solvates thereof, or pharmaceutical composition containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), are formulated in combination with one or more additional therapeutic agents and administered for the treatment of one or more opthalmic diseases described herein.

[000136] In certain embodiments, the combination treatments provided herein include administration of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), sequentially with one or more additional therapeutic agents for the treatment of one or more opthalmic diseases described herein.

[000137] In other embodiments, the combination treatments provided herein include administration of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), prior to administration of one or more additional therapeutic agents for the of one or more opthalmic diseases described herein.

[000138] In other embodiments, the combination treatments provided herein include administration of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), subsequent to

administration of one or more additional therapeutic agents for the treatment of one or more ophthalmic diseases described herein.

[000139] In certain embodiments, the combination treatments provided herein include administration of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), concurrently with one or more additional therapeutic agents for the treatment of one or more ophthalmic diseases described herein.

[000140] In certain embodiments, the combination treatments provided herein include administration of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) formulated with one or more additional therapeutic agents for the treatment of macular degeneration.

[000141] In certain embodiments of the combination therapies described herein, 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or pharmaceutically acceptable salts or solvates thereof, and the additional therapeutics agent(s) act additively. In certain embodiments of the combination therapies described herein, 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or pharmaceutically acceptable salts or solvates thereof, and the additional therapeutics agent(s) act synergistically.

[000142] In other embodiments, 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or a pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), is administered to a patient who has not previously undergone or is not currently undergoing treatment with another therapeutic agent.

[000143] In other embodiments, 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), are administered for prophylactic treatments. In other embodiments, 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition containing 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) in combination with one or more additional therapeutic agents or methods, are administered for prophylactic treatments. In other embodiments, 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), are administered for therapeutic treatments. In other embodiments, 2-(3,5-dichlorophenyl)benzo[d]oxazole-6- carboxylic acid (Tafamidis), or pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) in combination with one or more additional therapeutic agents or methods, are administered for therapeutic treatments.

[000144] In certain embodiments, 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) is administered chronically either alone or in combination with one or more additional therapeutic agents or methods. Chronic administration is for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition. In other embodiments, the administration of the compounds is temporarily suspended for a certain length of time (i.e., a "drug holiday").

[000145] The additional therapeutic methods used in combination with 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, photodynamic therapy (PDT), low dose radiation therapy, submacular surgery, RPE transplantation, macular translocation surgery, implantable miniature telescopes, laser photocoagulation of drusen, microstimulation therapy and laser treatment of drusen.

[000146] The additional therapeutic agents used in combination with 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to an effective amount of a retinyl derivative, including derivatives of all-trans-retinal and 13-cis-retinal, fenretinide and its active metabolites, an adjuvant, a second compound that modulates RBP or TTR levels or activity, nitric oxide (NO) inducers, statins, negatively charged phospholipids, anti-oxidants, minerals, anti-inflammatory agents, anti-angiogenic agents, matrix metalloproteinase inhibitors, and carotenoids.

[000147] The anti-oxidants used in combination with 2-(3,5-dichlorophenyl)benzo[d]oxazole-6- carboxylic acid (Tafamidis), or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, vitamin C, vitamin E, beta-carotene and other carotenoids, coenzyme Q, 4- hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (also known as Tempol), lutein, butylated hydroxytoluene, resveratrol, a trolox analogue (PNU-83836-E), and bilberry extract.

[000148] The minerals used in combination with 2-(3,5-dichlorophenyl)benzo[d]oxazole-6- carboxylic acid (Tafamidis), or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, copper-containing minerals, such as cupric oxide (by way of example only); zinc-containing minerals, such as zinc oxide (by way of example only); and selenium-containing compounds.

[000149] The negatively-charged phospholipids used in combination with 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, cardiolipin and phosphatidylglycerol. In certain embodiments, positively-charged and/or neutral phospholipids also provide benefit for patients with macular degenerations and dystrophies when used in combination with 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or a pharmaceutically acceptable salt or solvate thereof.

[000150] Carotenoids are naturally-occurring yellow to red pigments of the terpenoid group that can be found in plants, algae, bacteria, and certain animals, such as birds and shellfish.

