Methods for Treating Retinal Vasculopathy

Abstract

The present invention relates, inter alia, to methods of treating certain retinal vasculopathies, such as diabetic macular edema, diabetic retinopathy, and age-related macular degeneration, comprising treating a patient suffering from a retinal vasculopathy by administering to the patient a therapeutically effective dose of a compound disclosed herein.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 174,188, filed April 13, 2021, U.S. Provisional Application No. 63 / 237,454, filed August 26, 2021, U.S. Provisional Application No. 63 / 309,260, filed February 11, 2022, and U.S. Provisional Application No. 63 / 325,056, filed March 29, 2022, the disclosures of which are incorporated herein by reference.

[0002] FIELD OF THEINVENTION The present invention relates to methods of treating certain retinal vasculopathies, such as diabetic macular edema, diabetic retinopathy, and age-related macular degeneration. [Background technology]

[0003] 2. Background of the Invention Pathological angiogenesis remains one of the major challenges in the treatment of certain retinal vasculopathies, such as diabetic macular edema (DME), diabetic retinopathy (DR), and age-related macular degeneration (AMD), severe diseases that often lead to vision loss and blindness.

[0004] DME is a complication of diabetic retinopathy (DR) following chronic, poorly controlled diabetes and is the most common form of sight-threatening retinopathy in people with diabetes (Tan et al. 2016, IDF 2019). Approximately 1 in 14 patients with diabetes has some degree of DME (Coney 2019). The overall prevalence of DR in patients with diabetes using retinal imaging was estimated to be 35%, with sight-threatening DR present in 12% (WHO 2015). Prevalence depends on the type of diabetes and duration of the disease. For both types of diabetes, type 1 diabetes (T1D) and type 2 diabetes (T2D), after 25 years of duration, the prevalence is close to 30% (Browning et al. 2018).

[0005] Age-related macular degeneration (AMD) is the leading cause of severe vision loss in individuals >55 years of age in the developed world, accounting for 6-9% of legal blindness worldwide (Wong et al. Lancet Glob. Health (2014), Jonas et al. Asia Pac J. Ophthalmol (2017)). It is estimated that by 2040, approximately 288 million people worldwide will be affected by AMD (Wong et al. (2014)).

[0006] AMD is a multifactorial blinding disease. It has previously been demonstrated that oxidative stress, aging, DNA damage, and ultraviolet radiation can lead to AMD by affecting the autophagy function, cellular senescence, and immune-inflammatory response of retinal pigment epithelial (RPE) cells (Wang et al. Oxid Med Cell Longev. 2019).

[0007] The conventional standard treatments for stabilizing vision in patients with such eye diseases included laser photocoagulation, surgical vitrectomy, and photodynamic therapy with verteporfin. Currently, anti-vascular endothelial growth factor (anti-VEGF) therapies and their ability to restore vision in patients suffering from such eye vascular diseases have been widely used since the approval of Lucentis® (ranibizumab) in 2006 and Eylea® (aflibercept) in 2011.

[0008] However, such anti-VEGF treatments often resulted in off-target effects on healthy blood vessels. Thus, identifying molecular mismatches between healthy and diseased blood vessels would enable targeted therapies that selectively eliminate pathological vasculature while sparing blood vessels essential for physiological tissue function.

[0009] Another drawback of anti-VEGF standard therapies is that they require frequent (e.g., monthly or even twice-monthly intravitreal injections) and long-term administration to maintain visual improvement (Heier et al. Ophthalmology 2012;119:2537-48; the Comparison of Age-Related Macular Degeneration Treatment Trials [CATT] Research Group 2016 Ophthalmology 2016;123:1751-61). This has resulted in low patient compliance with this frequent treatment regimen.

[0010] There is also evidence that some patients experience a suboptimal response to anti-VEGF treatment, and that some patients do not respond to anti-VEGF treatment at all. See Brown DM, et al., Ophthalmology. 2013;120:2013-2022, and Nguyen-Khoa BA, et al., BMC Ophthalmol. 2012;12:11.

[0011] Thus, there is a need for the development of treatments for retinal vasculopathy that have advantages over standard treatments. Summary of the Invention

[0012] The present invention provides novel methods of treating DME or DR or AMD that have advantages over standard therapies.

