Treatment of Anatomical and Functional Retinal Atrophy

Abstract

Disclosed is a method for treating a subject with a retinal eye disease that is refractory to anti-VEGF treatment. The method comprises administering a therapeutically effective amount of one or more steroids after anti-VEGF treatment, thereby treating the retinal eye disease. Also disclosed is a method for treating a subject with a retinal eye disease that is refractory to anti-VEGF treatment, comprising administering a therapeutically effective amount of one or more compounds that can modulate the activity of a steroid receptor after anti-VEGF treatment. Also disclosed is a method for treating a subject with a retinal eye disease that is refractory to anti-VEGF treatment, comprising administering a therapeutically acceptable formulation of a steroid and at least a second therapeutically active compound after anti-VEGF treatment, at a concentration and dose sufficient to ameliorate the retinal eye disease.

Description

[Technical field]

[0001] The present invention relates to the field of treatment of one or more ocular conditions using one or more therapeutic compounds when one or more other forms of treatment have not been, are no longer, or are becoming less effective.

[0002] In one aspect, the invention relates to the administration of one or more therapeutic compounds to treat one or more retinal eye conditions that are refractory to one or more other therapeutic agents.

[0003] In one particular embodiment, the present invention is suitable for use in the treatment of one or more retinal ocular diseases that are refractory to one or more anti-VEGF treatments.

[0004] It will be convenient hereinafter to describe the invention in relation to age-related macular degeneration (AMD) and diabetic macular edema (DME), however it should be understood that the invention is not limited to just these disorders but relates to a wide range of conditions which affect the retina of the eye and which are routinely treated with anti-VEGF agents. [Background technology]

[0005] It should be understood that any discussion of a document, device, act or knowledge in this specification is included to explain the context of the invention. Moreover, discussions throughout this specification are based on the inventor's realization of the invention and / or identification of particular related technical problems. Moreover, any discussion of material such as a document, device, act or knowledge in this specification is included to explain the context of the invention in terms of the inventor's knowledge and experience, and therefore, any such discussion should not be construed as an admission that any of the material formed part of the prior art base or common general knowledge in the relevant art in Australia, or anywhere else, at or prior to the priority date of the disclosure and claims herein.

[0006] Vascular endothelial growth factor (VEGF) is a signaling protein produced by cells that stimulates the formation of new blood vessels (angiogenesis) in the embryonic circulatory system and the growth of blood vessels from pre-existing vasculature, such as after injury (angiogenesis).

[0007] VEGF exerts its biological effects through interaction with transmembrane receptors such as the tyrosine kinase receptors VEGFR1 and VEGFR2. The ligands that specifically bind to VEGFR1 are VEGF-A, VEGF-B, and PlGF, whereas the ligands that bind to VEGFR2 are VEGF-A, VEGF-C, VEGF-D, and VEGF-E.

[0008] However, overexpression of VEGF can lead to vascular disease, involving the retina of the eye. Overproduction of VEGF leads to retinal damage by: Increasing the permeability of existing blood vessels, allowing them to leak fluid and proteins into the retina and cause edema in the surrounding tissue; and Stimulating the growth of new blood vessels within the retina, from the retina outward onto the surface of the vitreous and into the space between the retina and the choroid, usually just beneath the retinal pigment epithelium.

[0009] Anti-VEGF therapeutics block VEGF. They can slow the growth of blood vessels in the eye and are widely used to treat certain retinal diseases: · Macular degeneration (MD), especially neovascular age-related macular degeneration (wet AMD), which involves abnormal overgrowth of blood vessels into the retina that can leak exudate and fluid from the choroid; Swelling of the retina, known as macular edema (ME), including angiographic cystoid macular edema (DME) and cystoid macular edema (CME), typically resulting from disease (e.g. diabetes), injury or eye surgery; Diabetic retinopathy (DR), in which abnormal new blood vessels form at the back of the eye as part of proliferative diabetic retinopathy (PDR), which can rupture and bleed; and Retinal vein occlusion, such as central retinal vein occlusion (CRVO) or branch retinal vein occlusion (BRVO), usually due to thrombosis.

[0010] For example, first-line anti-VEGF treatment for neovascular AMD consists of intravitreal injections of the humanized monoclonal antibodies bevacizumab (Avastin™) and ranibizumab (Lucentis™) and the recombinant fusion protein aflibercept (Eylea™).

[0011] Recently, combination therapies aimed at dual targeted inhibition of VEGR-A and VEGR-C / VEGR-D have begun to be explored. An example of a promising treatment of this type is OPT-302 (sVEGFR-3), a "snap" inhibitor of VEGF-C and VEGF-D being developed by Opthea Limited, intended for use in combination with either existing anti-VEGF-A agents, biosimilars, or novel therapeutics under development for wet AMD and DME.

[0012] Various studies have been conducted to investigate the possible association between patchy atrophy (MA) of the retinal pigment epithelium (RPE) and anti-VEGF treatment in patients with AMD. In a review article by Horani et al., which looked at various clinical trials on MA, it was noted that "while taking into account the figures and results from all relevant trials, the percentages represent the percentages from the total number of study eyes evaluated up to the mean follow-up period. The mean percentage of eyes free of baseline MA was 80%, with a median of 89%. The mean percentage of MA incidence was 29%, which was also the median. The mean prevalence of MA by the end of the study was 50%, with a median of 46%. For the included studies, the number of study eyes treated and followed up continuously until the end of the mean follow-up period ranged from 28 to 1024 eyes, with a median of 118 eyes, and a mean cohort size of 242 eyes" (Mania Horani, Sajjad Mahmood, Tariq M. Aslam (2020) A Review of Macular Atrophy of the Retinal Pigment Epithelium in Patients with Neovascular Age-Related Macular Degeneration: What is the Link? Part II. Ophthalmology and Therapy 9:35-75).

[0013] Geographic atrophy (GA) GA is an eye disease that can cause significant vision loss and affects approximately 5 million people worldwide.

[0014] An analysis of clinical data from the American Academy of Ophthalmology (AAO) IRIS® (Intelligent Research in Sight) Registry reported that more than 69,000 patients with GA showed significant disease progression over a two-year period, highlighting the need for urgent treatment (C. Francois and E. Rahimy (2020) New Findings from the IRIS Registry: Evaluating Geographic Atrophy in Real-world Clinical Practice presented at American Academy of Ophthalmology (AAO) 2020 Conference).

[0015] It was also reported that patients were nearly three times more likely to develop incipient wet age-related macular degeneration (AMD) in the eye with GA if wet AMD had already been detected in the fellow eye (ibid.).

[0016] Progression from GA to incipient wet AMD was observed in 4.7% of patients with bilateral GA (GA in both eyes) and 13.3% of patients with wet AMD in the opposite eye during the first 12 months, with rates at 24 months of 8.2% and 21.6% for bilateral GA and wet AMD in the opposite eye, respectively (ibid.).

[0017] neovascular AMD Anti-VEGF agents have significant efficacy as treatments for ocular diseases. However, some subjects are non-responsive or have a low response to anti-VEGF agents, or have a slow decline in the efficacy of anti-VEGF agents after repeated administration over time.

[0018] For example, patients with neovascular AMD are treated with an anti-VEGF agent until they become completely "dry," i.e., there is no fluid in the sub-reginal spaces. If the fluid returns or vision worsens, treatment is resumed with the same anti-VEGF agent, but the condition may not respond. Some patients begin to become dry in response to anti-VEGF treatment, but then begin to accumulate fluid again.

[0019] Intravitreal injection of anti-VEGF for AMD stops all blood vessel growth and therefore cannot be used indefinitely for conditions such as AMD. The main risk for macular degeneration is vascular insufficiency, and long-term use of anti-VEGF treatment may result in further vascular insufficiency, and further application of anti-VEGF agents will cause further risk of insufficient vascular supply.

[0020] Outer retinal atrophy (cRORA) is atrophy of the RPE that may be associated with extended duration of anti-VEGF treatment for AMD. Clinically, it appears as a bare spot in the fundus, identifiable by methods such as Cirrus Spectral Domain Optical Coherence Tomography (SD-OCT) imaging. The number of anti-VEGF injections has been shown to inversely correlate with the area and growth of cRORA (Complete RPE and Outer Retinal Atrophy in Patients Receiving anti-VEGF Treatment for Neovascular Age-related Macular Degeneration, Eng et al, PLoS One 2020;15(5)I e0232353,5 May 2020).

[0021] diabetic retinopathy Macular degeneration occurs primarily through damage to the outer retinal and choroidal vasculature, whereas diabetic retinopathy occurs primarily through damage to the inner retinal blood vessels. In the proliferative form of diabetic retinopathy, VEGF is thought to drive the process of vascular proliferation.

[0022] Anti-VEGF agents are an emerging treatment for PDR (and potentially non-proliferative DR) and may initially induce regression of PDR by reducing peripheral neovascularization due to ischemia. Intravitreal anti-VEGF agents may also be associated with causing retinal detachment by increasing fibrosis and regressing the vascular component of fibrovascular proliferation (A. Fung & M. Hui, PDR: A New Anti-VEGF Era?, Miophthalmology, 10 July 2018). Summary of the Invention [Problem to be solved by the invention]

[0023] Therefore, there is currently a need for alternative treatments for conditions that affect the retina of the eye. [Means for solving the problem]

[0024] It is an object of the present invention to provide an alternative therapy for retinal conditions when existing treatments do not have the desired results or cease to provide the desired results.

[0025] It is a further object of the present invention to alleviate at least one disadvantage associated with the related art.

[0026] It is an aim of the embodiments described herein to overcome or mitigate at least one of the above-mentioned disadvantages of related art systems, or at least to provide a useful alternative to related art systems.