Carotenoids are a large class of molecules in which more than 600 naturally occurring carotenoids have been identified. The use of carotenoids has been correlated with the maintenance of photoprotection necessary in photoreceptor cells. The carotenoids used in combination with 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, hydrocarbons (carotenes) and their oxygenated, alcoholic derivatives (xanthophylls), actinioerythrol, astaxanthin, canthaxanthin, capsanthin, capsorubin, .beta.-8'-apo-carotenal (apo-carotenal), -12'-apo-carotenal, a-carotene, β- carotene, "carotene" (a mixture of a- and β-carotenes), γ-carotenes, β-cyrptoxanthin, lutein, lycopene, violerythrin, zeaxanthin, and esters of hydroxyl- or carboxyl-containing members thereof. In certain embodiments the carotenoids are in cis-isomeric form, while in other embodiments the carotenoids are in trans-isomeric form. In certain embodiments the carotenoids are a racemic mixture.

[000151] The nitric oxide inducers used in combination with 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, compounds that stimulate endogenous NO or elevate levels of endogenous endothelium-derived relaxing factor (EDRFJ in vivo or are substrates for nitric oxide synthase. EDRF is a vascular relaxing factor secreted by the endothelium, and has been identified as nitric oxide or a closely related derivative thereof. Such compounds include, bit are not limited to, L-arginine, L-homoarginine, and N-hydroxy-L-arginine, including their nitrosated and nitrosylated analogs (e.g., nitrosated L-arginine, nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine, nitrosated L-homoarginine and nitrosylated L-homoarginine), precursors of L-arginine and/or physiologically acceptable salts thereof, including, for example, citrulline, ornithine, glutamine, lysine, polypeptides comprising at least one of these amino acids, inhibitors of the enzyme arginase (e.g., N-hydroxy-L-arginine and 2(S)-amino-6-boronohexanoic acid) and the substrates for nitric oxide synthase, cytokines, adenosine, bradykinin, calreticulin, bisacodyl, and phenolphthalein.

[000152] The nitric oxide inducers used in combination with 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, statins such as, by way of example only, rosuvastatin, pitivastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin, compactin, lovastatin, dalvastatin, fluindostatin, atorvastatin, atorvastatin calcium (which is the hemicalcium salt of atorvastatin), and dihydrocompactin.

[000153] The anti-inflammatory agents used in combination with 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, cromolyn, nedocromil, theophylline, zileuton, zafirlukast, montelukast, pranlukast, indomethacin, and lipoxygenase inhibitors; nonsteroidal antiinflammatory drugs (NSAIDs) (such as ibuprofen and naproxin); prednisone, dexamethasone, cyclooxygenase inhibitors (i.e., COX-1 and/or COX-2 inhibitors such as

NAPROXEN™, or CELEBREX™); statins (by way of example only, rosuvastatin, pitivastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin, compactin, lovastatin, dalvastatin, fluindostatin, atorvastatin, atorvastatin calcium (which is the hemicalcium salt of atorvastatin), and dihydrocompactin); disassociated steroids, non-steroidal anti-inflammatory drugs such as salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin, sulindac, etodolac, mefenamic acid, meclofenamate sodium, tolmetin, ketorolac, dichlofenac, ibuprofen, naproxen, naproxen sodium, fenoprofen, ketoprofen, flurbinprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam, tenoxicam, nabumetome, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, apazone and nimesulide, leukotriene antagonists including, but not limited to, zileuton, aurothioglucose, gold sodium thiomalate and auranofin, steroids including, but not limited to, alclometasone diproprionate, amcinonide, beclomethasone dipropionate, betametasone, betamethasone benzoate, betamethasone diproprionate, betamethasone sodium phosphate, betamethasone valerate, clobetasol proprionate, clocortolone pivalate, hydrocortisone, hydrocortisone derivatives, desonide, desoximatasone, dexamethasone, flunisolide, flucoxinolide, flurandrenolide,

halcinocide, medrysone, methylprednisolone, methprednisolone acetate, methylprednisolone sodium succinate, mometasone furoate, paramethasone acetate, prednisolone, prednisolone acetate, prednisolone sodium phosphate, prednisolone tebuatate, prednisone, triamcinolone, triamcinolone acetonide, triamcinolone diacetate, and triamcinolone hexacetonide and other anti-inflammatory agents including, but not limited to, methotrexate, colchicine, allopurinol, probenecid, thalidomide or a derivative thereof, 5-aminosalicylic acid, retinoid, dithranol or calcipotriol, sulfinpyrazone and benzbromarone.