[0013] The following are specifically contemplated as part of the invention of this disclosure: Embodiment 1. A method of treating a patient suffering from retinal vasculopathy comprising administering to the patient a therapeutically effective dose of a compound of formula I: TIFF2024516367000002.tif59134(R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid of a crystalline solid meglumine salt (compound-meglumine), wherein the therapeutically effective dose is up to 25ug of compound-meglumine per eye. Embodiment 2. The method of embodiment 1, wherein the meglumine in the crystalline solid meglumine salt of the compound of formula I is present in a stoichiometric ratio of 1 to 3. Embodiment 3. The method of embodiment 2, wherein the crystalline solid meglumine salt of the compound of formula I is stable at a temperature between 2° C. and 8° C. for greater than 12 months. Embodiment 4. The method of any of embodiments 1-3, wherein the patient has a baseline best corrected visual acuity (BCVA) of 70 to 20 letters on the Early Treatment Diabetic Retinopathy Study (ETDRS), or a baseline value of 20 / 40 to 20 / 400 on the Snellen chart. Embodiment 5. The method of any one of embodiments 1-4, wherein the patient has been previously treated with anti-vascular endothelial growth factor (anti-VEGF) therapy at baseline. Embodiment 6. The method of embodiment 5, wherein the previous treatment with an anti-VEGF therapy occurred in the preceding 6 month period. Embodiment 7. The method of embodiment 6, wherein the patient also exhibits a central subfield thickness (CST) of 350um or greater as measured by SD-OCT at baseline, 150μm or greater as measured by SD-OCT at baseline, 200μm or greater as measured by SD-OCT at baseline, 250μm or greater as measured by SD-OCT at baseline, 300μm or greater as measured by SD-OCT at baseline, or 350μm or greater as measured by SD-OCT at baseline. Embodiment 8. The method of any one of embodiments 1-7, wherein the patient has a hemoglobin A1C (HbA1C) of less than 12% at baseline, less than 11% at baseline, less than 10% at baseline, less than 9% at baseline, less than 8% at baseline, less than 7% at baseline, less than 6% at baseline, less than 5% at baseline, less than 4% at baseline, less than 3% at baseline, less than 2% at baseline, or less than 1% at baseline. Embodiment 9. The method of any of embodiments 1-8, wherein the patient has an intraocular pressure (IOP) of 23 mmHg or less at baseline, 22 mmHg or less at baseline, 21 mmHg or less at baseline, 20 mmHg or less at baseline, 19 mmHg or less at baseline, 18 mmHg or less at baseline, 17 mmHg or less at baseline, 16 mmHg or less at baseline, 15 mmHg or less at baseline, 14 mmHg or less at baseline, 13 mmHg or less at baseline, 12 mmHg or less at baseline, 11 mmHg or less at baseline, 10 mmHg or less at baseline, 9 mmHg or less at baseline, 8 mmHg or less at baseline, 7 mmHg or less at baseline, 6 mmHg or less at baseline, 5 mmHg or less at baseline, 4 mmHg or less at baseline, 3 mmHg or less at baseline, 2 mmHg or less at baseline, 1 mmHg or less at baseline. Embodiment 10. The method of any one of embodiments 1-19, wherein the therapeutically effective dose of compound-meglumine is 0.5ug, 1ug, 2ug, 2.5ug, 3ug, 4ug, 5ug, 6ug, 7ug, 8ug, 9ug, 10ug, 11ug, 12ug, 13ug, 14ug, 15ug, 16ug, 17ug, 18ug, 19ug, 20ug, 21ug, 22ug, 23ug, 24ug, or 25ug per eye. Embodiment 11. A therapeutically effective dose of compound-meglumine is 0.5 μg to 1 μg per eye, 1 μg to 2 μg per eye, 2 μg to 2.5 μg per eye, 2.5 μg to 3 μg per eye, 3 μg to 4 μg per eye, 4 μg to 5 μg per eye, 5 μg to 6 μg per eye, 6 μg to 7 μg per eye, 7 μg to 8 μg per eye, 8 μg to 9 μg per eye, 9 μg to 10 μg per eye, 10 μg to 11 μg per eye, 11 μg to 12 μg per eye, 12 μg to 14 μg per eye, 14 μg to 16 μg per eye, 15 μg to 17 μg per eye, 16 μg to 18 μg per eye, 17 μg to 19 μg per eye, 18 μg to 20 μg per eye, 19 μg to 21 μg per eye, 20 μg to 22 μg per eye, 21 μg to 24 μg per eye, 22 μg to 26 μg per eye, 23 μg to 27 μg per eye, 24 μg to 28 μg per eye, 25 μg to 29 μg per eye, 26 μg to 30 μg per eye, 27 μg to 31 μg per eye, 28 μg to 32 μg per eye, 29 μg to 33 μg per eye, 30 μg to 34 μg per eye, 31 μg to 35 μg per eye, 32 μg to 36 μg per eye, 33 μg to 37 μg per eye, 34 μg to 38 μg per eye, 35 μg to 39 μg per eye, 36 μ The method according to any one of embodiments 1 to 10, wherein the amount of the administered dose is 13 μg to 14 μg per eye, 14 μg to 15 μg per eye, 15 μg to 16 μg per eye, 16 μg to 17 μg per eye, 17 μg to 18 μg per eye, 18 μg to 19 μg per eye, 19 μg to 20 μg per eye, 20 μg to 21 μg per eye, 21 μg to 22 μg per eye, 22 μg to 23 μg per eye, 23 μg to 24 μg per eye, or 24 μg to 25 μg per eye. Embodiment 12. The method of any one of embodiments 1-11, wherein the therapeutically effective dose of compound-meglumine is 0.5-2ug per eye, 2-4ug per eye, 3-5ug per eye, 4-6ug per eye, 5-7ug per eye, 6-8ug per eye, 7-9ug per eye, 8-10ug per eye, 9-11ug per eye, 10-15ug per eye, 15-20ug per eye, 20-25ug per eye. Embodiment 13. The method of any one of embodiments 1-12, wherein the compound-meglumine is administered to the patient's eye first as a loading dose prior to administration of the therapeutically effective dose. Embodiment 14. The loading dose of compound-meglumine is 0.5 μg to 1 μg per eye, 1 μg to 2 μg per eye, 2 μg to 2.5 μg per eye, 2.5 μg to 3 μg per eye, 3 μg to 4 μg per eye, 4 μg to 5 μg per eye, 5 μg to 6 μg per eye, 6 μg to 7 μg per eye, 7 μg to 8 μg per eye, 8 μg to 9 μg per eye, 9 μg to 10 μg per eye, 10 μg to 11 μg per eye, 11 μg to 12 μg per eye, 13 μg to 14 μg per eye, 14 μg to 15 μg per eye, 15 μg to 16 μg per eye, 16 μg to 17 μg per eye, 17 μg to 18 μg per eye, 18 μg to 20 μg per eye, 19 μg to 21 μg per eye, 20 μg to 22 μg per eye, 21 μg to 24 μg per eye, 22 μg to 26 μg per eye, 23 μg to 27 μg per eye, 24 μg to 28 μg per eye, 25 μg to 29 μg per eye, 26 μg to 30 μg per eye, 27 μg to 31 μg per eye, 28 μg to 32 μg per eye, 29 μg to 40 μg per eye, 30 μg to 33 μg per eye, 31 μg to 34 μg per eye, 32 μg to 35 μg per eye, 33 μg to 36 μg per eye, 34 μg to 37 μg per eye, 35 μg to 38 μg per eye, 36 μg to The method according to embodiment 13, wherein the dose is 12 μg to 13 μg per eye, 13 μg to 14 μg per eye, 14 μg to 15 μg per eye, 15 μg to 16 μg per eye, 16 μg to 17 μg per eye, 17 μg to 18 μg per eye, 18 μg to 19 μg per eye, 19 μg to 20 μg per eye, 20 μg to 21 μg per eye, 21 μg to 22 μg per eye, 22 μg to 23 μg per eye, 23 μg to 24 μg per eye, or 24 μg to 25 μg per eye. Embodiment 15. The method of embodiment 13, wherein the loading dose of compound-meglumine is 0.5-2ug per eye, 2-4ug per eye, 3-5ug per eye, 4-6ug per eye, 5-7ug per eye, 6-8ug per eye, 7-9ug per eye, 8-10ug per eye, 9-11ug per eye, 10-15ug per eye, 15-20ug per eye, 20-25ug per eye. Embodiment 16. The method of any one of embodiments 13-15, wherein the total volume per eye of the loading dose of compound-meglumine is 50 ul. Embodiment 17. The method of any one of embodiments 1 to 13, wherein a therapeutically effective dose of the compound-meglumine is administered intravitreally to the patient's eye. Embodiment 18. The method of any one of embodiments 14-16, wherein a loading dose of compound-meglumine is administered intravitreally to the patient's eye. Embodiment 19. The method of any of embodiments 1-12, 17, wherein a therapeutically effective dose of compound-meglumine is administered intravitreally to the patient's eye every 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months. Embodiment 20. The method of any of embodiments 1-12, 17, wherein a therapeutically effective dose of the compound-meglumine is administered intravitreally to the patient's eye every 2-3 months, every 3-4 months, every 5-6 months, every 6-7 months, every 8-9 months, every 9-10 months, or every 11-12 months. Embodiment 21. The method of any of embodiments 1-12, 17, 19-20, wherein a therapeutically effective dose of compound-meglumine is administered intravitreally to the patient's eye as a single dose every 2 months, as a single dose every 3 months, as a single dose every 4 months, as a single dose every 5 months, as a single dose every 6 months, as a single dose every 7 months, as a single dose every 8 months, as a single dose every 9 months, as a single dose every 10 months, as a single dose every 11 months, or as a single dose every 12 months. Embodiment 22. The method of any of embodiments 1-12, 17, 19-20, wherein a therapeutically effective dose of the compound-meglumine is administered intravitreally to the patient's eye as a single dose every 2-3 months, as a single dose every 3-4 months, as a single dose every 5-6 months, as a single dose every 6-7 months, as a single dose every 8-9 months, as a single dose every 9-10 months, or as a single dose every 11-12 months. Embodiment 23. The method of any of embodiments 1-12, 17, 20-22, wherein the therapeutically effective dose of compound-meglumine is administered intravitreally to the patient's eye once as a single dose. Embodiment 24. The method of embodiment 23, wherein the therapeutically effective dose of the compound-meglumine is administered intravitreally to the patient's eye once as a single dose, without combination with a prior loading dose. Embodiment 25. The method of any of embodiments 13-16, 18, wherein the loading dose administered intravitreally to the patient's eye is administered as a monthly IVT injection for two months, or as a monthly IVT injection for three months, or as at least one IVT injection in two months, or as at least two IVT injections in two months, or as at least three IVT injections in two months, or as at least three IVT injections in three months, or as at least two IVT injections in three months. Embodiment 26. The method of embodiment 25, wherein the loading dose is followed by a break in treatment of at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months prior to administration of the therapeutically effective dose. Embodiment 27. The method of any of embodiments 1-26, wherein the patient exhibits a CST reduction of at least 40 μm from baseline, at least 50 μm from baseline, at least 60 μm from baseline, at least 70 μm from baseline, at least 80 μm from baseline, or at least 90 μm from baseline as measured by SD-OCT. Embodiment 28. The method of any of embodiments 1-27, wherein the patient further exhibits an absence of macular fluid compared to baseline when assessed by SD-OCT. Embodiment 29. The method of any of embodiments 1-27, wherein the patient further exhibits an absence of exudation compared to baseline when assessed by SD-OCT. Embodiment 30. The method of any of embodiments 1-29, wherein the patient does not require more than two anti-VEGF therapeutic rescues, or does not require more than three anti-VEGF therapeutic rescues, or does not require more than four anti-VEGF therapeutic rescues, or does not require more than five anti-VEGF therapeutic rescues. Embodiment 31 The method of embodiment 30, wherein the patient does not require any anti-VEGF rescue therapy. Embodiment 32. The method of any of embodiments 1-31, wherein the patient shows improvement in BCVA improvement compared to baseline of at least 5 ETDRS letters, BCVA improvement compared to baseline of at least 6 ETDRS letters, BCVA improvement compared to baseline of at least 7 ETDRS letters, BCVA improvement compared to baseline of at least 8 ETDRS letters, BCVA improvement compared to baseline of at least 9 ETDRS letters, BCVA improvement compared to baseline of at least 10 ETDRS letters, BCVA improvement compared to baseline of at least 15 ETDRS letters, or BCVA improvement compared to baseline of at least 20 ETDRS letters. Embodiment 33. The method of any of embodiments 1-32, wherein the patient exhibits a BCVA improvement of 5 to 7 ETDRS letters compared to baseline, a BCVA improvement of 6 to 8 ETDRS letters compared to baseline, a BCVA improvement of 7 to 9 ETDRS letters compared to baseline, a BCVA improvement of 10 to 15 ETDRS letters compared to baseline, a BCVA improvement of 15 to 20 ETDRS letters compared to baseline, a BCVA improvement of 20 to 25 ETDRS letters compared to baseline, or a BCVA improvement of 25 to 30 ETDRS letters compared to baseline. Embodiment 34. Patients have a decrease of at least 0.10 mm compared to baseline, all measured by fluorescein angiography (FA) or optical coherence tomography angiography (OCT-A). 2 or a reduction in the avascular area of ​​the eye of at least 0.20 mm compared to baseline 2 or a reduction in the avascular area of ​​the eye of at least 0.30 mm compared to baseline 2 or a reduction in the avascular area of ​​the eye of at least 0.40 mm compared to baseline 2 or a reduction in the avascular area of ​​the eye of at least 0.50 mm compared to baseline 2 A reduction in the avascular area of ​​the eye of at least 0.60 mm compared to baseline 2 A reduction in the avascular area of ​​the eye of at least 0.70 mm compared to baseline 2 A reduction in the avascular area of ​​the eye of at least 0.80 mm compared to baseline 2A reduction in the avascular area of ​​the eye of at least 0.90 mm compared to baseline 2 A reduction in the avascular area of ​​the eye of at least 1.0 mm compared to baseline 2 44. The method of any one of the preceding embodiments, wherein the subject exhibits a reduction in avascular area of ​​the eye. Embodiment 35. The method of any of embodiments 1-34, wherein the patient has a 2-stage improvement in Diabetic Retinopathy Severity Scale (DRSS) compared to baseline. Embodiment 36 The method of any of embodiments 1-35, wherein the patient exhibits regression of neovascularization compared to baseline as measured by FA or OCT-A. Embodiment 37. The method of any one of embodiments 1-36, wherein the retinal vasculopathy is diabetic macular edema (DME). Embodiment 38. The method of any one of embodiments 1 to 36, wherein the retinal vasculopathy is diabetic retinopathy (DR). Embodiment 39. The method of any one of embodiments 1 to 36, wherein the retinal vasculopathy is age-related macular degeneration (AMD). Embodiment 40. The method of any of embodiments 39, wherein the retinal vasculopathy is geographic atrophy (GA). Embodiment 41. The method of embodiment 38, wherein the patient also presented with non-proliferative diabetic retinopathy at baseline. Embodiment 42. The method of embodiment 38, wherein the patient also presented with proliferative diabetic retinopathy at baseline. [Brief description of the drawings]