[0027] In a first aspect of the embodiments described herein, there is provided a method for treating a subject having a retinal ocular disease that is refractory to anti-VEGF treatment, the method comprising administering to the subject a therapeutically effective amount of one or more steroids, preferably one or more mineralocorticoids or glucocorticoids, following the anti-VEGF treatment, thereby treating the retinal ocular disease.

[0028] In a second aspect of the embodiments described herein, there is provided a method for treating a subject having a retinal ocular disease that is refractory to anti-VEGF treatment, the method comprising administering to the subject, following anti-VEGF treatment, a therapeutically effective amount of one or more compounds capable of modulating the activity of a steroid receptor, preferably a glucocorticoid receptor and / or a mineralocorticoid receptor, thereby treating the retinal ocular disease.

[0029] In a third aspect of the embodiments described herein, there is provided a method for treating a subject having a retinal ocular disease that is refractory to anti-VEGF treatment, the method comprising administering to the individual, following anti-VEGF treatment, (a) a therapeutically acceptable formulation of a steroid suitable for delivery to the eye, and (b) at least a second therapeutically active compound at a concentration and dosage sufficient to ameliorate the retinal ocular disease.

[0030] In a particularly preferred embodiment of any one of the above aspects of the invention, the steroid is one or more mineralocorticoids or glucocorticoids or therapeutically active analogues, derivatives, homologues, pharma- ceutically acceptable salts or conjugates thereof.

[0031] The one or more mineralocorticoids or therapeutically active analogs, derivatives, homologs, pharma- ceutically acceptable salts, or conjugates thereof may include one or more of 11-desoxycortisone (11-DC); fludrocortisone; fludrocortisone acetate (FA); fludrocortisone acetonide; deoxycorticosterone acetate (DA); deoxycorticosterone (DS); or aldosterone; or therapeutically active analogs, derivatives, homologs, pharma- ceutically acceptable salts, or conjugates thereof.

[0032] The one or more glucocorticoids or therapeutically active analogs, derivatives, homologs, pharma- ceutically acceptable salts, or conjugates thereof may include one or more of cortisol, cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, triamcinolone acetonide, beclomethasone, fluocinolone, or therapeutically active analogs, derivatives, homologs, pharma- ceutically acceptable salts, or conjugates thereof.

[0033] The one or more mineralocorticoids and / or further glucocorticoids or therapeutically active analogues, derivatives, homologues, pharma- ceutically acceptable salts or conjugates thereof may comprise one or more dual acting compounds, each dual acting compound being capable of modulating the activity of both the mineralocorticoid receptor and the glucocorticoid receptor.

[0034] The dual action compound may comprise one or more of triamcinolone; triamcinolone acetonide; cortisol; cortisone; prednisone; prednisolone; methylprednisolone; fludrocortisone; fludrocortisone acetate; fludrocortisone acetonide; or a therapeutically active analogue, derivative, homologue, pharma- ceutically acceptable salt or conjugate thereof.

[0035] In a particularly preferred embodiment, the one or more mineralocorticoids or one or more glucocorticoids or therapeutically active analogs, derivatives, homologs, pharma- ceutically acceptable salts or conjugates thereof comprise fludrocortisone or a therapeutically active analogs, derivatives, homologs, pharma- ceutically acceptable salts or conjugates thereof, which may comprise one or more of fludrocortisone acetate and fludrocortisone acetonide.

[0036] In one particular embodiment, the one or more mineralocorticoids and / or one or more glucocorticoids or therapeutically active analogs, derivatives, homologs, pharma- ceutically acceptable salts, or conjugates thereof comprise triamcinolone acetonide or a therapeutically active analogs, derivatives, homologs, pharma- ceutically acceptable salts, or conjugates thereof.

[0037] In a particularly preferred embodiment of any one of the above aspects of the invention, the retinal eye disease is macular edema (ME), such as diabetic macular edema (DME), or age-related macular degeneration (AMD), including wet AMD or dry AMD.

[0038] As used herein, the term "refractory" when used in relation to retinal ocular diseases is intended to refer to no response, low response, adverse response, or decreased response over time to anti-VEGF therapy. An ocular condition may become refractory at any time during the course of anti-VEGF therapy and may fail from the beginning, or may have an initial period of successful treatment followed by decreased effectiveness or even harmful to the subject. An ocular condition may become refractory due to many factors, including persistent activation of other pathogenic pathways, hyperresistance, pharmacodynamic resistance, changes to angiogenic structures, redundant or compensatory angiogenic elements, persistent activation of the complement system and inflammatory responses, and genetic factors.

[0039] As used herein, the term "ocular condition" includes any ocular condition, such as an early or asymptomatic stage of ocular disease, that has proven refractory to anti-VEGR treatment.

[0040] According to any one of the above aspects, the retinal eye disease is an exudative eye disease, a condition at the back of the eye, macular degeneration, e.g., age-related macular degeneration (AMD), including both dry (geographic atrophy) and wet (choroidal neovascularization (CNV)), macular edema (ME), e.g., diabetic macular edema (DME), angiographic cystoid macular edema, cystoid macular edema (CMO), diabetic retinopathy (DR), e.g., proliferative diabetic retinopathy (PDR), and retinal vein occlusion, e.g., central retinal vein occlusion (CRVO) or branch retinal vein occlusion (BRVO), maculopathy, e.g., age-related maculopathy (ARM), exudative eye disease. or conditions, retinal pigment epithelium detachment (PED), forms of age-related macular degeneration, diabetic eye diseases or conditions such as diabetic retinopathy, corneal neovascularization, cyclitis, Hippel-Lindel disease, retinopathy of prematurity (also known as retrolental fibroplasia), pterygium, histoplasmosis, iris neovascularization, glaucoma, glaucoma-associated neovascularization, Purtcher retinopathy, ocular hypertension, macular edema, Coats' disease, uveitis such as anterior uveitis, sicca syndrome, inherited diseases associated with increased storage / accumulation of extracellular-intracellular lipids, juvenile macular degeneration, ocular allergies and ocular tumors. Ocular tumors may include retinoblastoma and / or melanoma.

[0041] The eye disease or condition may include a disease or condition of the back of the eye, such as an exudative disease or condition of the back of the eye. The eye disease or condition may include an eye disease or condition involving the retina, macula and / or fovea in the posterior region of the eye. Examples of eye diseases include macular edema, such as clinical macular edema or angiographic cystoid macular edema resulting from various etiologies, such as diabetes, exudative macular degeneration and macular edema resulting from laser treatment of the retina, retinal ischemia and choroidal neovascularization, retinal disease, inflammatory disease, uveitis associated with neoplasms, such as retinoblastoma or pseudoglioma, neovascularization after vitrectomy, vascular disease and neovascularization of the optic nerve. The retinal disease may be one or more of diabetic retinopathy, diabetic retinal edema, retinal detachment, age-related macular degeneration resulting from subretinal neovascularization, and myopic retinopathy. The vascular disease may be one or more of retinal ischemia, choroidal vascular insufficiency, choroidal thrombosis, and neovascular retinopathy resulting from carotid ischemia.

[0042] In one embodiment of any one of the above aspects, the ocular disease or condition comprises dry AMD, which is distinct from wet AMD and may include early AMD and geographic atrophy (GA).

[0043] The present invention may find application in exudative eye diseases and / or conditions, exudative eye diseases and / or conditions at the back of the eye, age-related macular degeneration, wet age-related macular degeneration, diabetic macular edema (DME), cystoid macular edema (CMO); macular disorders; and / or eye tumors. Eye tumors may include retinoblastoma and / or melanoma. Eye diseases and / or conditions may be diabetic eye diseases and / or conditions. Other eye diseases and / or conditions include (non-infectious) conjunctivitis, anterior uveitis and eye allergies.

[0044] According to any one of the above aspects, the eye disease and / or condition may be a diabetic eye disease and / or condition.

[0045] An effective amount of the compound of interest is preferably used in the method of the present invention. In the formulation, the concentration of the therapeutic compound may be within the range of about 0.01 wt% to about 10 wt%. Typically, the concentration is within the range of about 0.025 wt% to about 2.5 wt%.

[0046] The term "therapeutically effective amount" is used herein to refer to the amount of a therapeutic compound, either alone or in combination with one or more other compounds, that is sufficient to induce a therapeutic effect on one or more retinal ocular diseases. This term should not be understood to mean that administration should completely eradicate retinal ocular diseases. What constitutes a therapeutically effective amount will vary depending on the condition, particularly the biopharmacological properties of the compound used, the retinal ocular disease being treated, the frequency of administration, the mode of delivery, the characteristics of the subject to be treated, the severity of the retinal ocular disease and the subject's response. These are the types of factors that a person skilled in the art will recognize and be able to account for when formulating a composition for treatment as described herein.

[0047] The present invention may be used in medical or veterinary applications. The "subject" of treatment according to the present invention is a vertebrate animal, preferably a human.

[0048] In one embodiment of any one of the above aspects, one or more steroids are injected into the eye. The injection may include a suprachoroidal injection.

[0049] In another embodiment of any one of the above aspects, the one or more steroids are provided in a unit dose formulation. The unit dose formulation may be provided in a pre-filled syringe. The pre-filled syringe may include two barrels. The first barrel may include one or more steroids. The second barrel, which is different from the first barrel, may include one or more additional agents.

[0050] In another embodiment of any one of the above aspects, the one or more pharma- ceutically acceptable carriers, diluents, or excipients may include, for example, one or more surfactants or wetting agents. The surfactants may include polysorbates. The polysorbates may include one or more of polysorbate 20 and polysorbate 80. In certain embodiments, the surfactants include polysorbate 80. The pharma-ceutically acceptable carriers, diluents, or excipients may include carboxymethylcellulose (CMC).

[0051] In one embodiment of any one of the above aspects, the one or more steroids further comprise one or more of a pH-adjusted composition and water for injection. The pH-adjusted composition may include hydrochloric acid and / or sodium hydroxide.