[000154] The matrix metalloproteinases (MMPs) inhibitors used in combination with 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, Tissue Inhibitors of Metalloproteinases (TIMPs) (e.g., ΤΓΜΡ-1, T P-2, TIMP-3, or TIMP4), a₂-macroglobulin, tetracyclines (e.g., tetracycline, minocycline, and doxycycline), hydroxamates (e.g., batimistat, marimistat and TROCADE™), chelators (e.g., EDTA, cysteine, acetylcysteine, D-penicillamine, and gold salts), synthetic MMP fragments, succinyl mercaptopurines, phosphonamidates, hydroxaminic acids, the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase, collagenase-1 (MMP- Γ), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin- 1 (MMP-3), stromelysin-2 (MMP-IO), and stromelysin-3 (MMP-I1) andMMP-9 and MMP- 12.

[000155] The antiangiogenic or anti-VEGF drugs used in combination with 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, Rhufab V2 (LUCENTIS™), Tryptophanyl- tRNA synthetase (TrpRS), EyeOOl (Anti-VEGF Pegylated Aptamer), squalamine, RETAANE™ (anecortave acetate for depot suspension; Alcon, Inc.), Combretastatin A4 Prodrug (CA4P), MACUGEN™, MIFEPREX™ (mifepristone-ru486), subtenon triamcinolone acetonide, intravitreal crystalline triamcinolone acetonide, Prinomastat (AG3340— synthetic matrix metalloproteinase inhibitor, Pfizer), fluocinolone acetonide (including fluocinolone intraocular implant, Bausch & Lomb/Control Delivery Systems), VEGFR inhibitors (Sugen), VEGF-Trap (Regeneron/Aventis), anti-vascular endothelial cell growth factor antibody bevacizumab

(AVASTIN™), VEGF receptor tyrosine kinase inhibitors such as 4-(4-bromo- 2-fluoroanilino)-6- methoxy-7-(l-methylpiperidin-4-ylmethoxy)quinazoline (ZD6474), 4-(4-fIuoro-2-methylindol-5- yloxy)-6-methoxy-7-(3- pyrrolidin- 1 -ylpropoxy)quinazoline (AZD2171), vatalanib (PTK787) and SU1 1248 (sunitinib), linomide, and inhibitors of integrin νβ3 function and angiostatin.

[000156] Other pharmaceutical therapies used in combination with 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), or a pharmaceutically acceptable salt or solvate thereof, include, but are not limited to, VISUDYNE™ with use of a non-thermal laser, PKC 412, Endovion (NeuroSearch A/S), neurotrophic factors, including by way of example Glial Derived Neurotrophic Factor and Ciliary Neurotrophic Factor, diatazem, dorzolamide, Phototrop, 9-cis-retinal, eye medication (including Echo Therapy) including phospholine iodide or echothiophate or carbonic anhydrase inhibitors, AE-941 (AEterna Laboratories, Inc.), Sirna-027 (Sima Therapeutics, Inc.), pegaptanib (NeXstar Pharmaceuticals/Gilead Sciences), neurotrophins (including, by way of example only, NT-4/5, Genentech), Cand5 (Acuity Pharmaceuticals), ranibizumab (Genentech), INS-37217 (Inspire Pharmaceuticals), integrin antagonists (including those from Jerini AG and Abbott Laboratories), EG-3306 (Ark Therapeutics Ltd.), BDM-E (BioDiem Ltd.), thalidomide (as used, for example, by EntreMed, Inc.), cardiotrophin-1

(Genentech), 2-methoxyestradiol (Allergan/Oculex), DL-8234 (Toray Industries), NTC-200 (Neurotech), tetrathiomolybdate (University of Michigan), LYN-002 (Lynkeus Biotech), microalgal compound (Aquasearch/ Albany, Mera Pharmaceuticals), D-9120 (Celltech Group pic), ATX-S10 (Hamamatsu Photonics), TGF-beta 2 (Genzyme/Celtrix), tyrosine kinase inhibitors (Allergan, SUGEN, Pfizer), NX-278-L (NeXstar Pharmaceuticals/Gilead Sciences), Opt-24 (OPTIS France SA), retinal cell ganglion neuroprotectants (Cogent Neurosciences), N- nitropyrazole derivatives (Texas A&M University System), KP-102 (Krenitsky Pharmaceuticals), cyclosporin A, Timited retinal translocation", photodynamic therapy, (including, by way of example only, receptor-targeted PDT, Bristol-Myers Squibb, Co.; porfimer sodium for injection with PDT; verteporfin, QLT Inc.; rostaporfin with PDT, Miravent Medical Technologies;