[0014] [Figure 1] FIG. 1 shows a schematic diagram of the Phase I single ascending dose, safety and toxicity study as described in Example 1. [Diagram 2] FIG. 1 shows a schematic of a Phase 2a proof-of-concept study in DME as described in Example 2. [Diagram 3]Figure 1 shows the change from baseline in BCVA in DME patients as a result of the Phase I study described in Example 1. Note that aflibercept data taken from the published VISTA study is overlaid on the data for comparison purposes only. At all doses tested, 6 of 8 patients showed an increase in ETDRS letters from baseline at week 2. At week 4, 7 of 8 patients showed an increase in ETDRS letters from baseline, and at week 12, 6 of 8 patients showed an increase in ETDRS letters from baseline. [Figure 4] Figure 1 shows the change from baseline in BCVA in nAMD patients as a result of the Phase I study described in Example 1. At all doses tested, 3 of 4 patients showed an increase in ETDRS letters from baseline at week 2, and 2 of 4 patients showed an increase in ETDRS letters from baseline at week 4. At week 12, 2 of 4 patients showed an increase in ETDRS letters from baseline. Note that one patient was administered anti-VEGF rescue therapy. [Diagram 5] 1 shows the change from baseline in CST in DME patients as a result of the Phase I study described in Example 1. At all doses tested, 3 of 7 patients had a decrease in CST from baseline at week 2, and 2 of 7 patients showed a decrease from baseline at week 4. At week 12, 4 of 7 patients showed a decrease from baseline. [Figure 6] Figure 1 shows the change from baseline in CST in nAMD patients as a result of the Phase I study described in Example 1. At all doses tested, 2 out of 4 patients had a decrease in CST from baseline at week 2, and 3 out of 4 patients showed a decrease from baseline at week 4. At week 12, 3 out of 4 patients showed a decrease from baseline. Note that one patient was given anti-VEGF rescue therapy. [Figure 7] FIG. 1 shows a schematic of a Phase 2a proof-of-concept study in nAMD as described in Example 3. [Figure 8]1 shows the mean change in BCVA over 24 weeks in patients with DME as a result of a single injection of a compound of Formula I as described in the Phase I study disclosed in Example 1. [Figure 9] FIG. 1 shows the percentage of DME patients who achieved a threshold BCVA gain of either ≥5 letters or ≥10 letters, measured at weeks 4, 8, 12, and 24, after a single injection of a compound of Formula I in the Phase I study described in Example 1. [Figure 10] 1 shows the percentage of DME patients in the Phase I study described in Example 1 who did not meet Phase 2 DME rescue criteria (+75 μm or −10 ETDRS letters) with anti-VEGF therapy. [Figure 11] 1 shows the mean change in CST followed up to 24 weeks in a high dose cohort of eight DME patients after receiving a single injection of the compound of Formula I. See Example 1. [Figure 12] Figure 2 shows the plot change in BCVA measured by ETDRS for individual AMD patients in 10 patients at all doses tested. Five patients were given anti-VEGF rescue treatment, as indicated by the "gold" outline. See Example 1. [Figure 13] Figure 1 shows an intent-to-treat (ITT) analysis of the mean change in BCVA as measured by ETDRS letter count ± SEM in nine AMD patients (six AMD patients received anti-VEGF rescue treatment and three did not) at weeks 1, 2, 4, 8, 12, and 24 after a single injection of a compound of Formula I. See Example 1. [Figure 14] Figure 1 shows the intention to treat (ITT) analysis of the mean change in CST measured in μm±SEM in 10 AMD patients at 1, 2, 4, 8, 12, and 24 weeks after a single injection of a compound of formula I. See Example 1. [Figure 15] A comparison of the distribution of both the sodium salt form (Na salt) compared to the meglumine salt form in the vitreous humor, retina, and lens of New Zealand White rabbits is shown. See Example 4 and Table 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] Detailed Description of the Invention I. Definition The term "about" as used herein refers to the normal range of error for the respective value, which is readily known to one of ordinary skill in the art. Reference herein to "about" a value or parameter includes (and describes) embodiments that are directed to the value or parameter itself.

[0016] As used herein, "administering" refers to a method of providing a dose of the compound-meglumine to a patient suffering from retinal vasculopathy herein. The compositions utilized in the methods described herein can be administered, for example, intravitreally (e.g., by intravitreal injection), ocularly (e.g., by ocular injection), or intraocularly (e.g., by intraocular injection). The method of administration can vary depending on a variety of factors (e.g., the compound or composition being administered and the severity of the condition, disease, or disorder being treated).

[0017] As used herein, the term "anti-VEGF treatment" or "anti-VEGF therapy" refers to any currently approved anti-VEGF drug indicated for treating retinal vasculopathy. Such approved drugs include, for example, Lucentis® (ranibizumab) or Eylea® (aflibercept), and any approved biosimilar drug to ranibizumab or aflibercept.

[0018] As used herein, the term "baseline" in reference to a patient refers to the patient diagnosis presented to the attending medical practitioner prior to treatment according to the present invention.

[0019] As used herein, "best corrected visual acuity" (BCVA) refers to the measurement of the best corrected visual acuity that can be achieved using glasses or contact lenses. It can be measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol.

[0020] As used herein, "CST" refers to the change in central subfield thickness, also known as central foveal thickness, defined as the average thickness of the macula in a central 1 mm grid. Mean macular thickness is defined as the average of the thicknesses in nine sections. A clinically significant change in CST can be, for example, a reduction of 50 μm to 100 μm compared to baseline.

[0021] As used herein, the "Early Treatment of Diabetic Retinopathy Study" (ETDRS) is a type of measurement used to assess visual acuity when used in conjunction with improvement in letter count, where the geometric progression of symbols or letters used in the chart is called the logarithm of the minimum separation threshold angle (logMAR). Each row contains the same number of symbols or letters, and the value of each row is equal to 0.1 log units, or 25%, less than the preceding row (starting at the top of the chart). The patient is asked to read a series of letters of known height at a given distance, and the smallest legible letter read indicates the degree of near or distance visual acuity. This standardization allows for consistency in the assessment of near and distance visual acuity levels. Normal visual acuity is considered an ETDRS of 80 letters at a distance of 4 meters. A clinically meaningful improvement in the ETDRS is an increase of 10 to 15 letters in the ETDRS letter count at a distance of 4 meters compared to baseline.

[0022] As used herein, "exudate" or "retinal exudate" refers to lipid residues leaking from damaged capillaries that may appear in patients with DR, DME, or AMD. Specifically, the exudate that appears in AMD patients may be subretinal fluid (SRF). This originates from abnormal blood vessels leaking under the macula. Alternatively, the exudate that appears in AMD patients may be intraretinal fluid (IRF), which is increased retinal thickening associated with reduced retinal tissue reflectance to OCT. Finally, the exudate that appears in AMD patients may be cystoid edema. This multiple cystoid (cystoid) areas of fluid appear in the macula, causing retinal swelling or edema.

[0023] As used herein, "spectral domain optical coherence tomography" (SD-OCT) is a technique that provides high-resolution structural images with accurate retinal thickness measurements. It is the technique of choice for early detection of macular edema or retinal exudate and for follow-up of diabetic maculopathy.

[0024] As used herein, "hemoglobin A1c" (HbA1C) is a test that indicates a patient's average level of blood glucose over the past 2-3 months. It is also called the glycated hemoglobin test or glycated hemoglobin. HbA1C is commonly used to diagnose prediabetes and diabetes. Generally, normal HbA1C levels are below 5.7%, with levels of 5.7% to 6.4% generally indicating prediabetes and levels of 6.5% or higher generally indicating diabetes.

[0025] As used herein, "intraocular pressure" (IOP) is the fluid pressure inside the eye. IOP measurements are affected by corneal thickness and stiffness. Generally, normal intraocular pressure is understood to be between 10 mmHg and 20 mmHg.

[0026] As used herein, a "patient" when used alone (e.g., a "patient treated with a therapeutically effective dose of the compound-meglumine") refers to a patient suffering from a retinal vasculopathy. In contrast, a "DME patient" refers to a patient suffering from a specific retinal vasculopathy, DME. Additionally, an "AMD patient" refers to a patient suffering from a specific retinal vasculopathy, AMD. Additionally, a "DR patient" refers to a patient suffering from a specific retinal vasculopathy, DR.

[0027] As used herein, "retinal vasculopathy" refers to ocular diseases involving pathogenic angiogenesis, such as, for example, diabetic macular edema, diabetic retinopathy, and age-related macular degeneration. Other ocular diseases can include, for example, geographic atrophy.

[0028] As used herein, "treatment" ("treat" or "treating") refers to clinical intervention in an attempt to alter the natural course of the individual being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of the methods of treatment as claimed herein include, but are not limited to, preventing the occurrence or recurrence of DME, DR, or AMD, alleviating the symptoms of DME, DR, or AMD, reducing any direct or indirect pathological consequences of DME, DR, or AMD, slowing the rate of disease progression in DME, DR, or AMD, improving or alleviating the disease state in DME, DR, or AMD, and remission or improved prognosis for DME, DR, or AMD.