[0052] In another embodiment of any one of the above aspects, the one or more steroids comprises a pH of 6 to 8. The pH may comprise 6 to 7.5.

[0053] In one embodiment of any one of the above aspects, the one or more mineralocorticoids and / or the one or more glucocorticoids are included in a balanced salt solution. The balanced salt solution may include saline and a buffer. The balanced salt solution includes one or more of sodium chloride; potassium chloride; calcium chloride (anhydrous); magnesium chloride (hexahydrate); sodium acetate (trihydrate); sodium citrate (anhydrous); hydrochloric acid; sodium hydroxide and water for injection.

[0054] According to any one of the above aspects, the one or more steroids may comprise a sustained release composition.

[0055] In certain embodiments of any one of the above aspects, the one or more steroids may be sterilized.

[0056] In one embodiment of any one of the above aspects, at least one additional agent may be administered.

[0057] According to any one of the above forms, the one or more pharma- ceutically acceptable carriers may comprise cannabis, cannabis oil, or a pharma- ceutically effective cannabis or cannabis oil extract. The cannabis, cannabis oil, or a pharma-ceutically effective cannabis or cannabis oil extract may comprise a cannabinoid. The cannabinoid may comprise cannabidiol. The cannabis, cannabis oil, or a pharma-ceutically effective cannabis or cannabis oil extract may comprise low tetrahydrocannabinol (THC) cannabis, cannabis oil, or a pharma-ceutically effective extract thereof. The cannabis, cannabis oil, or a pharma-ceutically effective cannabis or cannabis oil extract may be obtained from Cannabis Ruderalis. The cannabis, cannabis oil, or a pharma-ceutically effective cannabis or cannabis oil extract may comprise a water-soluble dosage form. The cannabis oil may be obtained from cannabis seeds. The cannabis oil may be cold pressed.

[0058] According to one embodiment of any one of the above aspects, the cannabis oil may comprise omega fatty acids adjusted to about 80%-90%. That is, the cannabis oil comprises omega 3 (ALA), omega 6 (LA), omega 6 (GLA), and omega 9 (oleic acid), which in combination may amount to 80%-90% of the cannabis oil's composition.

[0059] In another embodiment of any one of the above aspects, the cannabis oil may comprise omega fatty acids adjusted to about 88%. That is, the cannabis oil may comprise about 88g of omega fatty acids per 100g of cannabis oil.

[0060] In yet another embodiment of any one of the above aspects, the cannabis oil may comprise about 15%-25% omega 3 (ALA), about 50%-60% omega 6 (LA), about 1%-5% omega 6 (GLA), and about 10%-15% omega 9 (oleic acid) per 100 g of cannabis oil.

[0061] In yet another embodiment of any one of the above aspects, the cannabis oil may comprise, per 20 g of cannabis oil, about 1 g to 5 g of omega 3 (ALA), about 5 g to 15 g of omega 6 (LA), about 0.2 g to 1 g of omega 6 (GLA), and about 1 g to 5 g of omega 9 (oleic acid).

[0062] In some embodiments of any one of the above aspects, the cannabis oil may comprise about 3.5g omega3 (ALA), about 11.2g omega6 (LA), about 0.4g omega6 (GLA), and about 2.5g omega9 (oleic acid).

[0063] In other embodiments of any one of the above forms, the cannabis oil may comprise about 3.3g omega3 (ALA), about 10.7g omega6 (LA), about 0.7g omega6 (GLA), and about 2.7g omega9 (oleic acid).

[0064] In other embodiments of any one of the above aspects, the cannabis oil may have an omega3 to omega6 ratio of about 1:5.2 to 5:16. The cannabis oil may have an omega3 to omega6 ratio of about 3.5:11.6. The cannabis oil may comprise a 1:3 ratio of omega3 and omega6.

[0065] In yet another embodiment of any one of the above aspects, the cannabis, cannabis oil or pharma- ceutical effective extract is intended for or is for use as a carrier or delivery vehicle for one or more steroids.

[0066] In yet another embodiment, the cannabis, cannabis oil; or pharma- ceutical active extract comprises a form suitable for administration by one or more of the following: oral, intradermal, intramuscular, intraperitoneal, parenteral, intravenous, subcutaneous, intranasal, epidural, sublingual, intracerebral, intravaginal, transdermal (e.g., via a patch), rectal, inhalation, transmucosal, or topical, in particular to the ear, nose, eye, or skin. The pharmaceutical composition may be injectable. Parenteral or injectable forms may include any form suitable for parenteral or injectable administration, such as injectable solutions, injectable suspensions, injectable emulsions, and injection in a form prepared at the time of use. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile solutions or suspensions, etc. The injectable form may be for intravitreal injection.

[0067] In another particular embodiment of any above aspect, the cannabis, cannabis oil or pharma- ceutically effective extract is preservative-free.

[0068] In another particular embodiment of any above aspect, the cannabis, cannabis oil or pharma- ceutical effective extract is prophylactic.

[0069] In a particular embodiment of any one of the above forms, the cannabis, cannabis oil or pharma-ceutically effective extract is sterilized.

[0070] Other aspects and preferred embodiments are disclosed herein and / or defined in the appended claims, which form part of the description of the invention.

[0071] Essentially, embodiments of the present invention stem from the recognition that certain compounds are effective for conditions that are refractory to existing treatments.

[0072] Advantages provided by the present invention include: · Improved outcomes for the treatment of eye conditions; ·Increased options for treating eye conditions.

[0073] Further scope of applicability of the embodiments of the present invention will become apparent from the detailed description set forth hereinafter. It should be understood, however, that the detailed description and specific examples, while indicating preferred embodiments of the present invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure herein will become apparent to those skilled in the art from this detailed description.

[0074] Brief description of the embodiment Further disclosure, objects, advantages and aspects of other preferred embodiments of the present application may be more fully understood by those skilled in the relevant art by reference to the following non-limiting examples taken in conjunction with the accompanying drawings, which are the disclosure herein given by way of illustration only and are therefore non-limiting.

[0075] Example 1 The efficacy and mechanism of FA and TA were examined in relation to their effects on regulating Ccl2, Il-6, Il-8 expression levels in Müller cells and retinal degeneration in PD models. Full details of the study are included in the Appendix.

[0076] Studies have identified novel anti-inflammatory and neuroprotective properties of TA, and more specifically FA, ​​in the treatment of retinal degeneration.

[0077] The data show that FA and TA do not induce toxicity in multiple human retinal cell lines, including photoreceptor-like (661W), Müller cells (MIO-M1), and RPE (APRE19). Addition of either FA or TA dramatically reduced the expression of Ccl2, Il-6, and Il-8 in Müller cells stimulated with Il1b or TNFa, which was dependent on glucocorticoid receptor signaling. Finally, administration of FA improved photoreceptor cell survival in PD, while TA had no significant effect.

[0078] Example 2 To evaluate the safety and tolerability of single-dose intravitreal (IVT) injections of 1 mg / 0.1 mL and 2 mg / 0.1 mL fludrocortisone acetate (FCA) in subjects with geographic atrophy (GA) secondary to age-related macular degeneration (AMD).

[0079] Methods: This was a two-part, dose-escalation prospective study. Part 1 involved a single participant treated with 1 mg / 0.1 ml and monitored up to 28 days after review by a safety review committee. Two subsequent participants were then administered the same dose. Part 2 involved a single participant treated with 2 mg / 0.1 ml and monitored up to 28 days after five additional participants received the dose. All participants were followed up for 6 months after baseline.

[0080] Complete ophthalmologic evaluations were performed at study visits, including GA area, best corrected visual acuity (BCVA), low-light BCVA, and intraocular pressure (IOP). Adverse events (AEs) were reported from the first administration of FCA until the end-of-study visit.

[0081] RESULTS: No serious AEs (ocular or systemic) were observed in 9 participants treated with either the 1 mg / 0.1 ml or 2 mg / 0.1 ml IVT FCA. There was no evidence of increased incidence of IOP or cataracts.

[0082] Neither BCVA nor LL-BCVA changed significantly in the study eye over the follow-up period (p=0.28 and 0.38, respectively). Mean GA area increased in the study (0.5 mm2 p=0.003) and fellow eyes (0.62 mm2 p=0.02) over 6 months. The difference between eyes was not significant (p=0.64) at the lower limit of the population norm.

