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WO-2026096543-A1 - SMALL MOLECULE THERAPY FOR OCULAR CONDITIONS

WO2026096543A1WO 2026096543 A1WO2026096543 A1WO 2026096543A1WO-2026096543-A1

Abstract

Provided are pharmaceutical compositions comprising a combination therapy having therapeutically effective amounts of sodium 4-phenyIbutylate and tauroursodeoxycholic acid for the treatment of an ocular condition in a subject. Also provided herein are methods using the combination therapy, and a pharmaceutical composition thereof, for preventing or treating an ocular condition in a subject.

Inventors

  • ZODE, Gulab
  • KAIPA, Balasankara Reddy

Assignees

  • THE REGENTS OF THE UNIVERSITY OF CALIFORNIA

Dates

Publication Date
20260507
Application Date
20251028
Priority Date
20241028

Claims (20)

  1. 1 . A pharmaceutical composition for the treatment of an ocular condition associated with elevated intraocular pressure (IOP), comprising: a combination therapy comprising therapeutically effective amounts of sodium 4- phenylbutytate (PBA) and tauroursodeoxy cholic acid (TUDCA), in a pharmaceutically acceptable carrier, diluent, and/or excipient.
  2. 2. The pharmaceutical composition of claim 1, wherein the ocular condition associated with elevated IOP is selected from glaucoma, ocular hypertension, uveitis, retinal detachment, pigment dispersion syndrome, pseudoexfoliation syndrome, large cataracts, tumors within the eye, steroid-induced ocular hypertension, steroid-induced glaucoma and eye damage from injury or surgery.
  3. 3. The pharmaceutical composition of claim 2, wherein the ocular condition is glaucoma.
  4. 4. The pharmaceutical composition of claim 1, wherein the combination therapy comprises PBA at a concentration of 0.5 mM to 4.0 mM.
  5. 5. The pharmaceutical composition of claim 4, wherein the combination therapy comprises PBA at a concentration of 1.0 mM to 2.0 mM.
  6. 6. The pharmaceutical composition of claim 1 , wherein the combination therapy comprises TUDCA at a concentration of 0.3 mM to 3.0 mM.
  7. 7. The pharmaceutical composition of claim 6, wherein the combination therapy comprises TUDCA at a concentration of 0.5 mM to 1.0 mM.
  8. 8. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is formulated for intravitreal injection, intracameral injection, subretinal injection, or for topical administration to the eye(s). Atorney docket No. 00058-090W01
  9. 9. The pharmaceutical composition of claim 8. wherein the pharmaceutical composition is formulated for topical administration to the eye(s) and is in the form of eye drops, eye ointment, or eye gel.
  10. 10. The pharmaceutical composition of claim 9, wherein the pharmaceutical composition comprises PBA at a concentration (% w/v) from 0.1 to 3.
  11. 1 1. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition comprises PBA at a concentration (% w/v) from 0.5 to 1.5.
  12. 12. The pharmaceutical composition of claim 9, wherein the pharmaceutical composition comprises TUDCA at a concentration (% w/v) from 0.05 to 1.5.
  13. 13. The pharmaceutical composition of claim 12, wherein the pharmaceutical composition comprises TUDCA at a concentration (% w/v) from 0.1 to 0.8.
  14. 14. The pharmaceutical composition of claim 9, wherein the pharmaceutical composition comprises PBA and TUDCA in a pharmaceutically acceptable carrier, diluent, and/or excipient and a preservative at the following concentrations (% w/v): Concentration (% w/v) PBA 1 TUDCA 0.5 Dibasic Sodium Phosphate 0.2 Hydroxypropyl Methylcellulose 0.5 Polysorbate 80 0.05 Benzalkonium Chloride 0.01 Sodium Chloride 0.75 Edetate Disodium (EDTA) 0.01 NaOH / HC1 as needed to provide a pH 7.4 Purified Water as needed up to 100%.
  15. 15. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable diluent is buffered saline or purified water. Atorney docket No. 00058-090W01
  16. 16. The pharmaceutical composition of claim 1. wherein the pharmaceutically acceptable carrier, diluent, and/or excipient includes sodium citrate, hydroxy ethyl cellulose, sodium hydroxide (to adjust pH), hydrochloric acid (to adjust pH), mannitol, sodium phosphate, dibasic sodium phosphate, carbomer 974P, tyloxapol, edetate disodium, hydroxypropyl methylcellulose, polysorbate 80, sodium chloride, edetate disodium and/or purified water.
  17. 17. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition further comprises a preservative.
  18. 18. The pharmaceutical composition of claim 17, wherein the preservative is benzalkonium chloride.
  19. 19. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition further comprises additional medication(s) selected from a prostaglandin analogue, a betablocker, a carbonic anhydrase inhibitor, a corticosteroid, a Rho kinase inhibitor, an alpha- adrenergic agonist, and/or a miotic.
  20. 20. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition further comprises additional medication(s) selected from bimatoprost, tafluprost, latanoprost, travoprost, betaxolol, timolol, brinzolamide. dorzolamide, brimonidine. and netarsudil.