[0029] Compositions and methods The present invention provides methods for treating certain retinal vasculopathies, such as diabetic macular edema (DME), diabetic retinopathy (DR), and age-related macular degeneration (AMD).

[0030] DME is a complication of diabetic retinopathy (DR) following chronic, poorly controlled diabetes and is the most common form of sight-threatening retinopathy in people with diabetes. Approximately 1 in 14 patients with diabetes has some degree of DME. The World Health Organization reported in 2015 that the overall prevalence of DR in patients with diabetes using retinal imaging was estimated to be 35%, with sight-threatening DR present in 12%. The prevalence depends on the type of diabetes and the duration of the disease. After 25 years of duration, the prevalence is closer to 30% for both types of diabetes, type 1 diabetes and type 2 diabetes. In the United States, at least 5.5 million individuals over the age of 40 are estimated to have DR in the absence of DME, and an additional 800,000 to 1 million patients have DME. By some estimates, only 40% of them are diagnosed and treated, and about 5% are diagnosed and observed.

[0031] Diabetic macular edema (DME), macular thickening secondary to diabetic retinopathy (DR), results from blood-retinal barrier defects leading to vascular leakage and fluid accumulation. See Bhagat N, et al., Surv Ophthalmol. 2009;54:1-32. DME is associated with the expression of several inflammatory factors, including vascular endothelial growth factor (VEGF), intercellular adhesion molecule-1 (ICAM-1), interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1), and leukostasis. See Funatsu H, et al., Ophthalmology. 2009;116:73-79, and Miyamoto K, et al., Proc Natl Acad Sci USA. 1999;96:10836-10841. Moreover, the expression of these factors correlates with both disease severity as well as retinal vascular permeability, thus confirming their important pathogenetic role.

[0032] DR: The prevalence of diabetic retinopathy increases with age and is the most common cause of blindness in people over 50 years of age. It is a multifactorial disorder, and hyperglycemia exerts toxic effects on cells and inflammatory cytokines involved in many aspects of diabetic eye disease. Diabetic retinopathy involves thickening of the capillary basement membrane, preventing pericytes from contacting the endothelial cells of the capillaries. Loss of pericytes can increase capillary leakage and lead to breakdown of the blood-retinal barrier. Weakened capillaries can lead to aneurysm formation and further leakage. The duration and severity of hyperglycemia are factors related to the development of diabetic retinopathy. These effects of hyperglycemia can also impair nerve function in the retina. This is the early stage of diabetic retinopathy, called non-proliferative diabetic retinopathy.

[0033] Diabetic retinopathy is also a degenerative disease of the neural retina that is associated with alterations in neural function prior to the development of clinical vascular disease. Retinal capillaries can become occluded in diabetes causing areas of ischemia in the retina. The non-perfused tissue responds by inducing new blood vessel growth (i.e., neovascularization) from pre-existing vessels. These new vessels can also cause vision loss, a condition called proliferative diabetic retinopathy, because the new vessels are fragile and prone to leaking blood into the eye. In advanced proliferative diabetic retinopathy, the neovascular, VEGF-mediated response continues with retinal neovascularization, putting the eye at further risk of severe vision loss due to the development of vitreous hemorrhage or tractional retinal detachment. Irreversible vascular or neural damage is possible without treatment, highlighting the need for early intervention.

[0034] AMD Age-related macular degeneration (AMD) is a leading cause of visual impairment and severe vision loss. It ranks third among causes of visual impairment worldwide, with a prevalence of blindness of 8.7%.

[0035] AMD is a multifactorial disorder caused by the deterioration of the central portion of the retina, with dysregulation in complement, lipid, angiogenic, inflammatory, and extracellular matrix pathways involved in its pathogenesis. AMD pathology is characterized by the progressive accumulation of characteristic yellow deposits called drusen (e.g., accumulations of extracellular proteins and lipids) in the macula, between the retinal pigment epithelium and the underlying choroid, which are believed to damage the retina over time.

[0036] There are two basic types of AMD: "dry" and "wet". Approximately 85%-90% of AMD cases are "dry" (atrophic) type, or geographic atrophy (GA), and 10-15% are "wet" (exudative) type, or neovascular AMD (nAMD). Dry AMD is defined by the gradual loss of retinal pigment epithelium (RPE) and photoreceptor cells in the macula. Patients affected by dry AMD gradually lose central vision due to the death of photoreceptor cells and their close relatives, retinal pigment epithelium (RPE) cells, accompanied by the deposition of drusen. Wet AMD is characterized by abnormal blood vessel growth beneath the macular epithelium. Wet AMD results in vision loss due to abnormal blood vessel growth (e.g., choroidal neovascularization) in the choriocapillaris through Bruch's membrane. Clinically, it is classified as early (medium-sized drusen and retinal pigmentary changes) to late (neovascular and atrophic) stages.

[0037] Compositions of the Invention : It has recently been shown that pathological vasculature in the retina is selectively involved in cellular senescence (Crespo-Garcia et al., Cell Metabolism 2021, 33, 1-15). Senolytic Bcl-xL inhibitors with the potential to remove senescent cells from tissues without altering healthy resident cells in the eye have been developed for administration to patients suffering from DME, DR, and AMD. In this way, proinflammatory factors secreted by such senescent cells, i.e., senescence-associated secretory phenotype (SASP), are selectively removed.

[0038] In some embodiments of the claimed invention, the compound used to treat patients suffering from DME or DR or AMD is a crystalline solid meglumine salt of the compound of formula I (also known as "compound-meglumine"), The file is TIFF2024516367000003.tif58128.

[0039] The compound of formula I is also referred to as (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid. In another embodiment of the claimed invention, the compound-meglumine is used to treat a patient suffering from DME, DR, or AMD, and the meglumine is present in a stoichiometric ratio of 1 to 3. In another embodiment, the compound-meglumine is stable for 12 months or more at a temperature between 2° C. and 8° C. See International Application PCT / CN2020 / 127666, which is incorporated by reference in its entirety.

[0040] The compound of formula I is in the sodium salt form. It has been shown to be unstable at 2-8°C. As a potential commercial therapeutic, such instability is not feasible. Therefore, as disclosed in PCT / CN2020 / 127666, a more stable salt form of the compound, compound-meglumine, was created. To enable bridging data to regulatory agencies to allow substitution of compound-meglumine of the compound of formula I in clinical trials and beyond without compromising patient safety or efficacy, the pharmacokinetics of compound-meglumine were compared to the pharmacokinetics of the sodium salt form of the compound of formula I. See Example 4, Figure 15, and Table 1.

[0041] doseIn some embodiments of the claimed invention, the therapeutically effective dose of the compound-meglumine as described above used to treat DME, DR, AMD patients is about 0.5 μg per eye, about 1 μg per eye, about 2 μg per eye, about 2.5 μg per eye, about 3 μg per eye, about 4 μg per eye, about 5 μg per eye, about 6 μg per eye, about 7 μg per eye, about 8 μg per eye, about 9 μg per eye, about 10 μg per eye, about 11 μg per eye, about 12 μg per eye, about 13 μg per eye, about 14 μg per eye, about 15 μg per eye, about 16 μg per eye, about 17 μg per eye, about 18 μg per eye, about 19 μg per eye, about 20 μg per eye, about 21 μg per eye, about 22 μg per eye, about 23 μg per eye, about 24 μg per eye, about 25 μg per eye, about 26 μg per eye, about 27 μg per eye, about 28 μg per eye, about 29 μg per eye, about 30 μg per eye, about 31 μg per eye, about 32 μg per eye, about 33 μg per eye, about 34 μg per eye, about 35 μg per eye, about 36 μg per eye, about 37 μg per eye, about 38 μg per eye, about 39 μg per eye, about 40 ... about 9 μg, about 10 μg per eye, about 11 μg per eye, about 12 μg per eye, about 13 μg per eye, about 14 μg per eye, about 15 μg per eye, about 16 μg per eye, about 17 μg per eye, about 18 μg per eye, about 19 μg per eye, about 20 μg per eye, about 21 μg per eye, about 22 μg per eye, about 23 μg per eye, about 24 μg per eye, or about 25 μg per eye. In other embodiments, the total volume per eye of a therapeutically effective dose of compound-meglumine as described above is 50 μl.

[0042] In some embodiments of the claimed invention, the therapeutically effective dose of the compound-meglumine as described above used to treat DME, DR, or AMD is 0.5 μg to 1 μg per eye, 1 μg to 2 μg per eye, 2 μg to 2.5 μg per eye, 2.5 μg to 3 μg per eye, 3 μg to 4 μg per eye, 4 μg to 5 μg per eye, 5 μg to 6 μg per eye, 6 μg to 7 μg per eye, 7 μg to 8 μg per eye, 8 μg to 9 μg per eye, 9 μg to 10 μg per eye, 10 μg to 12 μg per eye, 15 μg to 16 μg per eye, 17 μg to 18 μg per eye, 18 μg to 19 μg per eye, 19 μg to 20 μg per eye, 20 μg to 25 μg per eye, 21 μg to 26 μg per eye, 22 μg to 27 μg per eye, 23 μg to 28 μg per eye, 24 μg to 29 μg per eye, 25 μg to 30 μg per eye, 26 μg to 31 μg per eye, 27 μg to 28 μg per eye, 28 μg to 29 μg per eye, 29 μg to 30 μg per eye, 30 μg to 31 μg per eye, 31 μg to 32 μg per eye, 32 μg to 33 μg per eye, 33 μg to 34 μg per eye, 34 μg to 35 μg per eye, 35 μg to 36 μg per eye, 36 μg to 37 μg per eye, 37 μg to 38 μg per eye, 38 μg to 39 μg per eye In another embodiment, the total volume per eye of a therapeutically effective dose of a compound-meglumine as described herein is 50 μl.