[0083] Conclusions: Intravitreal FCA is clinically safe, well tolerated, does not increase IOP, and has promising efficacy in terms of GA lesion growth. [Brief description of the drawings]

[0084] [Figure 1] Illustrates the effect of FA and TA on retinal cell viability in vitro. The effect of FA (A-C) and FA (D-F) on cell viability was assessed using the MTT assay on immortalized human cells derived from Müller glia (MIO-M1), RPE (ARPE-19), and photoreceptor cells (661W). ·A-C: Addition of FA had no significant effect (P>0.05) on the viability of all cell lines evaluated compared to the DMSO alone group. The exception was MIO-M1 cells (A), which had a slight decrease at the highest concentration (10ug / uL, P<0.05). ·D-F: Similarly, introduction of TA had no significant effect (P>0.05) on viability across all lines except MIO-M1 (D) and 661W cells (E), which had a slight decrease at 10ug / uL (P<0.05). Statistical significance was determined using one-way ANOVA and Turkey's post-hoc test. Results are presented as mean ± SEM. [Diagram 2] Illustrating the regulation of proinflammatory cytokine expression by FA and TA in vitro. The effects of FA and TA on the induction of Ccl2, Il-6, and Il-8 expression by MIO-M1 cells were assessed following their stimulation with either IL-1β (A-B) or TNF (C-D). ·A-B: Following stimulation with IL-1β, MIO-M1 cells showed a marked increase in Ccl2, Il-6, and Il-8 expression (P<0.05). However, when FA was added to the culture medium during IL-1β stimulation (A), the upregulation of Ccl2, Il-6, and Il-8 was suppressed to near baseline levels (P<0.05). A significant decrease in the expression of Ccl2, Il-6, and Il-8 was also observed in the group where TA was added instead (P<0.05). C-D: Stimulation with TNF induced a similar, though less pronounced, upregulation of Ccl2, Il-6, and Il-8 in MIO-M1 cells (P<0.05). This effect was also significantly inhibited when FA or TA was added to the medium (P<0.05). Statistical significance was determined using one-way ANOVA and Turkey's post-hoc test. Results are presented as mean ± SEM. [Diagram 3] Contribution of glucocorticoid and mineralocorticoid receptor signaling to the anti-inflammatory effect of FA in vitro. The inhibitory effect of FA on Ccl2, Il-6, and Il-8 expression in Il-1b-stimulated MIO-M1 cells was further examined through co-incubation with selective antagonists (A-D). ·A-B: Addition of RU486, a glucocorticoid receptor antagonist (A), was found to completely abrogate FA-mediated suppression of Ccl2, Il-6, and Il-8 after IL-b stimulation (P<0.05). However, incubation with RU28318, a mineralocorticoid receptor antagonist (B), did not significantly alter the expression of Ccl2, Il-6, and Il-8 compared to MIO-M1 cells treated with Il1b and FA alone (P>0.05). ·C-D: Incubation with either the androgen receptor PF998425 (C) or estrogen receptor ICI182780 (D) antagonists did not alter the suppression of Ccl2, Il-6, and Il-8 by FA after Il1-b stimulation (P>0.05). Statistical significance was determined using two-way ANOVA and Turkey's post-hoc test. *Denotes significant change compared to FA+IL-1β. Results are presented as mean ± SEM. [Figure 4]Illustrating the neuroprotective properties of FA and TA against retinal cell death in mice after PD. The effect of intravitreal injection of either FA or TA against photoreceptor cell degeneration after PD was determined by a combination of OCT segmentation (A), ERG recordings (B), and abundance of apoptotic TUNEL+ photoreceptor cells (C). ·A-C: ONL measurements quantified from OCT images of the center of the lesion area (1-2 / 2-3 mm eccentric from the optic nerve) showed significant preservation in ONL thickness in the FA-treated group compared to controls after PD (B) (C, P<0.05). In contrast, no significant changes were observed in the TA-treated group (P>0.05). ·D-E: FA-treated mice showed significantly greater a-wave (D) and b-wave (E) ERG responses compared to both control and TA-treated groups (P<0.05). F-H: After exposure to PD, mice treated with FA were found to have significantly fewer TUNEL+ photoreceptor cells than vehicle-treated mice (P<0.05). Conversely, mice treated with TA showed no significant change in the number of TUNEL+ photoreceptor cells (P>0.05). Statistical significance was determined using either one-way ANOVA (A,F, Turkey's post-hoc test) or two-way ANOVA (D,E, Turkey's post-hoc test). Scale bars represent 50 μm. GCL (ganglion cell layer); INL (inner nuclear layer); ONL (outer nuclear layer). [Diagram 5] Illustrating the effect of FA and TA on macrophage infiltration in mice after PD. Infiltration of activated macrophages into the outer retina after PD was quantified using immunolabeling for IBA1 (A) (B-C, green). A-C: Abundance of IBA1+ macrophages within the outer retina after PD (A), which was spatially contemporaneous with destruction to the ONL and subretinal space (B, arrows). In contrast, a significant decrease in the number of IBA1+ cells was observed in both FA- and TA-treated groups compared to controls, with FA showing the most obvious trend (P<0.0001). Statistical significance was determined using one-way ANOVA. Scale bars represent 50 μm. GCL (ganglion cell layer); INL (inner nuclear layer); ONL (outer nuclear layer). [Figure 6] Examples of atrophy as measured by Heidelberg Region Finder software: (A) baseline multicolor, (B) baseline fluorescein angiogram, (C) baseline autofluorescence, (D) baseline Region Finder, (E) 1 month, (F) 2 months, (G) 3 months, and (H) 6 months. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0085] Accordingly, the present invention provides a method for treating a subject having one or more retinal ocular diseases that are refractory to anti-VEGF treatment, comprising administering to the subject a therapeutically effective amount of one or more steroids, preferably mineralocorticoids or glucocorticoids, following anti-VEGF treatment, thereby treating the one or more retinal ocular diseases.

[0086] Steroids suitable for administration include, but are not limited to, cortisol, cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, triamcinolone (Aristocort™, Kenalog™), betamethasone (Celestone™), budesonide, fluormetholone (fluorometholone acetate (Flarex™, Eflone™), fluormetholone alcohol (FML™, FML-Mild™, FluorOP™), medrysone alcohol (HMSO), ethoxyquin, ethylhexyl ketone (ETK), ... These include loteprednol tabonate (Lotemax™, Alrex™) and anecortave acetate (Alcon™), beclomethasone, fludrocortisone, deoxycorticosterone, aldosterone, triamcinolone acetonide (TA), 11-desoxycortisone (11-DC), fludrocortisone (FA), deoxycorticosterone acetate (DA), deoxycorticosterone (DS), fluocinolone or a therapeutically active analog, derivative, homolog, pharma- ceutically acceptable salt or conjugate thereof. It will be understood that the above list is representative and not exhaustive.

[0087] A therapeutically effective amount of one or more compounds may be capable of modulating the activity of steroid receptors, preferably glucocorticoid receptors and / or mineralocorticoid receptors, following anti-VEGF treatment, thereby treating retinal ocular diseases.

[0088] The one or more compounds may include one or more dual action compounds, each of which is capable of modulating the activity of both the mineralocorticoid receptor and the glucocorticoid receptor. The dual action compounds may include, for example, one or more of cortisol; cortisone; prednisone; prednisolone; methylprednisolone; fludrocortisone acetate; deoxycorticosterone acetate; aldosterone or a therapeutically active analog, derivative, homolog, pharma- ceutically acceptable salt or conjugate thereof.

[0089] Mineralocorticoids In a preferred embodiment, the one or more mineralocorticoids may include one or more of triamcinolone acetonide (TA); 11-desoxycortisone (11-DC); fludrocortisone (FA); deoxycorticosterone acetate (DA); deoxycorticosterone (DS); or aldosterone; or a therapeutically active analog, derivative, homolog, pharma- ceutically acceptable salt or conjugate thereof. Homologs include molecules of the same chemical type but differ by fixed increments of atoms or constants. The mineralocorticoid may further include one or more pharma- ceutically acceptable carriers, diluents or excipients.

[0090] In particularly preferred embodiments, the mineralocorticosteroid has the general structure: [ka] (wherein: R1 is CH3, CH=O, CH2OH, CR=O, CH2NH2, COCHCH2, NO2, X or CH2X, where X is F, Cl, Br; R2 is H, OH, =O, NH2 or CN; R3 is H, CH3 or CH2OH; R4 is H, F or Cl; R5 is H, OH, =O, SH, NH2CN, NO2, CH3, CH2OH, CH=O, X, CH2X, OR, OCOR, OPO(OR)2, =CH2 or CHR, where X is F, Cl, Br; R6 is H, CH3, or X, where X is F, Cl, Br; R7 is H, OH, CH3, alkyl, Ph, X, OCH3, OR, SCOCH3, SCOR, OCOR, CH2OH, CH2X, CH=O, CR=O or NHCOR, where X is F, Cl, BR; R8 is H, OH, CH3, CH2CH3, SH, NH2 or X, where X is F, Cl, Br; R9 is H, OH, SH, NH2, CH3, CH2CH3 or X, where X is F, Cl, Br; R 10 is H, OH, CH3, CH2CH3, SH, NH2, CH2OH, CH2CH2OH, OR, OCOR, OPO(OR)2, NHCOR, CH=O, X or CH2X, where X is F, Cl, Br.

[0091] In particularly preferred embodiments, the mineralocorticosteroid has the general structure: [ka] (wherein: R1 is CH3, CH=O, or COCHCH2; R2 is H, OH, or =O; R3 is H, CH3, or CH2OH; R4 is H or F; R5, R6, and R7 are H; R8 is H or OH).

[0092] In particularly preferred embodiments, the mineralocorticosteroid has the general structure: [ka] (wherein: A is O, S, NH, CH2, CHOH, C=O, CHX, CHCH3, CH2CH2, OCH2, SCH2, NHCH2, NRCH2, NCOR, where X is F, Cl, Br; B is H, OH, SH, NH2, CH2OH, CH2CH2OH, CH=O, X, CH2X, OR, OCOR, OPO(OR)2, NHCOR, where X is F, Cl, Br; R1 is H, CH3, CH=O, CH2OH; R2 is H, F, or Cl; R3 is H, CH3, or X, where X is F, Cl, Br; R4 is H, OH, CH3, alkyl, Ph, X, OCH3, SH, NH2, OR, SCOCH3, SCOR, OCOR, CH2OH, CH2X, CH=O, CR=O, SR or NHCOR, where X is F, Cl, Br; R5 is H, CH3, CH2CH3, OH, SH, NH2 or X, where X is F, Cl, Br; R7 is H, OH, SH, NH2, NO2, CH=O, CH3, CO2H, CN, CH2CH3, CH2X or X, where X is F, Cl, Br.

[0093] Glucocorticoids In preferred embodiments, the glucocorticoid may comprise one or more of cortisol, cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone (Aristocort™, Kenalog™), beclomethasone (Celestone™), fludrocortisone, deoxycorticosterone, aldosterone, fluocinolone or a therapeutically active analogue, derivative, homologue, pharma- ceutically acceptable salt or conjugate thereof.