Description

Atorney docket No. 00058-090W01 SMALL MOLECULE THERAPY FOR OCULAR CONDITIONS CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority under 35 U.S.C. §119 from Provisional Application Serial No. 63/713.008, filed October 28, 2024 the disclosure of which is incorporated herein by reference. STATEMENT OF GOVERNMENT SUPPORT [0002] This invention was made with Government support under Grant Nos: EY260177 and EY028616, awarded by the National Institutes of Health. The Government has certain rights in the invention. INCORPORATION BY REFERENCE OF SEQUENCE LISTING [0003] Accompanying this filing is a Sequence Listing entitled, “00058-090W01.xml” created on October 28, 2025, and having 3,736 bytes of data, machine formatted on IBM-PC, MS-Windows operating system. The sequence listing is hereby incorporated by reference in its entirety for all purposes. TECHNICAL FIELD [0004] Provided are pharmaceutical compositions comprising a combination therapy having therapeutically effective amounts of sodium 4-phenylbutytate and tauroursodeoxy cholic acid for the treatment of an ocular condition in a subject. Also provided herein are methods using the combination therapy, and a pharmaceutical composition thereof, for preventing or treating an ocular condition in a subject. BACKGROUND [0005] Glaucoma is the leading cause of irreversible blindness, and it is often associated with elevated intraocular pressure (IOP) due to damage to trabecular meshwork (TM) cells. Elevated IOP leads to axonal loss and blindness. The trabecular meshwork (TM) maintains normal IOP by regulating aqueous humor (AH) outflow resistance. In glaucoma, there is increased resistance to aqueous humor outflow through TM, thus elevating IOP. About 70% outflow is regulated by TM; however, most of the current drug treatments approved for glaucoma target AH production via the ciliary body. Despite TM being major site of glaucomatous pathology, drugs acting directly on TM pathology has not yet been developed and vision loss continues to progress in some glaucoma patients, thus highlighting a critical Atorney docket No. 00058-090W01 need to develop an effective treatment that targets TM outflow to prevent vision loss in glaucoma patients. SUMMARY [0006] Provided herein is a therapy comprising a combination therapy of small molecule therapeutics that is highly effective in lowering intraocular pressure (IOP) and can therefore be used for the treatment of eye diseases or disorder associated with elevated IOP. The combination therapy disclosed herein can be used alone or in combination with other IOP lowering medications, such as latanoprost, to treat said eye disorders or diseases. Latanoprost, and other prostaglandin inhibitors lower IOP by increasing the flow of natural eye fluids out of the eye. As such, latanoprost and similar drugs work mechanistically in a manner different from the small molecule therapy disclosed herein. Accordingly, use of the small molecule therapy of the disclosure with latanoprost, and like drugs, would be expected to be highly effective in reducing IOP. Additionally, the combination therapy disclosed herein can be used in combination with a gene-editing therapy or an antisense oligo that lowers the expression of gene product(s) that cause elevated IOP to treat said eye disorders or diseases. The combination therapy disclosed herein can also be used as a preventative to prevent or counteract adverse effects of medications, like corticosteroids, in elevating IOP in subjects. [0007] In the studies presented herein, recombinant TM cells that stably expressed a glaucoma gene were used to determine whether the use of sodium 4-phenylbutytate (PBA) and tauroursodeoxy cholic acid (TUDCA) in combination would restore normal TM function. It was found that the use of PBA with TUDCA effectively reversed glaucomatous phenotypes in the recombinant TM cells in a synergistic manner. A combination therapy of PBA and TUDCA. therefore, provides an effective therapy for glaucoma pathology by reducing mitochondrial dysfunction, preventing protein aggregation, and upregulating anti-apoptotic genes. It is expected that a combination therapy of PBA and TUDCA would be effective for treating all forms of glaucoma. [0008] In addition, the combination of PBA and TUDCA provides direct neuroprotectant effects, thereby preventing neuronal damage due to elevated IOP. iStent® or MIGS procedures have been developed to lower IOP in glaucoma patients. However, the procedures often fail after 1 -2 years due to fibrosis in TM. Accordingly, a combination Atorney docket No. 00058-090W01 therapy comprising PBA and TUDCA is likely to aid iStent® or MIGS to increase overall success by preventing fibrosis in TM. In a particular embodiment, the disclosure provides a pharmaceutical composition for the treatment of an ocular condition associated with elevated intraocular pressure (IOP), comprising: a combination therapy comprising therapeutically effective