[0043] In other embodiments of the claimed invention, the therapeutically effective dose of compound-meglumine as described above used to treat DME, DR, or AMD is 0.5-2 μg per eye, 2-4 μg per eye, 3-5 μg per eye, 4-6 μg per eye, 5-7 μg per eye, 6-8 μg per eye, 7-9 μg per eye, 8-10 μg per eye, 10-15 μg per eye, 15-20 μg per eye, 20-25 μg per eye. In other embodiments, the total volume per eye of the therapeutically effective dose of compound-meglumine as described herein is 50 μl.

[0044] Methods for monitoring and diagnosing retinal vasculopathy Standardized ophthalmic examination techniques known in the art include detailed slit lamp biomicroscopic evaluation, which allows for evaluation of the central retinal anatomy, including, for example, the eyelids, ocular adnexa, eyelashes, corneal surface, anterior chamber, pupil, lens, vitreous cavity, and optic nerve and macula. Another method is gonioscopy, which allows for detailed examination of the anterior chamber angle. Indirect ophthalmoscopy allows for evaluation of the retinal periphery, which is important in monitoring vitreous and peripheral retinal disorders.

[0045] Functional tests of visual acuity are known in the art and include, for example, best corrected visual acuity, contrast visual acuity, and low light visual acuity, color vision (including Ishihara and Farnsworth-Munsell tests) and visual field assessment (including Humphrey Automated Perimetry and Microperimetry), tear production (Schirmer test), and tonometry to measure intraocular pressure (IOP). These are used in conjunction with structural tests, including, for example, anterior and posterior segment photography, corneal pachymetry, ultrasound, ultrasound biomicroscopy, optical coherence tomography (OCT), optical coherence tomography angiography (OCTA), fluorescein angiography (FA), intravenous fluorescein angiography (IVFA), and fundus autofluorescence (FAF). Imaging, such as computed tomography (CT) or magnetic resonance imaging (MRI) scans, are utilized to evaluate ocular, periocular, and orbital structures, as well as the optic nerve, visual pathways, and intracranial portions of the visual cortex in the brain. These tests allow visualization of the structural integrity and thickness of layers of the eye and surrounding structures, as well as assessment of blood flow and circulation. Advanced functional tests of the retina, optic nerve, and visual pathway / visual cortex, including electrophysiological tests such as full-field and multifocal electroretinograms, visual evoked potentials, and microperimetry, are also used to diagnose and monitor disease progression and the effects of therapy. Those skilled in the art will be able to deploy appropriate methodologies known in the art to diagnose, measure, and monitor the retinal vasculopathy described herein.

[0046] patient In some embodiments of the claimed invention, a therapeutically effective dose of the compound-meglumine as described above for use in treating patients suffering from DME is administered to a patient who not only suffers from DME but also has diabetic retinopathy (DR). In other embodiments, the DME patient suffers from not only DME but also non-proliferative DR. In other embodiments, the DME patient suffers from proliferative DR.

[0047] In some embodiments of the claimed invention, a therapeutically effective dose of compound-meglumine as described above is used to treat a patient suffering from AMD. Specifically, the AMD patient may suffer from dry AMD or GA. Specifically, the AMD patient may suffer from wet AMD or nAMD. In other embodiments of the claimed invention, the AMD patient treated with a therapeutically effective dose of compound-meglumine as described above has a baseline best corrected visual acuity (BCVA) of 70 to 20 letters on the Early Treatment of Diabetic Retinopathy Study (ETDRS) or a baseline value of 20 / 40 to 20 / 400 on the Snellen chart before treatment.

[0048] In some embodiments of the claimed invention, DME, DR, or AMD patients treated with a therapeutically effective dose of compound-meglumine as described above have been previously treated with an anti-vascular endothelial growth factor (anti-VEGF) therapy prior to treatment with the claimed invention. In other embodiments, as described herein, the previous treatment with an anti-VEGF therapy occurred in the preceding 6 month period prior to treatment with the method of the claimed invention. In other embodiments, in addition to having a previous treatment with an anti-VEGF therapy, the DME, DR, or AMD patient also exhibited a central subfield thickness (CST) of 350 um or greater as measured by SD-OCT at baseline prior to treatment with the method of the claimed invention.

[0049] In some embodiments of the claimed invention, DME, DR, or AMD patients treated with a therapeutically effective dose of compound-meglumine as described above have a hemoglobin A1C (HbA1C) of less than 12% at baseline, less than 11% at baseline, less than 10% at baseline, less than 9% at baseline, less than 8% at baseline, less than 7% at baseline, less than 6% at baseline, less than 5% at baseline, less than 4% at baseline, less than 3% at baseline, less than 2% at baseline, or less than 1% at baseline, 3 months prior to treatment with the methods of the claimed invention.

[0050] In some embodiments of the claimed invention, DME, DR, or AMD patients treated with a therapeutically effective dose of compound-meglumine as described above have a baseline blood glucose level of 23 mmHg or less, 22 mmHg or less, 21 mmHg or less, 20 mmHg or less, 19 mmHg or less, 18 mmHg or less, 17 mmHg or less, 16 mmHg or less, 15 mmHg or less, or 26 mmHg or less, or 27 mmHg or less, or 28 mmHg or less, or 29 mmHg or less, or 30 mmHg or less, or 31 mmHg or less, or 32 mmHg or less, or 33 mmHg or less, or 34 mmHg or less, or 35 mmHg or less, or 36 mmHg or less, or 37 mmHg or less, or 38 mmHg or less, or 39 mmHg or less, or 40 mmHg or less, or 41 mmHg or less, or 42 mmHg or less, or 43 mmHg or less, or 44 mmHg or less, or 45 mmHg or less, or 46 mmHg or less, or 47 mmHg or less, or 48 mmHg or less, or 49 mmHg or less, or 50 mmHg or less, or 51 mmHg or less, or 52 mmHg or less, or 53 mmHg or less, or 54 mmHg or less, or 55 mmHg or less, or 56 mmHg or less, or 57 mmHg or less, or 58 mmHg or less, or 59 mmHg or less, or 60 mmHg or less, or 61 mmHg or less, or 62 mmHg or less, or 63 mmHg or less, or 64 mmHg or Have an intraocular pressure (IOP) of the following: 14mmHg or less at baseline, 13mmHg or less at baseline, 12mmHg or less at baseline, 11mmHg or less at baseline, 10mmHg or less at baseline, 9mmHg or less at baseline, 8mmHg or less at baseline, 7mmHg or less at baseline, 6mmHg or less at baseline, 5mmHg or less at baseline, 4mmHg or less at baseline, 3mmHg or less at baseline, 2mmHg or less at baseline, 1mmHg or less at baseline.

[0051] In some embodiments of the claimed invention, DME, DR, or AMD patients treated with a therapeutically effective dose of compound-meglumine as described above, the patient exhibited a central subfield thickness (CST) of 100 μm or more as measured by SD-OCT at baseline, 150 μm or more as measured by SD-OCT at baseline, 200 μm or more as measured by SD-OCT at baseline, 250 μm or more as measured by SD-OCT at baseline, 300 μm or more as measured by SD-OCT at baseline, or 350 μm or more as measured by SD-OCT at baseline, prior to treatment with the method of the claimed invention.

[0052] AdministrationIntravitreal (IVT) is a route of administration of drugs, such as the compound-meglumine described herein, in a procedure in which the drug is placed directly into the space at the back of the eye called the vitreous cavity, which is filled with a jelly-like liquid called vitreous humor gel. The procedure is usually performed by a trained retina specialist in an office setting. In some embodiments of the claimed invention, a therapeutically effective dose of the compound-meglumine used to treat DME, DR, or AMD, as described above, is administered intravitreally to the patient's eye. In other embodiments, a therapeutically effective dose of the compound-meglumine used to treat DME, DR, or AMD, as described above, is administered as a single IVT dose to the patient's eye.

[0053] In some embodiments of the claimed invention, the compound-meglumine as described above is first administered intravitreally to the eye of a DME, DR, or AMD patient as a loading dose prior to administration of a therapeutically effective dose as described above. In such cases, the loading dose of the compound-meglumine as described above used to treat a DME, DR, or AMD patient is about 0.5 μg per eye, about 1 μg per eye, about 2 μg per eye, about 2.5 μg per eye, about 3 μg per eye, about 4 μg per eye, about 5 μg per eye, about 6 μg per eye, about 7 μg per eye, about 8 μg per eye, about 9 μg per eye, about 10 μg per eye, about 12 μg per eye, about 14 μg per eye, about 16 μg per eye, about 17 μg per eye, about 18 μg per eye, about 19 μg per eye, about 20 μg per eye, about 21 μg per eye, about 22 μg per eye, about 23 μg per eye, about 24 μg per eye, about 25 μg per eye, about 26 μg per eye, about 27 μg per eye, about 28 μg per eye, about 29 μg per eye, about 30 μg per eye, about 31 μg per eye, about 32 μg per eye, about 33 μg per eye, about 34 μg per eye, about 35 μg per eye, about 36 μg per eye, about 37 μg per eye, about 38 μg per eye, about 39 μg per eye, about 40 ... about 10 μg per eye, about 11 μg per eye, about 12 μg per eye, about 13 μg per eye, about 14 μg per eye, about 15 μg per eye, about 16 μg per eye, about 17 μg per eye, about 18 μg per eye, about 19 μg per eye, about 20 μg per eye, about 21 μg per eye, about 22 μg per eye, about 23 μg per eye, about 24 μg per eye, or about 25 μg per eye. In other embodiments, the total volume per eye of the compound-meglumine loading dose as described above is 50 μl.