[0094] Homologs include molecules of the same chemical type but differ by fixed increments of atoms or constants. The glucocorticoid may further comprise one or more pharma- ceutically acceptable carriers, diluents or excipients.

[0095] formulation An effective amount of the compound of interest is preferably used in the method of the present invention. In the formulation, the concentration of the therapeutic compound may be within the range of about 0.01 wt% to about 10 wt%. Typically, the concentration is within the range of about 0.025 wt% to about 2.5 wt%.

[0096] The exact pharmaceutical formulations used in the methods of the present invention will vary according to a wide range of commercial and scientific criteria. The skilled reader will appreciate that the above invention may contain other agents.

[0097] For example, the formulation used is preferably prepared using physiological saline solution as a medium. The pH of the formulation can be maintained at a substantially neutral pH (e.g., about 7.4, within the range of about 6.5 to about 7.4) by a suitable buffer known to those skilled in the art. Any pharmacologically acceptable buffer suitable for application to the eye can be used, such as Tris or phosphate buffer, acetate buffer, citrate buffer, phosphate buffer or borate buffer. Suitable water-soluble buffers that may be used are sodium carbonate, sodium borate, sodium phosphate, sodium acetate, sodium bicarbonate.

[0098] These agents may be present in amounts sufficient to maintain the pH of the system. As such, the buffering agent may be in an amount as high as about 5 wt% of the total formulation.

[0099] Any diluent used in preparing a pharma- ceutically acceptable formulation may be preferably selected so as not to unduly affect the biological activity of the formulation. Examples of diluents that are particularly useful for injectable formulations include water, organic or inorganic salt solutions, Ringer's solution, dextrose solution, and Hank's solution.

[0100] In addition, the pharmaceutical formulations used in the methods of the invention may contain additives such as other buffers, diluents, carriers, adjuvants or excipients.

[0101] Other agents may be used in the formulation for various purposes. These include, for example, preservatives, cosolvents, surfactants, oils, humectants, emollients, chelating agents, stabilizers, osmolality regulators, or antioxidants. Water-soluble preservatives that can be used include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, sodium bisulfate, phenylmercuric acetate, phenylmercuric nitrate, ethyl alcohol, methylparaben, polyvinyl alcohol, benzyl alcohol, and phenylethyl alcohol. A suitable surfactant may be, for example, Tween 80.

[0102] Other agents that may be used include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, polosamer, carboxymethylcellulose, hydroxyethylcellulose, purified water. Osmolality adjusters may include, for example, sodium chloride, potassium chloride, mannitol, and glycerin. Antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, butylated hydroxytoluene. The efficacy, effective dose, formulation, contraindications, vendor, etc. of the compounds in the formulation are available or known to those skilled in the art.

[0103] These agents may be present in individual amounts of from about 0.001 wt% to about 5 wt%, and preferably from about 0.01 wt% to about 2.0 wt%.

[0104] Administration In carrying out the method of the present invention, the pharma- ceutically acceptable compound may be administered to the patient by any method that results in delivery of the therapeutic compound to the site of the condition affecting the retina of the eye. Any of the formulations may be administered by an ocular route, for example, topically (extraocular application), subconjunctivally, subocularly, intraocularly, via an ocular implant, or systemically (oral or another parenteral route). Administration of the composition is preferably by intraocular injection, although other modes of administration may be effective.

[0105] In highly preferred forms of the invention, when the compound is administered by intravitreal injection for the treatment of a retinal condition of the eye, the active compound should be as concentrated as possible to minimize the injection volume.

[0106] Preferably, the compositions are administered in unit dosage forms suitable for single administration of a precise dose. For example, the compositions of the present invention can be provided in the form of a single unit dose in a pre-prepared syringe ready for administration.

[0107] Solid dispersions and solubilized formulations of therapeutic compounds can be used to practice the therapeutic methods of the invention. In the case of intraocular formulations, the therapeutic compound is delivered at a concentration high enough to reach a final concentration in the target ocular compartment (such as the posterior cavity for the treatment of retinal diseases) in the range of about 0.1 μmol / L to about 10 μmol / L. Typically, for this mode of delivery, the final concentration of the therapeutic compound is in the range of 0.25 μmol / L to about 5 μmol / L.

[0108] Topical application of the formulations of the present invention may be as ointments, gels or drops or formulations that gel in situ upon contact with the tear fluid of the eye or the external surface of the eye. When administered topically, the concentration of therapeutic compound administered may depend on the particular subject, the underlying disease and its severity, frequency of administration and other factors as known to those of skill in the art. Sample concentrations include, but are not limited to, about 0.5 μg / ml to about 500 μg / ml, more preferably about 1.0 μg / ml to about 100 μg / ml, and even more preferably about 5 μg / ml to about 50 μg / ml.

[0109] The formulations may also be administered as topical ointments or solutions, intravenous solutions or suspensions, or by intraocular injection, as sustained release formulations with carriers such as microparticles, microcapsules, or liposomes, as are known to those of skill in the art.

[0110] A sustained release drug delivery system can be administered intraocularly to provide sustained release of the formulation over an extended period of time. For example, the sustained or extended release delivery system can be provided in the form of an implant.

[0111] FA has been shown to be effective in treating DME and other wet retinal diseases. FA has also been tested in safety studies in geographic atrophy. MA occurs as a result of long-term treatment with anti-VEGF. It is intended to test FA first, and possibly TA, in DME that is refractory to Eylea and other anti-VEGFs.

[0112] Appendix (Method and Results of Example 1) method In vitro experiments The immortalized retinal cells used were: MIO-M1 cells (Mueller cell-derived; Mueller 1 Moorefields, Institute of Ophthalmology, Dr A. Limb, Institute of Ophthalmology, University College, UK); ARPE19 (RPE-derived; ATCC CRL-2302, American Tissue Culture Collection, VA, USA); and 661W cells (photoreceptor-like derived; kindly donated by Dr Muayyad R. Al-Ubaidi, Department of Cell Biology, University of Oklahoma Health Sciences Centre, Oklahoma City, OK, USA). Cells from Cell Bank Australia were identified and validated.

[0113] MTT assay Using the immortalized retinal cell lines MIO-M1, 661W and ARPE19, MTT assays were performed to assess cellular metabolic activity based on the availability of cellular NAPDH. Treatments included exposure to one of the following: FA (10–0.01 μg / μl, provided by Professor Ben Boyd, Monash University, Australia), TA (10–0.01 μg / μl, Honeywell, USA) and dexamethasone (10–0.0001 μg / μl, Sigma-Aldrich, MO, USA). All corticosteroids used in vitro were dissolved in 20% dimethyl sulfoxide (DMSO) (Sigma-Aldrich, MO, USA) and ultrapure endotoxin-free 0.1 M PBS (Thermo Fisher Scientific, MA, USA). At 12 h after the addition of corticosteroids, 10 μl of MTT reagent (Roche, Switzerland) was added to each well. To protect against light, the plate was wrapped in foil and stored in the dark at 37°C, 5.0% CO2 for 4 hours. Using a bright-field Zeiss Axiovert 200 inverted microscope (Carl Zeiss Meditec, Dublin, CA, USA), the cells were monitored for the formation of insoluble purple formazan precipitate crystals in live cells. Then, 100 μl of MTT solubilization solution was added and incubated again in the dark at 37°C, 5.0% CO2 for 24 hours. Quantification of the MTT assay was performed by measuring absorbance at 570 nm using a Tecan Infinite® 200 PRO (Tecan, Maennedorf, Switzerland).

[0114] IL-1β and TNF-α stimulation IL-1β and TNF-α were administered to MIO-M1 cells to initiate an inflammatory response and to test the anti-inflammatory properties of selected corticosteroids. MIO-M1 cells were grown in 24-well plates to a cell density of 50,000 cells / well using growth medium and fetal bovine serum as described (section 2.1.1). MIO-M1 cells were loaded with either IL-1β or TNF-α (R&D Systems, MN, USA) at 1 ng / μl. Experimental wells were treated with either FA, TA, or dexamethasone at 1 μg / μl. 12 hours after addition, growth medium was removed from each well and replaced with 860 μl of TRIzol (Thermo Fisher Scientific, MA, USA), vortexed approximately 20 times, and then placed into a clean 1.5 ml Eppendorf tube for ribonucleic acid (RNA) extraction.

[0115] Handling and keeping of animals All experiments performed were in accordance with the ANU Animal Experimentation Ethics Committee (AEEC, protocol #A2014 / 56) with the ARVO Statement for Use of Animals in Ophthalmic and Vision Research. 60-day-old C57BL / 6J mice were used in this study. Animals were born, bred, and maintained under dark conditions (5 lux) prior to photooxidative damage.

[0116] Optical Coherence Tomography (OCT) Optical coherence tomography (OCT) was used to obtain in vivo cross-sectional and fundus images of mouse retinas.

[0117] Intravitreal injection Intravitreal injections were performed on 60-day-old C57BL / 6J mice. Treatments included exposure to FA or TA dissolved in a suspension (consisting of 0.5% w / v carboxymethylcellulose and 0.4% v / v Tween 80). The final concentration of drug in the vitreous cavity was estimated to be 1 mg / ml.

[0118] Photooxidative Damage in a Mouse Paradigm Age-matched C57BL / 6J mice (60 days old) were exposed to continuous 100K lux white LED light for 5 days with free access to food and water. During this period, 1% atropine sulfate (minimum 1% atropine sulfate eye drops; Bausch and Lomb, USA) was administered twice daily to both eyes to dilate the pupils. Subsequently, animals were euthanized with carbon dioxide (CO2).

[0119] Electroretinography (ERG) Electroretinography (ERG) was used to assess the functional response of the rodent retina to full-face flash stimulation under dark-adapted conditions using published methods in dark-reared control and photooxidatively damaged animals.

