WO2025072429A1

WO2025072429A1 - Sustained release of fenofibrate to treat age-related macular degeneration or diabetic retinopathy

Info

Publication number: WO2025072429A1
Application number: PCT/US2024/048541
Authority: WO
Inventors: Fred CHASALOW; Jerry Katzman
Original assignee: Retinalgenix Technologies Inc
Current assignee: Retinalgenix Technologies Inc
Priority date: 2023-09-27
Filing date: 2024-09-26
Publication date: 2025-04-03
Anticipated expiration: 2026-03-27

Abstract

The present invention relates to the administration of sustained release formulations of fenofibrate to treat age-related macular degeneration or diabetic retinopathy.

Description

Docket No.164853-01202 SUSTAINED RELEASE OF FENOFIBRATE TO TREAT AGE-RELATED MACULAR DEGENERATION OR DIABETIC RETINOPATHY This application claims priority to U.S. Provisional Application Nos.63/585,846, filed September 27, 2023, and 63/642,434, filed May 3, 2024, each incorporated by reference in their entirety. Field of the Invention The present invention relates to the administration of sustained release formulations of fenofibrate to treat age-related macular degeneration or diabetic retinopathy. Background of the Invention Age-related macular degeneration (AMD) is a disease characterized by progressive degenerative abnormalities in the macula, a small area in the central portion of the retina. AMD is characteristically a disease of the elderly and is the leading cause of blindness in individuals >50 years of age in developed countries. In the United States, it is estimated that approximately 6% of individuals 65-74 years of age, and 20% of those older than 75 years of age, are affected with AMD. Because of increasing life expectancy in developed and developing countries, the elderly sector of the general population is expected to increase at the greatest rate in coming decades. In the absence of adequate prevention or treatment measures, the number of cases of AMD with visual loss is expected to grow in parallel with the aging population. AMD is classified into one of two general subgroups; the non-neovascular (dry) form of the disease (dry AMD) and the neovascular form of the disease (wet AMD). Dry AMD is more prevalent, accounting for approximately 90% of all AMD cases. It is characterized by degeneration of the macula and, with continued progression over multiple years, may ultimately

1 164863.01201/150638578v.1 result in atrophy of the central retina associated with central vision loss. By contrast, wet AMD, although less prevalent, is more likely to cause sudden, often substantial, loss of central vision. Dry AMD is a significant cause of moderate and severe loss of central vision and is bilateral in most patients. In dry AMD, thinning of the retinal pigment epithelial cells (RPE) in the macula develops, along with other age-related changes to the adjacent retinal tissue layers. Dry AMD is characterized by the presence of drusen (yellow crystalline deposits that develop within the macula) located under the RPE. When the condition is severe, dry AMD results in marked thinning and/or atrophy of the macula, resulting from the loss of the RPE and associated capillaries (choriocapillaris). This form of late stage dry AMD is associated with thinning and loss of function of the neural retinal located above the affected RPE. This collective phenotype in late stage dry AMD is termed geographic atrophy (GA). The progressive degeneration of light- sensitive photoreceptor cells in GA leads to severe visual loss in affected eyes. In addition, dry AMD can progress to the wet form of the disease. There is a continuing need for improved treatments of age-related macular degeneration. Summary of the Invention The present inventors have surprisingly found that sustained release formulations of fenofibrate are effective for the treatment of age-related macular degeneration (AMD) or diabetic retinopathy. Fenofibrate is metabolized by the body to fenofibric acid. The inventors discovered that the amount of fenofibric acid in the tissue needs to remain at a constant therapeutic level in order to maintain efficacy. A spike in fenofibric concentration levels, as is observed with typical fenofibrate immediate release dosage forms, does not provide therapeutic tissue levels of fenofibric acid for a sufficient time to treat AMD. The present invention addresses this issue. Accordingly, in a first aspect, the present invention is directed to a method of treating age-related macular degeneration (AMD) or diabetic retinopathy comprising ophthalmically administering to a subject (such as a subject in need thereof) a dosage form comprising an effective amount of fenofibrate in a sustained manner, such as for at least 12 hours or at least 1 day (e.g., at least 2, 3, 4, 5, or 7 days).