[0054] In yet other embodiments of the claimed invention, the compound-meglumine as described above is administered intravitreally to the eye of a DME, DR, or AMD patient first as a loading dose prior to administration of a therapeutically effective dose as described above. In such cases, the loading dose of the compound-meglumine as described above used to treat a DME, DR, or AMD patient is 0.5-2 μg per eye, 2-4 μg per eye, 3-5 μg per eye, 4-6 μg per eye, 5-7 μg per eye, 6-8 μg per eye, 7-9 μg per eye, 8-10 μg per eye, 10-15 μg per eye, 15-20 μg per eye, 20-25 μg per eye. In other embodiments, the total volume per eye of the loading dose of the compound-meglumine as described herein is 50 μl.

[0055] In some embodiments of the claimed invention, the compound-meglumine as described above is first administered intravitreally to the eye of a DME, DR, or AMD patient as a loading dose prior to administration of a therapeutically effective dose as described below. In such cases, the loading dose is administered intravitreally to the eye of a DME, DR, or AMD patient as a monthly IVT injection for two months, or as a monthly IVT injection for three months, or as at least one IVT injection in two months, or as at least two IVT injections in two months, or as at least three IVT injections in two months, or as at least three IVT injections in three months, or as at least two IVT injections in three months. In other embodiments of the claimed invention, the compound-meglumine as described above is first administered intravitreally to the eye of a DME, DR, or AMD patient as a loading dose before administering a therapeutically effective dose, as described below, and then a break in treatment of at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months is imposed before administering a therapeutically effective dose, as described below.

[0056] In some embodiments of the claimed invention, a therapeutically effective dose of the compound-meglumine as described above is administered intravitreally to the eye of a DME, DR, or AMD patient every 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. In other embodiments, a therapeutically effective dose of the compound-meglumine as described above is administered intravitreally to the eye of a DME, DR, or AMD patient every 2-3, 3-4, 5-6, 6-7, 8-9, 9-10, or 11-12 months. In other embodiments of the claimed invention, a therapeutically effective dose of the compound-meglumine as described above is administered intravitreally to the eye of a DME, DR, or AMD patient as a single dose every 2 months, a single dose every 3 months, a single dose every 4 months, a single dose every 5 months, a single dose every 6 months, a single dose every 7 months, a single dose every 8 months, a single dose every 9 months, a single dose every 10 months, a single dose every 11 months, or a single dose every 12 months. In other embodiments, a therapeutically effective dose of the compound-meglumine as described above is administered intravitreally to the eye of a DME, DR, or AMD patient as a single dose every 2-3 months, a single dose every 3-4 months, a single dose every 5-6 months, a single dose every 6-7 months, a single dose every 8-9 months, a single dose every 9-10 months, or a single dose every 11-12 months.

[0057] In other embodiments, a therapeutically effective dose of compound-meglumine as described above is administered intravitreally once as a single dose to the eye of a DME, DR, or AMD patient, either in combination with or without a prior loading dose as described above.

[0058] EffectivenessIn some embodiments, the methods of the claimed invention described herein result in DME, DR, or AMD patients exhibiting a CST reduction, as measured by SD-CST, of at least 40 μm from baseline after being treated with a method of the invention, at least 50 μm from baseline after being treated with a method of the invention, at least 60 μm from baseline after being treated with a method of the invention, at least 70 μm from baseline after being treated with a method of the invention, at least 80 μm from baseline after being treated with a method of the invention, or at least 90 μm from baseline after being treated with a method of the invention.

[0059] In other embodiments, the methods of the claimed invention described herein provide that after being treated with the methods of the invention, DME, DR, or AMD patients exhibit an absence of macular fluid compared to baseline when assessed by SD-OCT.

[0060] In some embodiments, the methods of the claimed invention described herein result in a DME, DR, or AMD patient not needing more than two anti-VEGF therapeutic rescues, or not needing more than three anti-VEGF therapeutic rescues, or not needing more than four anti-VEGF therapeutic rescues, or not needing more than five anti-VEGF therapeutic rescues. In still other embodiments, the methods of the claimed invention described herein result in a patient not needing any anti-VEGF therapeutic rescues at all.

[0061] In some embodiments, the methods of the claimed invention described herein result in DME, DR, or AMD patients showing improvement in BCVA improvement of at least 5 ETDRS letters compared to baseline, or at least 6 ETDRS letters compared to baseline, or at least 7 ETDRS letters compared to baseline, or at least 8 ETDRS letters compared to baseline, or at least 9 ETDRS letters compared to baseline, or at least 10 ETDRS letters compared to baseline, or at least 15 ETDRS letters compared to baseline, or at least 20 ETDRS letters compared to baseline. In other embodiments, the methods of the claimed invention described herein result in DME, DR, or AMD patients exhibiting a BCVA improvement of 5 to 7 ETDRS letters compared to baseline, a BCVA improvement of 6 to 8 ETDRS letters compared to baseline, a BCVA improvement of 7 to 9 ETDRS letters compared to baseline, a BCVA improvement of 10 to 15 ETDRS letters compared to baseline, a BCVA improvement of 15 to 20 ETDRS letters compared to baseline, a BCVA improvement of 20 to 25 ETDRS letters compared to baseline, or a BCVA improvement of 25 to 30 ETDRS letters compared to baseline.

[0062] In some embodiments, the methods of the claimed invention described herein provide for patients with DME, DR, or AMD to have a decrease in blood flow of at least 0.10 mm compared to baseline, all as measured by fluorescein angiography (FA) or optical coherence tomography angiography (OCT-A). 2 or a reduction in the avascular area of ​​the eye of at least 0.20 mm compared to baseline 2 or a reduction in the avascular area of ​​the eye of at least 0.30 mm compared to baseline 2 or a reduction in the avascular area of ​​the eye of at least 0.40 mm compared to baseline 2 or a reduction in the avascular area of ​​the eye of at least 0.50 mm compared to baseline 2A reduction in the avascular area of ​​the eye of at least 0.60 mm compared to baseline 2 A reduction in the avascular area of ​​the eye of at least 0.70 mm compared to baseline 2 A reduction in the avascular area of ​​the eye of at least 0.80 mm compared to baseline 2 A reduction in the avascular area of ​​the eye of at least 0.90 mm compared to baseline 2 A reduction in the avascular area of ​​the eye of at least 1.0 mm compared to baseline 2 This results in a reduction in the avascular area of ​​the eye.

[0063] In other embodiments, the methods of the claimed invention described herein result in a DME, DR, or AMD patient having a 2-step improvement in the Diabetic Retinopathy Severity Scale (DRSS) compared to baseline.

[0064] In yet other embodiments, the methods of the claimed invention described herein result in DME, DR, or AMD patients exhibiting regression of neovascularization compared to baseline as measured, for example, by FA or OCT-A. EXAMPLES

[0065] The following are examples of methods and compositions of the present invention. Given the general description provided above, it will be understood that various other embodiments may be practiced.

[0066] Example 1: Evaluation of safety and tolerability studies of the compound of formula I in patients with diabetic macular edema or neovascular age-related macular degeneration This is a Phase 1, open-label, first-in-human (FIH), single ascending dose (SAD) study consisting of approximately four cohorts. The total number of patients was at least three patients per cohort, plus three additional patients in the maximum tolerated dose (MTD) cohort. The compound of formula I was administered intravitreally, and all patients were followed for approximately six months.

[0067] The rationale for enrolling patients with DME in the first-in-human trial is based on the fact that IVT injections are an invasive procedure that is not risk-free. As with other IVT-injected drugs approved by the FDA, this trial enrolled patients with DME to establish the pharmacology, safety, and preliminary efficacy of the drug in the disease population due to the potential risks posed by IVT injections. Single-dose toxicity is being tested using the proposed route of administration in the target population. In addition, this was designed to determine the safety profile of different doses and determine if there were any dose-limiting toxicities (DLTs).

[0068] Patients enrolled in the FIH study are those diagnosed with DME (as defined by the AAO PPP DME Guidelines

[2019] ) with a BCVA of 35 letters on the ETDRS (corresponding to 20 / 200 on the Snellen chart) or less in the study eye and visual acuity in the non-study eye better than 35 letters on the ETDRS (20 / 200 on the Snellen chart). Enrolled patients may also have non-proliferative diabetic retinopathy (NPDR) with DME, who, in the opinion of the investigator, are unlikely to benefit from or have failed current treatment options and therefore no significant additional harm is expected. Other inclusion and exclusion criteria ensure that those enrolled do not have retinal diseases other than DME that may impair BCVA, prevent BCVA improvement, require medical or surgical intervention during the study period, confound the interpretation of the results, or interfere with the evaluation of toxicity of the ophthalmological evaluation in the study eye. Patients enrolled were not selected because they had any condition, including laboratory findings and medical history or findings in the pre-study evaluation, that, in the opinion of the Investigator, constituted a risk or contraindication to participation in the study, or that might interfere with the study objectives, conduct, or evaluations, or that might prevent the patient from participating fully in all aspects of the study.