[0120] The animals were dark-adapted overnight before starting the ERG experiments. Animals were anesthetized as described above, and all retinal recordings were performed in a dark room with minimal red light source.

[0121] TUNEL Terminal deoxynucleotidyl transferase (Tdt) dUTP nick end labeling (TUNEL) is an established technique used to detect apoptotic and necrotic cells.

[0122] immunohistochemistry Details of the primary and secondary antibodies are listed in Table 1.

[0123] [Table 1]

[0124] Quantification of TUNEL and IBA1 positive cells The retina was divided equally into eight quadrants. Each quadrant was visualized using a confocal microscope (LSM 5, Zeiss, Germany) and analyzed by TUNEL. + Cells and IBA1 +Cells were identified and counted, and data were graphed and analyzed using Prism 6 software (GraphPad Software, CA, USA).

[0125] Quantitative real-time polymerase chain reaction After purification of RNA, cDNA was synthesized using Bioline Tetro kit (Bioline, Australia) according to the manufacturer's instructions. Quantitative real-time polymerase chain reaction (QRT-PCR) was performed to characterize gene expression changes in animal and cell culture samples. TaqMan hydrolysis probes (Applied Biosystems, USA) and gene expression master mix (Applied Biosystems, USA) were used. Clear 384-well plates (Applied Biosystems, USA) were used with each biological sample plated in duplicate. Reaction mixtures per sample were set up, which included 0.5 μl cDNA, 4 μl ribonuclease-free water, 5 μl gene expression master mix and 0.5 μl Taqman primer probes (Thermo Fisher Scientific) as listed in Table 2.5. Amplification of each sample was performed using a QuantStudio 12K Flex QRT-PCR machine (Applied Biosystems, USA). The comparative cycle threshold (Ct) method (ΔΔCt) was used and GAPDH was used as a reference gene because it is known not to alter its expression after retinal photooxidative damage. Data were analyzed using QuantStudio 12K Flex software (Applied Biosystems, USA).

[0126] [Table 2]

[0127] Statistical analysis, image acquisition and presentation All data were analyzed using Prism 6 software (GraphPad Software, CA, USA). Analyses included one-way analysis of variance (ANOVA) and unpaired Student's t-tests, with appropriate post-hoc tests as indicated. Results were presented as standard error of the mean. Statistical significance was considered as P<0.05. All images were acquired using an A1 Nikon confocal microscope (Nikon, Tokyo, Japan). Images were acquired using NIS-Elements AR software (Nikon, Tokyo, Japan) and uniformly processed using Photoshop CS6 (Adobe Systems, CA, USA).

[0128] result Cytotoxicity of corticosteroids to retinal cells. The effect of FA and TA on the viability of MIO-M1, 661W and ARPE19 cells by MTT assay indicates that 1 μg / μl does not significantly alter cell viability across these lines (FIG. 1, P<0.05). Therefore, all subsequent experiments were performed using this dose of FA and TA, respectively.

[0129] FA and TA regulate the expression of chemokines and cytokines Upon exposure to the proinflammatory stimulus IL-1β, gene expression of three major inflammatory markers, CCL2, IL-6, and IL-8, is significantly increased in MIO-M1 cells (Figure 2, P<0.05). Figure 2 shows the response of MIO-M1 cells exposed to IL-1β, which resulted in upregulated expression of CCL2, IL-6, and IL-8 genes. Treatment with FA restored gene expression levels of CCL2, IL-6, and IL-8 to baseline levels (Figure 2A, P<0.05). Following stimulation with TNF-α, similar levels of upregulation of CCL2, IL-6, and IL-8 were observed in MIO-M1 cells, which was significantly reduced by treatment with FA (Figure 2C, P<0.05).

[0130] Treatment of stimulated cells with TA significantly reduced CCL2, IL-6, and IL-8 expression to approximately one-third of stimulated levels (IL-1β alone) (Fig. 2B, P<0.05). A similar pattern of response in gene expression of CCL2, IL-6, and IL-8 was observed when TNF-α was used as the proinflammatory stimulus, and gene expression levels of selected inflammatory markers were also significantly reduced after addition of TA (Fig. 2D, P<0.05).

[0131] FA regulates the expression of chemokines and cytokines through the mifepristone / (RU486)-sensitive glucocorticoid receptor By inclusion of receptor blockers, it was found that the effect of FA on the expression of target genes was negated in the presence of the glucocorticoid receptor blocker mifepristone (RU486), but not in the presence of RU28318 (MR blocker), PF998425 (androgen blocker), or ICI182780 (estrogen blocker) (Figure 3). The results indicate that the effect of FA on the expression of CCL2, IL-6, and IL-8 is mediated through the glucocorticoid receptor. This pattern was also observed for TA.

[0132] FA is a protective and anti-inflammatory agent in PD models of retinal degeneration Compared to controls, suspension+FA injected mice had significantly less TUNEL activity in the outer retina at 5 days of PD, unlike suspension alone injected mice and suspension+TA injected mice. + In both suspension+TA and suspension+FA injected mice, IBA1 cells were significantly increased in number compared to controls (P<0.05, FIG. 4A). +There was a significant decrease in cells (P<0.05) in mice injected with suspension vehicle alone, but not in those injected with suspension vehicle alone (Figure 4B). Suspension+FA injected mice had significantly greater ONL thickness ratios at 1-2 mm and 2-3 mm superior to the optic nerve compared to controls (P<0.05, Figure 4C), a difference detectable by OCT (Figure 4D-G). This effect was not observed in suspension+TA injected animals. Histological findings are shown in Figure 4H-O. ERG analysis shows that mice intravitreally injected with suspension+FA had significantly higher a-wave and b-wave responses after 5 days of PD (P>0.05). Mice injected with suspension alone or suspension+TA had ERG responses indistinguishable from PD control / untreated animals (Figure 4P-Q). No significant differences in cone responses were observed between experimental groups (Figure 5.4R).

[0133] Collectively, the key measures examined, including photoreceptor cell death, microglia / macrophage recruitment, ONL thickness and retinal function, contribute to assessing the efficacy of corticosteroids post-PD.

[0134] Appendix (Method and Results of Example 2) Age-related macular degeneration (AMD) is the leading cause of severe vision loss in people over 65 years of age in Western countries (1). In the United States, approximately 1.75 million people have the advanced form of AMD (2, 3). Early signs of AMD (drusen and pigmentary changes) are common in individuals over 65 years of age and precede the visually devastating advanced form. The advanced forms of AMD are classified as either choroidal neovascularization (wet, or exudative) or geographic atrophy (dry).

[0135] Geographic atrophy (GA) is a disease characterized by thinning and loss of the retinal pigment epithelium (RPE) and concomitant atrophy of the photoreceptors and choriocapillaris (4). Clinically, GA is characterized by gradually expanding islands of dead retinal cells at the back of the eye. GA can result in significant visual function deficits in reading, night vision, and dark adaptation, resulting in dense, irreversible scotomas in the visual field, but the initial decline in VA can be relatively limited if the fovea is spared. If the fovea is involved, GA can rapidly cause blindness. GA is responsible for approximately 20% of all legal cases of blindness in North America, and incidence and prevalence are increasing due to higher life expectancies (5).

[0136] AMD is a highly complex disease influenced by multiple factors, including aging, genetic predisposition, environmental factors, oxidative stress, and inflammatory effects (2, 6, 7). Smoking, age, alcohol consumption, diet, and obesity are important risk factors for oxidative stress (7, 8). High body mass index, cardiovascular disease, hypertension, and various dietary patterns are less consistent risk factors (9). Several single nucleotide polymorphisms (SNPs) that confer increased or decreased risk of inflammation have been identified. These include the well-understood complement factor H (CFH), CX3CR1, Toll-like receptor 3 (TLR3), TLR4, and interleukin 8 (IL-8) (10).

[0137] Although AMD is not a classical inflammatory disease, inflammatory cells have an important role in the pathogenesis and progression of AMD (6, 11, 12). Evidence also suggests that some infectious agents are associated with AMD. Interleukin 6 (IL-6) has also been found to be upregulated in neovascular AMD and GA, and it has been associated with the progression of GA (13).

[0138] Fludrocortisone acetate (9-α-fluoro(Fiuoro)-11β.17α,21-trihydroxy-4-pregnene-3,20-dione acetate, FCA) is a synthetic steroid with potent mineralocorticoid effects and high glucocorticoid activity (14), and therefore has anti-inflammatory and anti-allergic properties. FCA is a mineralocorticoid receptor and glucocorticoid receptor agonist that binds to cytoplasmic receptors, translocates to the nucleus, and subsequently initiates the transcription of glucocorticoid-responsive genes such as lipocortin and inhibits phospholipase A2. It prevents the release of arachidonic acid, a precursor of prostaglandins and leukotrienes, both of which are important mediators in the pro-inflammatory response mechanism. In addition, the drug exerts its mineralocorticoid effects on the distal tubules and collecting ducts of the kidney by inducing permease, an enzyme that controls Na+ permeability in cells, thereby enhancing Na+ reabsorption and water retention as well as increasing K+ and H+ excretion.

[0139] The objective of this study was to evaluate the safety and tolerability of a single intravitreal (IVT) administration of FCA in patients with GA over a 6-month period.

[0140] method Test Design This monocentric, phase 1b, prospective, open-label, single-dose, dose-escalation clinical trial was conducted with nine participants enrolled at a single center between August 2019 and April 2021. All patients were followed up for 6 months after baseline. Ethical approval was obtained prior to initiation and the trial was listed in the Australian and New Zealand Clinical Trial Registry (accessible via www.anzctr.org.au; ANZCTR number 12618001308280). An independent data and safety committee provided clinical trial oversight. The trial adhered to the tenets of the Declaration of Helsinki. Informed consent was obtained from all participants prior to enrollment in the study.