2 164863.01201/150638578v.1 In a second aspect, the present invention is directed to a method of treating age-related macular degeneration (AMD) or diabetic retinopathy comprising ophthalmically administering one or more sustained release dosage forms of fenofibrate (e.g., as a hydrogel). In the first and second aspects (treatment of AMD or diabetic retinopathy), upon administration, fenofibrate passes through a lipophilic layer in the eye and is converted (hydrolyzed by an esterase) to its active form, fenofibric acid. In one embodiment of any of the methods described herein, the AMD is dry AMD. In one embodiment of any of the methods described herein, the AMD is wet AMD. In one embodiment of any of the methods described herein, each dosage form is in the form of a hydrogel. In one embodiment of any of the methods described herein, each dosage form is in the form of a topical ocular device, such as a contact lens. In one embodiment of any of the methods described herein, the release duration of the fenofibrate from the dosage form is at least about 12 hours. In one embodiment of any of the methods described herein, the release duration of the fenofibrate from the dosage form is at least about 1 day. In one embodiment of any of the methods described herein, the release duration of the fenofibrate from the dosage form is at least about 3 days. In one embodiment of any of the methods described herein, the release duration of the fenofibrate from the dosage form is at least one week. In one embodiment of any of the methods described herein, the one or more dosage form(s) provides from about 0.01 mg or 0.05 mg fenofibrate per day to about 0.5 mg fenofibrate per day, such as from about 0.05 to about 0.145 mg daily or from about 0.1 to about 0.2 mg daily. In one embodiment any of the methods described herein, the one or more dosage form(s) provides about 0.10 mg fenofibrate per day, about 0.11 mg fenofibrate per day, about 0.12 mg

3 164863.01201/150638578v.1 fenofibrate per day, about 0.13 mg fenofibrate per day, about 0.14 mg fenofibrate per day, about 0.15 mg fenofibrate per day, about 0.16 mg fenofibrate per day, about 0.17 mg fenofibrate per day, about 0.18 mg fenofibrate per day, about 0.19 mg fenofibrate per day, or about 0.2 mg fenofibrate per day. In one embodiment of any of the methods described herein, the fenofibrate is in micronized form in the dosage form. In one embodiment of any of the methods described herein, fenofibrate has a median particle size (D₅₀) of from about 1 to about 100 microns. In one embodiment of any of the methods described herein, the fenofibrate is in nanoparticulate form in the dosage form. In one embodiment of any of the methods described herein, fenofibrate has a median particle size (D₅₀) of from about 1 to about 999 nanometers. In one embodiment of any of the methods described herein, the dosage form provides a fluctuation of fenofibrate concentration in the blood (or serum) of less than about 100%, a swing less than about 100%, or both. Detailed Description of the Invention Definitions As used herein, the term “t_max” denotes the time to reach the maximal plasma concentration (Cmax) after administration. “C_min” refers to the minimum plasma trough level. “C_average” is the average concentration over a time period and is determined as the AUC_0-t divided by the time period (t). As used herein, the term “AUC_0-infinity” denotes the area under the plasma concentration versus time curve from time 0 to infinity. As used herein, the term “AUC0-t” denotes the area under the plasma concentration versus time curve from time 0 to time t.

4 164863.01201/150638578v.1 As used herein, the term “swing” denotes (Cmax-Cmin)/Cmin. As used herein, the term “fluctuation” denotes (Cmax-Cmin)/Caverage. As used herein, the term “peak-trough fluctuation” denotes C_max/C_min. As used herein, the term “ophthalmically administering” refers to administration directly to the eye, e.g., to a non-corneal surface of the sclera. The term "subject" or “patient” refers to an animal, such as a mammal, for example a human. The methods described herein can be useful in both human therapeutics and veterinary applications. In some embodiments, the patient is a mammal, and in some embodiments, the patient is human. For veterinary purposes, the term “subject” and “patient” include, but are not limited to, farm animals including cows, sheep, pigs, horses, and goats; companion animals such as dogs and cats; exotic and/or zoo animals; laboratory animals including mice, rats, rabbits, guinea pigs, and hamsters; and poultry such as chickens, turkeys, ducks, and geese. The term “effective amount”, as used throughout, is defined as any amount necessary or sufficient to produce a desired physiologic response. By way of example, for the ophthalmic administration treatment of AMD, the systemic dosage of the fenofibrate can be from about 0.01 to about 0.5 mg daily, including for example, from about 0.05 to about 0.145 mg daily or from about 0.1 to about 0.2 mg daily. The dosage can be adjusted by methods known in the art based on properties of fenofibrate, the subject receiving it, the mode of administration, type and severity of the disease to be treated or prevented, and the like. The preparation of fenofibrate is known in the art, such as in U.S. Patent No.4,058,552. Fenofibric acid is the active metabolite of fenofibrate. Fenofibrate is poorly soluble in water, which limits its absorption in the gastrointestinal tract. Alternative formulations and strategies have been used to overcome this problem. See, e.g., U.S. Patent Nos.4,800,079 and 4,895,726 (micronized fenofibrate); U.S. Patent No.6,277,405 (micronized fenofibrate in a tablet or in the form of granules inside a capsule); U.S. Patent. No.6,074,670 (the immediate release of micronized fenofibrate in a solid state); U.S. Patent No.5,880,148 (combination of fenofibrate and vitamin E); U.S. Patent No.5,827,536 (diethylene glycol monoethyl ether (DGME) as