[0069] Escalation from a single dose of 0.5 μg, 1.0 μg, 2.5 μg, or 5.0 μg of the compound of formula I in a 50 μL injection volume was designed to limit FIH exposure to doses with a >5-fold margin against PAD of the compound of formula I in mice and not exceed a >2-fold safety margin against the NOAEL. The design allowed for detection of unexpected acute toxicity in sentinel patients, followed by detailed review of all available data by a Safety Assessment Committee (SAC) before adding additional patients to dose groups. See Figure 1.

[0070] Inclusion Criteria: - Patients with non-proliferative diabetic retinopathy (DR) or nAMD who have DME. • Active choroidal neovascularization (CNV) associated with age-related macular degeneration as evidenced by FA and SD-OCT on day 1, including DME involving the fovea with a central subfield thickness (CST) ≥ 350 μm for SD-OCT and nAMD, and the presence of intraretinal or subretinal fluid. • Early Treatment Diabetic Retinopathy Study (ETDRS) with BCVA of 55 letters or less in the study eye (most affected) at screening and day 1. • Patients who are capable of giving informed consent and who are willing and able to submit to all study-related procedures and assessments.

[0071] Exclusion criteria: Any ocular / intraocular / periocular infection or inflammation in either eye. • History of vitreous hemorrhage in the study eye within 2 months prior to screening, and subretinal hemorrhage with an area of ​​hemorrhage ≥ 4 papillary areas in the study eye. • Any retinal vascular disease or retinal degeneration other than DME or nAMD in the study eye. History of systemic and intraocular steroid use for 6 months prior to Day 1. Use of intravitreal non-biodegradable steroid implants (e.g., Iluvien®, Yutiq®, Retisert®) is prohibited. • Significant ocular opacities, including cataracts, that may interfere with VA, toxicity assessment, or fundus imaging. Any uncontrolled medical condition that, in the opinion of the Investigator, would prevent participation in this study.

[0072] At the end of the Phase I study, data demonstrated that no adverse events attributable to the compound of formula I were noted at any of the doses tested. Compound of formula I at doses up to 10 μg was well tolerated with a favorable safety profile through 24 weeks. No dose-limiting toxicity was observed, and there was no evidence of acute inflammation, infection, increased IOP, or bleeding. A total of two non-serious, non-drug-related AEs were reported.

[0073] Overall, at all doses tested, 10 of the 12 DME and nAMD patients in the study showed an increase in ETDRS letters from baseline at 2 weeks, as did 9 of the 12 patients at 4 weeks. At 12 weeks, 8 of the 12 DME and nAMD patients showed an increase in ETDRS letters from baseline. In the higher dose cohorts of 5ug and 10ug, 6 of 6 patients showed an increase in ETDRS letters from baseline at 2 weeks, and 5 of 6 patients at 4, 8, and 12 weeks. See Figure 3 for DME patients and Figure 4 for nAMD patients. At 24 weeks, 8 of the 12 DME patients showed a sustained increase in ETDRS letters as measured by the mean change in BCVA. See Figure 8. This sustained BCVA increase after a single injection of the compound of formula I is also shown graphically in Figure 9 when assessed at 4, 8, 12, and 24 weeks.

[0074] In the AMD patients studied, rapid improvement in BCVA was observed after a single injection of the compound of Formula I, which appeared to either improve or stabilize through six months after injection. See Figures 12 and 13. Among the six AMD patients who received anti-VEGF rescue treatment, there was minimal change in either mean BCVA, see Figures 12 and 13. Note that in Figure 13, the intention-to-treat (ITT) analysis excluded one patient, 235-0020, who received anti-VEGF rescue treatment, whose individual plot is shown in Figure 12.

[0075] Additionally, at all doses tested, 6 of 12 DME and nAMD patients in the study showed a decrease in CST from baseline at 2 weeks, 5 of 12 patients showed a decrease at 4 weeks, 8 of 12 patients showed a decrease at 8 weeks, and 5 of 10 patients showed a decrease at 12 weeks. In the higher dose cohorts of 5ug and 10ug, 4 of 6 patients showed a decrease in CST from baseline at 2 weeks, 3 of 6 patients showed a decrease at 4 weeks, 5 of 6 patients showed a decrease at 8 weeks, and 3 of 5 patients showed a decrease at 12 weeks. See Figure 5 for DME patients and Figure 6 for nAMD patients. At 24 weeks, the 8 DME patients in the higher dose cohort showed a mean CST that appeared to return to baseline. See Figure 11. Of the nine AMD patients analyzed, including six who received anti-VEGF rescue and three who did not, there was minimal change in mean CST over 24 weeks, see FIG. 14, demonstrating improvement or stabilization of CST over 24 weeks after a single injection of the compound of formula I.

[0076] Additionally, FIG. 10 shows that after a single injection of a compound of Formula I, 62.5% of DME patients in this study did not meet Phase 2 DME rescue criteria with anti-VEGF therapy, being +75um or -10 ETDRS letters, through 6 months.

[0077] A single IVT injection of up to 10 μg of the compound of Formula I was safe and well tolerated in patients with advanced DME or nAMD through 12 and 24 weeks. Disease-related biological activity was observed by increased BCVA, decreased CST, intraretinal, and subretinal fluid in this patient population.

[0078] Example 2: Evaluation of the safety and biological activity following a single intravitreal injection of a compound of formula I in patients with DME A phase 2a, proof-of-concept (POC), prospective, multicenter, randomized, single-blind, sham-controlled study was conducted to evaluate the safety, tolerability, and evidence of activity of a single IVT injection of the compound of formula I in subjects with DME. A total of about 62 patients will be enrolled 1:1 in the study or sham study arm to evaluate the primary objective. All patients will be followed for about 24 weeks. See Figure 2.

[0079] The primary efficacy endpoint is the change from baseline in CST at week 24 as assessed by SD-OCT. SD-OCT imaging data will be evaluated by the reading center. The primary efficacy endpoint will be analyzed by mixed models for repeated measures (MMRM).

[0080] Patients were diagnosed with DME (as defined by the AAO PPP DME Guidelines 2019) with a BCVA of 70-20 letters on the ETDRS (corresponding to 20 / 40-20 / 400 on the Snellen Chart) in the study eye and visual acuity better than 35 letters on the ETDRS (20 / 200 on the Snellen Chart) in the non-study eye.

[0081] The planned dose of the compound of Formula I is 5 μg, escalated to 10 μg following favorable safety data in the Phase 1 SAD study described in Example 1.

[0082] Inclusion Criteria: To be included in this study, each individual must meet all of the following criteria: 1.Patients aged 18 years or older. 2. Patients with non-proliferative DR and DME who have received at least 3 anti-VEGF treatments in the preceding 6 months prior to Day 1, with the last anti-VEGF given 3-5 weeks prior to Day 1. 3. DME involving the fovea with central subfield thickness (CST) ≥ 350 μm on SD-OCT at screening. 4. BCVA in the study eye (most affected) at Screening and Day 1 of 70–20 letters on the ETDRS (corresponding to 20 / 40–20 / 400 on the Snellen chart), at the discretion of the investigator if both eyes are equal. 5. BCVA in the non-test eye is ≥35 letters on the ETDRS (equivalent to 20 / 200 on the Snellen chart). 6. IOP ≤ 23mmHg in the study eye. 7. Clear optics and adequate pupil dilation to allow for CFP and proper BCVA assessment. 8. Patient is capable of giving informed consent and is willing and able to submit to all study-related procedures and evaluations.

[0083] Exclusion Criteria: If an individual meets any of the following criteria, he or she is ineligible for this study: 1. Concurrent disease or structural damage in the study eye, other than DME, that may impair BCVA, prevent BCVA improvement, require medical or surgical intervention during the study, confound interpretation of results, or interfere with evaluation of toxicity or CFP in the study eye. This includes, but is not limited to: Macular edema of non-diabetic etiology Clinically significant subretinal fibrosis ·Subfoveal lipids Cataracts requiring surgery during the study period RPE atrophy or tears or ruptures involving the macula Clinically significant macular hole Clinically significant non-infectious uveitis Vitreomacular traction Clinically significant epiretinal membrane (ERM) Aphakia · Pseudophakia with anterior chamber intraocular lens (A / C IOL) 2. HbA1c ≥ 12 and / or recent evidence of uncontrolled diabetes 3. Any ocular / intraocular / periocular infection or inflammation in either eye in the past 4 weeks prior to screening (mild blepharitis is permitted) 4. History of vitreous hemorrhage in the study eye within 2 months prior to screening 5. History of IVT, subconjunctival, or periocular steroids in the 3 months prior to screening 6. History of vitrectomy in the study eye 7. History of intraocular, periocular, or corneal surgery in the study eye within 3 months prior to screening, or anticipated need for such surgery during the study. 8. History of panretinal photocoagulation (within 6 months) or macular laser photocoagulation (within 3 months) in the test eye prior to administration 9. History of corneal transplant in the study eye 10. Concomitant use of more than two medications for the treatment of glaucoma and unstable glaucoma in the study eye (i.e., inadequate IOP control). 11. Any condition, including laboratory findings and medical history or findings in the pre-study evaluation, that in the opinion of the Investigator, constitutes a risk or contraindication to participation in the study or that may interfere with the study objectives, conduct, or evaluation, or that may prevent the patient from participating fully in all aspects of the study. 12. Presence of severe myopia (-8 diopters or greater) in the study eye 13. History of systemic and intraocular steroid use for 6 months prior to Day 1. Use of intravitreal non-biodegradable steroid implants (e.g., Iluvien®, Yutiq®, Retisert®) is prohibited. 14. Significant ocular opacities, including cataracts, that may interfere with visual acuity, toxicity assessment, or fundus imaging 15. Intraocular surgery, including cataract surgery, in the study eye within 3 months of screening 16. Known allergy to dyes injected during FA 17. Known allergies to any of the components of the compound of formula I (phosphate buffered saline and polysorbate 80) 18. Female patients of childbearing potential who are pregnant, nursing, or who do not agree to use highly effective methods of contraception (e.g., progesterone-only hormonal contraception, double barrier, or intrauterine device) during the study and for 3 months after the last dose of a compound of Formula I. Postmenopausal women (>45 years of age and no menses for >1 year) and women who have been surgically sterilized are exempt from these requirements. 19. Male patients who, if sexually active with a female partner of childbearing potential, do not agree to use highly effective methods of contraception for 3 months after the study and the last dose of a compound of formula I. 20. Patients who have received or are concurrently receiving another investigational drug or vaccine trial within 3 months of screening, including patients who have previously received treatment in a trial using a compound of Formula I. 21. Any uncontrolled medical condition that, in the opinion of the investigator, would prevent participation in this study, including but not limited to, history of malignancy within the past 3 years (except non-facial, basal cell carcinoma is permitted), history of myocardial infarction within the past 6 months, or concomitant therapy.