[0141] Test drug Fludrocortisone acetate was formulated for intravitreal administration as a powder solution for injection, ensuring long-term stability similar to other corticosteroids (15). Vials contained 10 mg of FCA powder, reconstituted with sterile sodium chloride solution (0.9%) according to the appropriate dose prior to injection.

[0142] Study population Inclusion criteria for the study eyes were as follows: diagnosis of GA secondary to AMD confirmed using fundus autofluorescence (FAF) imaging, GA area of ​​≥1.9 to ≤17 mm2 (1 and 7 disc areas (DA), respectively), and best-corrected visual acuity (BCVA) of ≥24 letters using the Early Treatment Diabetic Retinopathy Trial (ETDRS) chart.

[0143] Exclusion criteria were: GA due to causes other than AMD such as Stargardt disease, cone-rod dystrophy or toxic maculopathy such as Plaquenil maculopathy, spherical equivalent of refractive error showing >6 diopters of myopia or axial length >26 mm, evidence or history of exudative (wet) AMD including evidence of retinal pigment epithelium (RPE) lip or evidence of neovascularization anywhere within the retina based on fluorescein angiogram in one eye within 12 months that may disrupt visual performance or be precipitated by intraocular steroids. Patients were excluded if they had any of the following: retinal disease with a high risk of developing glaucoma, intraocular surgery (including lens replacement) within 3 months prior to treatment, aphakia or absence of posterior capsule, previous breach of the posterior capsule not occurring as a result of yttrium aluminum garnet (YAG) laser posterior capsulotomy in association with a prior posterior space intraocular lens implant at least 60 days prior to day 0, glaucoma or family history of glaucoma, any contraindication to IVT injections including current ocular or periocular infection, history of uveitis or endophthalmitis, or history of IVT injections within 12 months.

[0144] If both eyes met the criteria, the eye with the best visual acuity at the screening visit was designated the study eye.

[0145] Testing Protocol A full ophthalmologic evaluation was performed at each study visit, including GA area, BCVA, low-luminance BCVA (LL-BCVA), and intraocular pressure (IOP) assessed via FAF imaging. Participants were evaluated at screening, baseline, days 1, 7, 14, 28, 60, 90, and 150 (end of study). Blood and urine samples were collected for safety analyses at screening, baseline, days 7, 28, and 150.

[0146] Part 1 of the study included a single participant treated with FCA at 1 mg / 0.1 ml to evaluate safety and tolerability. This participant was followed for 28 days before the results were reviewed by an independent Data Safety Monitoring Board (DSMB). After approval by the DSMB, two additional participants were treated with FCA at 1 mg / 0.1 ml and followed for an additional 28 days after treatment before the start of Part 2.

[0147] Part 2 involved a single dose of 2 mg / 0.1 ml FCA in a single participant with 28 days of follow-up as in Part 1. The DSMB reviewed the results of the remaining 5 participants prior to enrollment.

[0148] Evaluation items Fundus autofluorescence was captured using a Heidelberg Spectralis (Heidelberg Engineering, Heidelberg, Germany). Assessment of size and progression of GA was performed using FAF, which was performed by two graders (TH and EC) in a blinded fashion using Heidelberg Region Finder software version 2.6.2.0, a semi-automated program used to quantify areas of atrophy (Figure 1). Baseline FAF images were defined and used to evaluate subsequent visits using the Region Finder software. If there was a discrepancy of more than 20% between the two graders, a third grader (AC) evaluated the images. Areas of peripapillary atrophy were not included in the measurements. GA was defined as a well-demarcated area of ​​hypofluorescence relative to FAF from the absence of the RPE layer over the neurosensory retina (reference).

[0149] BCVA was assessed at 4 meters at each study visit using ETDRS charts after subjective refraction. LL-BCVA was assessed similarly to neutral density lenses. IOP was assessed by Goldmann applanation tonometry. Adverse events were reported from the first dose of FCA in the first patient to the last visit in the last patient.

[0150] statistical analysis Statistical analyses were primarily descriptive and were performed using SPSS software, version 24.0 (SPSS, Inc, Chicago, IL). A summary of safety data is presented in the Results. Descriptive statistics (mean, standard deviation (SD), median, minimum and maximum) are calculated for summary of continuous data. Paired t-tests were performed to assess changes from baseline and two-sample t-tests were performed to compare interocular changes.

[0151] Safety data will be summarized, including vital signs, clinical safety laboratories, and adverse events. Adverse events (AEs) were coded using the Medical Dictionary for Regulatory Activities (MedDRA), but data will be summarized by System Organ Class and preferred terminology.

[0152] result Nine participants were enrolled in this study and their baseline characteristics are presented in Table 3. The mean age of participants was 79.7±6.2 years and 55% were female. The mean baseline BCVA and LL-BCVA were 53.1±10.0 letters and 39.3±11.2 letters, respectively. The mean baseline area of ​​GA was 9.50±5.7.

[0153] [Table 3]

[0154] An early pilot participant receiving 1 mg / ml fludrocortisone acetate experienced a loss of 22 letters (>= 15 letters) on Day 14, which was deemed most likely not related to IP by the DSMB as there were no indications of any other adverse events or safety concerns.

[0155] One participant receiving 2 mg / ml fludrocortisone acetate experienced a nasal subconjunctival hemorrhage in the study eye at day 90 that resolved after 1 week. No other adverse events were observed throughout the study.

[0156] No significant increase in IOP (≧10 mmHg) was observed in any patient throughout the study. The mean change in IOP was −0.25 mmHg at day 150 compared to baseline (p=0.75) (Table 4). No significant changes in temperature, heart rate, systolic or diastolic blood pressure were observed throughout the study (all cases p>0.05).

[0157] Four of nine patients (44.4%) had a native lens; formal grading of lens opacity was not performed as part of the protocol. One participant had significant lens opacity at screening (which did not interfere with imaging), but no participant required / underwent cataract surgery during the study.

[0158] [Table 4]

[0159] GA area progression The mean area of ​​geographic atrophy increased over the study period in both the study eye (0.5 mm2 p=0.003) and the fellow eye (0.62 mm2 p=0.02). The change in area was not significant between eyes (p=0.64) (Table 4).

[0160] Consideration This study demonstrates that intravitreal FCA is clinically safe and well tolerated in this cohort of patients with geographic atrophy secondary to AMD. Typical side effects of intraocular steroids, including increased intraocular pressure and lens opacity, were not observed in this study. Furthermore, no systemic adverse events were observed during this titration study.

[0161] A recent meta-analysis of 23 studies reported that the natural progression of GA lesions in untreated eyes was 1.66 mm2 / year (16). Results from the Proxima A and Proxima B clinical trials reported growth rates of 2.09 mm2 / year and 1.90 mm2 / year, respectively, over the first 12 months. Another study by Schmitz-Valckenberg et al. (17) reported a change of 0.88 mm2 over 6 months. Findings from our study showed that GA progression was lower in both treated eyes (0.5 mm2) and fellow eyes (0.62 mm2) over the study period, which may indicate a possible therapeutic effect of FCA.

[0162] Low-light visual acuity is known to be a predictor of vision loss in patients with GA, given that it can detect changes in central function earlier than standard VA assessment. (18-20) Our findings, which showed no deterioration in LLVA over the study period, are encouraging and may be considered worthy of further detailed studies in larger cohorts.

[0163] Previous studies evaluating intravitreal glucocorticoid treatment have found improvements in blood-retinal barrier (BRB) function (21, 22). These findings are consistent with preclinical studies using FCA in vitro and in vivo in mouse models of AMD (23). In those experiments, FCA was found to have potent anti-inflammatory effects and to be neuroprotective in AMD models.

[0164] In clinical trials, it has been previously reported that monocular treatments can affect the fellow eye, (24-26) meaning that comparison of measures between treated and fellow eyes cannot serve as a valid control and that a population standard is the most useful comparator. Given that both treated and fellow eyes showed a slower rate of progression compared to previous reports, a similar sympathetic response could also be observed in the untreated fellow eye.

[0165] Maddess et al. recently reported that there was a significant correlation between peripheral macular area in treated and untreated nAMD eyes treated with anti-VEGF based on monthly evaluations over a 15-month period (see Rai et al., forthcoming). Thus, the inventors suggest that their findings may indicate that intraocular injection of FCA at 2 mg / ml may slow the rate of GA progression, but that much larger study groups over a longer time frame are required to formally make such a conclusion.

[0166] Limitations of this study are the small sample size and the absence of formal lens grading, both of which were considered non-essential to the primary objective of this safety study. Additional limitations of the study include the small sample size and short study time. Strengths of this study include its prospective design.

[0167] In summary, the data show that intravitreal FCA is clinically safe and well tolerated. Treatment with FCA does not increase IOP and has promising efficacy in terms of GA lesion growth and LLVA. Furthermore, longer-term studies with larger sample sizes and multiple dosing schedules may contribute to assessing the efficacy of FCA in reducing GA progression.

[0168] While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications. This application is generally intended to cover any variations, uses, or adaptations of the invention in accordance with the principles of the invention, which are within known or customary practice within the art to which the invention pertains, including departures from the present disclosure as applicable to the essential features previously described.

[0169] Since the present invention can be embodied in several forms without departing from the spirit of the essential characteristics of the present invention, it is to be understood that the above-described embodiments should not be construed as limiting the present invention, unless otherwise specified, but should be broadly construed within the spirit and scope of the present invention as defined in the appended claims. The described embodiments are to be considered in all respects as merely illustrative and not restrictive.

[0170] Various modifications and equivalent arrangements are intended to be within the spirit and scope of the invention and the appended claims. Accordingly, it is to be understood that the specific embodiments are illustrative of the many ways in which the principles of the invention can be practiced. In the following claims, means-plus-function clauses are intended to cover structures that perform the defined function and equivalent structures, not just structural equivalents.