talaporfin sodium with PDT, Nippon Petroleum; motexafin lutetium, Pharmacyclics, Inc.), antisense oligonucleotides (including, by way of example, products tested by Novagali Pharma SA and ISIS-13650, Isis Pharmaceuticals), laser photocoagulation, drusen lasering, macular hole surgery, macular translocation surgery, implantable miniature telescopes, Phi-Motion Angiography (also known as Micro-Laser Therapy and Feeder Vessel Treatment), Proton Beam Therapy, microstimulation therapy, Retinal Detachment and Vitreous Surgery, Scleral Buckle, Submacular Surgery, Transpupillary Thermotherapy, Photosystem I therapy, use of RNA interference (RNAi), extracorporeal rheopheresis (also known as membrane differential filtration and Rheotherapy), microchip implantation, stem cell therapy, gene replacement therapy, ribozyme gene therapy (including gene therapy for hypoxia response element, Oxford Biomedica; Lentipak, Genetix; PDEF gene therapy, GenVec), photoreceptor/retinal cells transplantation (including transplantable retinal epithelial cells, Diacrin, Inc.; retinal cell transplant, Cell Genesys, Inc.), and acupuncture.

[000157] In certain embodiments, the subject, in conjunction with administration of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), pharmaceutical composition or combination therapy described herein are also monitored for physiological manifestations of ophthalmic diseases. In certain embodiments the subject, in conjunction with administration of 2- (3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), pharmaceutical composition or combination therapy described herein are also monitored for physiological manifestations of retinoid-related disease processes. By way of example only, the subject may be monitored for physiological manifestations of age-related macular degenerations or dystrophies, including the formation of drusen in the eye of the subject, measuring the levels of lipofuscin in the eye of the subject, measuring the auto-fluorescence of A2E and precursors of A2E, and measuring N- retinylidene-N-retinylethanolamine levels in the eye of the subject. In certain embodiments, the subject is monitored for changes or perturbations in vitamin A levels, as well as RBP and TTR levels or activity in a biological sample.

Kits

[000158] Also provided herein are pharmaceutical packs or kits that include one or more containers containing 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) useful for the treatment or prevention of an ophthalmic disease. In other embodiments, such

pharmaceutical packs or kits include one or more containers containing 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) useful for the treatment or prevention of an ophthalmic disease and one or more containers containing an additional therapeutic agent, including but not limited to those listed above. In certain embodiments, such pharmaceutical packs or kits optionally include instructions for its administration 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis).

[000159] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference for all purposes.

Examples [000160] Mice with a null mutation for the gene abcr were used to assess the acute and chronic effects of compounds on serum RBP4 levels and on A2E accumulation in the eye. Duration of treatment time and pharmacological measurements vary according to specific study protocols. In acute experiments both male and female abcr -/- mice (B6.129 background; age = 4-6 months) were used to assess effects of vehicle or compounds on serum RBP4 levels. In chronic experiments, male abcr -/- mice (B6.129 background; age = 60-65 days at study onset) were chronically treated with either vehicle or compounds for up to 1 month. To determine effects on serum RBP4 levels, serial bleeds were obtained via retro-orbital bleeds or by tail nicks at specific times after oral administration of vehicle or compounds. Serum RBP4 was measured using the dual mouse/rat RBP4 ELISA kit (RB0642PP; AdipoGen, Seoul, Korea; assay range: 0.19-12 ng/ml, sensitivity > 60 pg/ml). Mice were treated with either vehicle, 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) or fenretinide. Figures 1-3 show the serum RBP4 levels obtained for various concentration of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) relative to vehicle and fenretinide.

[000161] Steady-state levels of ocular A2E in ABCA4 -I- mice chronically treated with either vehicle or compounds for up to 28 days were measured as followed. At the indicated times, the mice were euthanized and both eyes were collected and frozen on dry ice. Each eye was individually homogenized in phosphate buffer (PBS) using Qiagen TissueLyser and extracted with an acetonitrile/methanol mixture. The organic phase was analyzed by HPLC and mass

spectrometry. Identity of the indicated compounds was confirmed by online spectral analysis and by coelution with authentic standards.