5 164863.01201/150638578v.1 solubilizer for fenofibrate); and U.S. Patent No.5,545,628 (the combination of fenofibrate with one or more polyglycolyzed glycerides), all of which are incorporated herein in their entireties. Effective amounts and schedules for administering fenofibrate can be determined empirically and making such determinations by methods known in the art. The dosage ranges for administration are those large enough to produce the desired effect in which one or more symptoms of the disease or disorder are affected (e.g., reduced or delayed). The dosage should not be so large as to cause substantial adverse side effects, such as unwanted cross-reactions, cell death, and the like. Generally, the dosage will vary with the type of neurodegenerative disease, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition and can be determined by those in the art. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosages can vary and can be administered in one or more dose administrations daily. Pharmaceutical Compositions Provided herein is a sustained release pharmaceutical composition comprising an effective amount of fenofibrate in a pharmaceutically acceptable carrier. Hydrogels Suitable hydrogels for use in the methods of treating AMD described herein are disclosed in, e.g., Kurchhof et al., Eur. J. Pharm. Biopharm., 2015, 95(Pt. B):227-37, and Fang et al., “Hydrogels-Based Ophthalmic Drug Delivery Systems for Treatment of Ocular Diseases,” 127:112212 (2021), https://doi.org/10.1016/j.msec.2021.112212. In one embodiment, the contact lens comprises a silicone lens comprising a hydrogel. In one embodiment, the lens is porous to oxygen.

6 164863.01201/150638578v.1 Ophthalmic Administration - Contact Lenses Ophthalmic administration may be performed using, e.g., a non-degradable topical ocular device, shaped to adhere to a non-corneal surface of the sclera, with a matrix designed to provide continuous drug delivery of fenofibrate to the eye, at sustained drug concentration(s) that can treat age-related macular degeneration (AMD). Suitable compositions for sustained ophthalmic administration of fenofibrate in the methods of the present invention are also described in U.S. Patent No.10,603,274, which is hereby incorporated by reference. Suitable contact lenses that can be used for sustained ophthalmic administration of fenofibrate in the methods of the present invention are also described in International Publication No. WO 2014/038004, U.S. Patent No.10,603,274, and Ross et al., Biomaterials, 217:119285, 2019, each of which are hereby incorporated by reference. The contact lens, for instance, can be made of a hydrogel formed by polymerizing methafilcon (available from Kontur Kontact Lens Company of Hercules, CA). In one embodiment, the fenofibrate is incorporated into a delivery system which is then formed as a film on the contact lens (such as polymerized methafilcon). Each of the patents and published patent applications recited herein is expressly incorporated by reference in its entirety.

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Claims

WHAT IS CLAIMED IS 1. A method of treating age-related macular degeneration (AMD) comprising ophthalmically administering an effective amount of a dosage form comprising fenofibrate in a sustained manner for at least 12 hours.

2. A method of treating age-related macular degeneration (AMD) comprising ophthalmically administering a sustained release dosage form of fenofibrate.

3. A method of treating diabetic retinopathy comprising ophthalmically administering an effective amount of a dosage form comprising fenofibrate in a sustained manner for at least 12 hours.

4. A method of treating diabetic retinopathy comprising ophthalmically administering a sustained release dosage form of fenofibrate.

5. The method of any one of claims 1-4, wherein the dosage form is in the form of a contact lens.

6. The method of any one of claims 1-4, wherein the dosage form is in the form of a hydrogel.

7. The method of any one of claims 1-6, wherein the release duration of the fenofibrate from the dosage form is at least 12 hours.

8. The method of any one of claims 1-6, wherein the release duration of the fenofibrate from the dosage form is at least 1 day.

9. The method of any one of claims 1-6, wherein the release duration of the fenofibrate from the dosage form is at least 3 days.

10. The method of any one of claims 1-6, wherein the release duration of the fenofibrate from the dosage form is at least one week.

11. The method of any one of claims 1-10, wherein the dosage form provides from about 0.05 to about 0.5 mg fenofibrate per day.

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12. The method of any one of claims 1-11, wherein the fenofibrate is in micronized form in the dosage form.

13. The method of claim 11, wherein the fenofibrate has a median particle size of from about 1 to about 100 microns.

14. The method of any one of claims 1-13, wherein the dosage form provides a fluctuation of fenofibrate concentration in the blood of less than 100%, a swing less than 100%, or both.

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