[0171] When a Markush group or other group is used herein, all individual members of the group and all possible combinations and subcombinations of the group members are intended to be included individually in the disclosure. Unless otherwise specified, the invention can be practiced using any combination of components described or exemplified herein.

[0172] Whenever a range, e.g., a temperature range, a time range, or a composition or concentration range, is given within the specification, all intermediate ranges and subranges, as well as all individual values ​​contained within the given range, are intended to be included in the disclosure. It will be understood that any subrange or individual value within a range or subrange included in the description herein may be excluded from the claims herein.

[0173] As used herein, "comprising" is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended, and does not exclude additional unrecited elements or method steps. As used herein, "consisting of" excludes any element, step, or ingredient not specified in the claim element. As used herein, "consisting essentially of" does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim. The broad term "comprising" is intended to encompass the narrower "consisting essentially of" and the even narrower "consisting of." Thus, any recitation herein of a phrase "comprising one or more claim elements" (e.g., "comprising A") is intended to encompass the narrower terms, e.g., "consisting essentially of" and "consisting of." Thus, the broader term "comprising" is intended to provide specific support in each use herein for either "consisting essentially of" or "consisting of." The inventions illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations not specifically disclosed herein.

[0174] Those skilled in the art will understand that materials and methods other than those specifically exemplified can be used in the practice of the invention without resorting to undue experimentation. Any art-known functional equivalents of any such materials and methods are intended to be included in the present invention. The terms and expressions used are used as terms of description and not of limitation, and there is no intention in the use of the terms and expressions to exclude any equivalents of the features shown and described or portions thereof, but it is understood that various modifications are possible within the scope of the invention claimed. Thus, although the present invention has been specifically disclosed by example, it should be understood that any features, modifications and variations of the preferred embodiments and concepts disclosed herein may be used by those skilled in the art, and that such modifications and variations are considered to be within the scope of the invention as defined by the appended claims.

[0175] Each reference cited herein is incorporated in its entirety. Such references may provide sources of materials; alternative materials, methodological details, as well as additional uses of the invention.

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Glucocorticoids exert differential effects on the endothelium in an in vitro model of the blood-retinal barrier.Acta Ophthalmol.2019;97(2):214-24. 22.Lee JY,Eun CK,Kim YW,Kim HJ,Jung YJ,Jae SY,et al.The steroid effect on the blood-ocular barrier change induced by triolein emulsion as seen on contrast-enhanced MR images.Korean J Radiol.2008;9(3):205-11. 23.Racic T,Chang A,Fernando N,Brandli A,Natoli R,Penfold P,et al.Anti-inflammatory and neuroprotective properties of the corticosteroid fludrocortisone in retinal degeneration.Exp Eye Res.2021;212:108765. 24.Aghayeva FA,Chronopoulos P,Schuster AK,Pfeiffer N,Hoffmann EM.Inter-eye relationship of intraocular pressure change after unilateral trabeculectomy,filtering canaloplasty,or PreserFlo TM microshunt implantation.Graefes Arch Clin Exp Ophthalmol.2021;259(10):3045-53. 25.Gibbens MV.Sympathetic influences on the consensual ophthalmotonic reaction.Br J Ophthalmol.1988;72(10):750-3. 26.Rao HL,Senthil S,Garudadri CS.Contralateral intraocular pressure lowering effect of prostaglandin analogues.Indian J Ophthalmol.2014;62(5):575-9.

Claims

1. 1. A pharmaceutical composition for treating a subject having retinal eye conditions that are refractory to anti-VEGF treatment, comprising a therapeutically effective amount of one or more steroids, wherein the therapeutically effective amount of one or more steroids is administered to the subject after anti-VEGF treatment.

2. 1. A pharmaceutical composition for treating a subject having a retinal ocular condition that is refractory to anti-VEGF treatment, comprising a therapeutically effective amount of one or more compounds capable of modulating the activity of a steroid receptor, preferably a glucocorticoid receptor and / or a mineralocorticoid receptor, wherein the therapeutically effective amount of the one or more compounds is administered to the subject after anti-VEGF treatment, thereby treating the retinal ocular condition.

3. 1. A pharmaceutical composition for treating a subject having a retinal ocular condition that is refractory to anti-VEGF treatment, comprising: (a) a therapeutically acceptable formulation of a steroid suitable for delivery to the eye; and (b) at least a second therapeutically active compound at a concentration and dosage sufficient to ameliorate said retinal ocular condition. wherein (a) and (b) are administered after anti-VEGF treatment.

4. 4. The pharmaceutical composition of claim 1 or claim 3, wherein the steroid is one or more mineralocorticoids or glucocorticoids or therapeutically active analogues, derivatives, homologues, pharmaceutically acceptable salts or conjugates thereof.

5. A pharmaceutical composition described in any one of claims 1 to 3, wherein the one or more steroids or the one or more compounds include one or more dual action compounds, each dual action compound being capable of modulating the activity of both the mineralocorticoid receptor and the glucocorticoid receptor.

6. A pharmaceutical composition described in any one of claims 1 to 3, wherein the one or more steroids or the one or more compounds comprise one or more of 11-desoxycortisone (11-DC); fludrocortisone; fludrocortisone acetate (FA); fludrocortisone acetonide; deoxycorticosterone acetate (DA); deoxycorticosterone (DS); or aldosterone; or a therapeutically active analogue, derivative, homologue, pharmaceutically acceptable salt or conjugate thereof.

7. A pharmaceutical composition described in any one of claims 1 to 3, wherein the one or more steroids or the one or more compounds comprise one or more of cortisol, cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, triamcinolone acetonide, beclomethasone, fluocinolone or therapeutically active analogues, derivatives, homologues, pharmaceutically acceptable salts or conjugates thereof.

8. A pharmaceutical composition described in any one of claims 1 to 3, wherein the one or more steroids or the one or more compounds comprise one or more of triamcinolone; triamcinolone acetonide; cortisol; cortisone; prednisone; prednisolone; methylprednisolone; fludrocortisone; fludrocortisone acetate; fludrocortisone acetonide; or therapeutically active analogs, derivatives, homologs, pharmaceutically acceptable salts or conjugates thereof.

9. A pharmaceutical composition according to any one of claims 1 to 3, wherein the one or more steroids or the one or more compounds comprise fludrocortisone or a therapeutically active analogue, derivative, homologue, pharmaceutically acceptable salt or conjugate thereof, and optionally the therapeutically active analogue, derivative, homologue, pharmaceutically acceptable salt or conjugate thereof may comprise one or more of fludrocortisone acetate and fludrocortisone acetonide.

10. A pharmaceutical composition described in any one of claims 1 to 3, wherein the one or more steroids or the one or more compounds comprise triamcinolone acetonide or a therapeutically active analog, derivative, homolog, pharmaceutically acceptable salt or conjugate thereof.

11. 4. The pharmaceutical composition of any one of claims 1 to 3, wherein the retinal ocular condition is macular edema (ME), such as diabetic macular edema (DME), or age-related macular degeneration (AMD), including wet AMD or dry AMD.

12. The retinal ocular condition may be an exudative ocular condition, a back of the eye condition, macular degeneration, e.g., age-related macular degeneration (AMD), including both dry (geographic atrophy) and wet (choroidal neovascularization (CNV)), macular edema (ME), e.g., diabetic macular edema (DME), angiographic cystoid macular edema, cystoid macular edema (CMO), diabetic retinopathy (DR), e.g., proliferative diabetic retinopathy (PDR), and retinal vein occlusion, e.g., central retinal vein occlusion (CRVO) or branch retinal vein occlusion (BRVO), maculopathy, e.g., age-related maculopathy (ARM), exudative ocular diseases or conditions, retinal pigment epithelial detachment (PED), 4. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is used to treat eye diseases including glaucoma, glaucoma-associated neovascularization, glaucoma-associated ocular conditions such as glaucoma-associated ocular hypertension, ...

13. 4. The pharmaceutical composition of any one of claims 1 to 3, wherein the retinal ocular condition comprises a back of the eye disease or condition, including an exudative back of the eye disease or condition, and optionally the back of the eye disease or condition comprises an ocular disease or condition involving the retina, macula and / or fovea in the posterior region of the eye.

14. The pharmaceutical composition according to any one of claims 1 to 3, wherein said retinal ocular condition comprises dry AMD, optionally distinct from exudative AMD, early AMD and geographic atrophy (GA).

15. The pharmaceutical composition of any one of claims 1 to 3, wherein the retinal ocular condition is a diabetic eye disease and / or condition.

16. 4. The pharmaceutical composition of any one of claims 1 to 3, wherein the therapeutically effective amount comprises a range of about 0.01 wt% to about 10 wt%, optionally about 0.025 wt% to about 2.5 wt%.

17. The pharmaceutical composition of any one of claims 1 to 3, wherein the one or more steroids or the one or more compounds are injected into the eye, optionally wherein the injection comprises a suprachoroidal injection.

18. 4. The pharmaceutical composition of any one of claims 1 to 3, wherein the one or more steroids or the one or more compounds are provided in a unit dose formulation, optionally the unit dose formulation is provided in a pre-filled syringe, optionally the pre-filled syringe comprises two barrels.

19. A pharmaceutical composition according to any one of claims 1 to 3, which comprises one or more pharmaceutically acceptable carriers, diluents or excipients, such as one or more surfactants or wetting agents.

20. A pharmaceutical composition according to any one of claims 1 to 3, comprising one or more pharmaceutically acceptable carriers in the form of cannabis, cannabis oil or a pharmaceutically active cannabis or cannabis oil extract, optionally wherein the carrier comprises cannabis oil containing about 80% to 90% adjusted omega fatty acids.

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