HPLC/MS/MS method for A2E analysis

[000162] HPLC method: Extracted samples of A2E in methanol were injected onto a heated (45°C) Waters Acquity HSS T3 column, 1.8μιη, 2.1 x 50mm. Using an Agilent 1200SL binary pump, the mobile phases were delivered at 650μΕ/ηιίη., and used 0.1% TFA in A. H20 and B. MeOH. A gradient elution method began with 82% B for 3 minutes, then increased in a linear fashion to 90% over 5 minutes. After a one minute washout at 100% B, the gradient was returned to starting conditions and held until the end of the run at 10.5 minutes.

[000163] Mass Spectrometry: The column eluent was directed into either an Applied Biosystems API4000 or a Thermo Quantum Ultra mass spectrometer using positive mode electrospray ionization. On the API4000 the MRM transitions for A2E, and internal standard A2H, were m/z 592.5—105.0 and m/z 648.6— 358.4 respectively. The declustering potential (DP) and collision energy (CE) was 76 and 45 for A2E, and 161 and 55 for A2H. On the Quantum the MRM transitions were m/z 592.5— 105.2 for A2E, and m/z 648.5 -145.1 for A2H. A tube lens setting of 147 was used for both analytes, with collision energies of 58 for A2E and 47 for A2H.

[000164] The change in accumulation of A2E in the eye with and without the administration of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) is shown in Figure 4.

Claims

WE CLAIM:

1. A method for treating an ophthalmic disease comprising administering to a subject in need thereof, a therapeutically effective amount of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6- carboxylic acid or a physiologically acceptable salt thereof.

2. The method of claim 1, wherein the ophthalmic disease is a macular degenearation disease, a retinol mediated disease or a retinol binding protein 4 mediated disease.

3. The method of claim 3, wherein the macular degeneration disease is selected from age related macular degeneration, Stargardt' s Disease, Cone-Rod Dystrophy, Corneal Dystrophy, Fuch's Dystrophy, Sorsby's Macular Dystrophy, Best Disease, and Juvenile Retinoschisis, dry macular degeneration and wet macular degeneration.

4. The method of any of claims 1-4, wherein the subject is a human.

5. The method of any of claims 1-5, wherein 2-(3,5-dichlorophenyl)benzo[d]oxazole-6- carboxylic acid is administered in combination with a second therapeutic agent.

6. The method of any of claims 1-5, wherein the method further comprises the administration a second compound selected from the group consisting of fenretinide, an inducer of nitric oxide production, an antioxidant, an anti-inflammatory agent, a mineral, an anti-oxidant, a carotenoid, a negatively charged phospholipid and a statin.

7. A pharmaceutical composition for modulating the binding to retinol binding protein 4 to transthyretin comprising 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid , or a physiologically acceptable salt thereof, and a physiologically acceptable carrier.

8. A pharmaceutical compositions for treating ophthalmic diseases comprising 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid , or a physiologically acceptable salt thereof, and a physiologically acceptable carrier.

9. A method of modulating the binding of retinol binding protein 4 to transthyretin in a cell, wherein the method comprises contacting the cell with an effective amount of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid or a physiologically acceptable salt thereof, thereby modulating the binding of retinol binding protein 4 to transthyretin.

10. A method for effecting the rate of N-retinylidene-N-retinylethanolamine progression,

comprising administering to subject in need thereof a therapeutically effective amount of 2- (3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid or a physiologically acceptable salt thereof.

11. A method for effecting the rate of transport of retinol to the eye, comprising administering to subject in need thereof a therapeutically effective amount of 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid or a physiologically acceptable salt thereof.

12. A compound for use in a method of medical treatment, wherein the method of medical

treatment is for treating an ophthalmic disease, wherein the disease is selected from age related macular degeneration, Stargardt' s Disease, Cone- Rod Dystrophy, Corneal Dystrophy, Fuch's Dystrophy, Sorsby's Macular Dystrophy, Best Disease, and Juvenile Retinoschisis, dry macular degeneration and wet macular degeneration, and wherein the compound is 2-(3,5- dichlorophenyl)benzo[d]oxazole-6-carboxylic acid or a physiologically acceptable salt thereof.