[0084] The compound of formula I is administered via IVT injection.After IVT injection, the patient is monitored for elevated IOP, reduced optic nerve head perfusion, and possible injection complications (e.g., vitreous hemorrhage, retinal breaks, etc.).In addition, the patient should immediately report any symptoms that indicate endophthalmitis, such as eye pain, swelling, redness, opacity, and gradual loss of vision.

[0085] The control is a sham procedure (i.e., needle-free, empty sterile syringe) contacted to the surface of the test eye to mimic an IVT injection. Patients may be prescribed prophylactic antibiotic eye drops after the study or a sham procedure according to the institution's preferred practice pattern and documented.

[0086] Permitted Treatments: Permitted concomitant treatments in / for the study eye and sham eye include: ·Local antibiotics administered prophylactically via IVT injection and local / systemic antibiotics used to treat AE. Artificial tears Steroid use is permitted only under the following conditions: Topically (e.g., for treating atopic dermatitis), by inhalation (e.g., for treating asthma), or by local injection (e.g., for epidural or joint injection) -Topical steroids in the fellow eye -Topical use of steroids for treatment of inflammation (e.g., uveitis) in the study eye. Concomitant intravitreal therapy in the fellow eye is permitted but cannot be administered within 7 days of treatment with the blinded study medication.

[0087] Prohibited Treatments: There are no known contraindications to administration of a compound of Formula I. Once randomized into this study, patients are not permitted to receive any treatment for management of DME in the study eye, unless it is rescue treatment. Systemic (oral, intramuscular, and intravenous) steroids are not permitted unless for adverse event (AE) treatment. All systemic steroids should be discontinued prior to study drug administration. Patients should not be receiving any therapy that would interfere with IVT injections. Patients are prohibited from receiving any medications for the study eye that, in the opinion of the Investigator and / or Medical Monitor, may affect the study results.

[0088] Example 3: Phase 2a Evaluation of Safety, Tolerability, and Evidence of Activity Following a Single Intravitreal Injection of a Compound of Formula I in Patients with nAMD This is a Phase 2a proof-of-concept (POC) study. To evaluate the primary objective, the total number of patients is about 40 patients who will be enrolled and randomized 1:1 to either the compound of formula I or a sham test arm. All patients will be followed for about 16 weeks.

[0089] The objective of this Phase 2a study is to evaluate the local and systemic safety and tolerability following a single IVT injection of the compound of Formula I compared to sham at weeks 8 and 16. The primary endpoint of this Phase 2a study is to determine the ocular and systemic safety and tolerability of a single IVT injection of the compound of Formula I as assessed by treatment-emergent adverse events (TEAEs). Secondary endpoints are to evaluate biological activity, efficacy parameters, and retinal structural improvement following a single IVT injection of the compound of Formula I. Specifically, the study will investigate the proportion of patients requiring two or more anti-VEGF rescues over 8 and 16 weeks, duration of effect as measured by time from randomization to receipt of standard of care as determined by the investigator based on rescue criteria, change in BCVA from baseline to weeks 8 and 16, change in CST from baseline to weeks 8 and 16 as assessed by SD-OCT, change in retinal fluid from baseline to weeks 8 and 16 as assessed by SD-OCT, and the proportion of patients with absence of exudation: subretinal fluid (SRF), intraretinal fluid (IRF), and / or cystoid edema. Additional endpoints are to evaluate efficacy parameters and retinal structural improvement in patients after a single IVT injection of a compound of formula I, which are change from baseline in capillary perfusion to weeks 8 and 16 as assessed by OCT-A and FA, and change in drusen volume from baseline to weeks 8 and 16.

[0090] This study will enroll patients 50 years of age or older with nAMD with best corrected visual acuity (BCVA) of 70-20 letters on the Early Treatment Diabetic Retinopathy Study (ETDRS) (corresponding to 20 / 40-20 / 400 on the Snellen chart) at screening and day 1. Patients will receive a single 50 μL IVT injection of 10 μg of the compound of Formula I or sham. See Figure 7.

[0091] Inclusion criteria To be included in the study, each individual must meet all of the following criteria: 1. Patients aged 50 years or older. 2. Active choroidal neovascularization (CNV) associated with age-related macular degeneration as evidenced by FA and SD-OCT on day 1 and confirmed by a central reading center with the presence of intraretinal or subretinal fluid. 3. Patients with neovascular AMD who have received at least 3 anti-VEGF treatments in the preceding 6 months prior to Day 1, with the last anti-VEGF given 3-6 weeks prior to Day 1. 4. BCVA in the study eye (most affected) at Screening and Day 1 of 70–20 letters on the ETDRS (corresponding to 20 / 40–20 / 400 on the Snellen chart). If both eyes are equal, at the discretion of the investigator. 5. BCVA in the non-test eye is ≥35 letters on the ETDRS (equivalent to 20 / 200 on the Snellen chart). 6. IOP ≤ 23mmHg in the study eye. 7. Clear optics and adequate pupil dilation to allow for CFP and proper BCVA assessment. 8. Patient is capable of giving informed consent and is willing and able to submit to all study-related procedures and evaluations.

[0092] Exclusion criteria If an individual meets any of the following criteria, he or she is ineligible for this study: 1. Concurrent disease or structural damage in the study eye, other than nAMD, that may impair BCVA, prevent BCVA improvement, require medical or surgical intervention during the study, confound interpretation of results, or interfere with evaluation of toxicity or CFP in the study eye. This includes, but is not limited to: Macular edema of etiology other than nAMD Clinically significant subretinal fibrosis ·Subfoveal lipids Cataracts requiring surgery during the study period RPE atrophy or tears or ruptures involving the macula Clinically significant macular hole Clinically significant non-infectious uveitis Vitreomacular traction Clinically significant epiretinal membrane (ERM) Aphakia · Pseudophakia with anterior chamber intraocular lens (A / C IOL) 2. Any ocular / intraocular / periocular infection or inflammation in either eye within the past 4 weeks prior to screening (mild blepharitis is permitted). 3. Subretinal hemorrhage with an area of ​​hemorrhage ≥ 4 papillary areas in the study eye. 4. History of vitrectomy in the study eye. 5. History of intraocular, periocular, or corneal surgery in the study eye within 3 months prior to screening, or anticipated need for such surgery during the study. 6. History of panretinal photocoagulation (within 6 months) or macular laser photocoagulation (within 3 months) in the study eye prior to dosing. 7. History of corneal transplant in the study eye. 8. Concomitant use of more than two medications for the treatment of glaucoma and unstable glaucoma in the study eye (i.e., inadequate IOP control). 9. Any condition, including laboratory findings and medical history or findings in the pre-study evaluation, which, in the opinion of the Investigator, constitutes a risk or contraindication to participation in the study or which may interfere with the study objectives, conduct, or evaluations, or which may prevent the patient from participating fully in all aspects of the study. 10. Presence of severe myopia (-8 diopters or greater) in the study eye. 11. Current or history of chronic therapy with systemic or topical ocular corticosteroids (defined as multiple doses taken daily for 3 or more consecutive days at any time within 6 months prior to enrollment). Use of intravitreal non-biodegradable steroid implants (e.g., Iluvien®, Yutiq®, Retisert®) is prohibited. 12. Significant ocular opacities, including cataracts, that may interfere with VA, toxicity assessment, or fundus imaging. 13. Intraocular surgery, including cataract surgery, in the study eye within 3 months of screening. 14. Known allergy to any of the components of the compounds of formula I (phosphate buffered saline and polysorbate 80) or clinically relevant sensitivity to fluorescein dye. 15. Female patients of childbearing potential who are pregnant, nursing, or who do not agree to use highly effective methods of contraception (e.g., progesterone-only hormonal contraception, double barrier, or intrauterine device) during the study and for 3 months after the last dose of a compound of Formula I. Postmenopausal women (>45 years of age and no menses for >1 year) and women who have been surgically sterilized are exempt from these requirements. 16. Male patients who, if sexually active with a female partner of childbearing potential, do not agree to use highly effective methods of contraception for 3 months after the study and the last dose of a compound of formula I. 17. Patients who have received or are concurrently receiving another investigational drug or vaccine trial within 3 months of screening, including patients who have previously received treatment in a trial with a compound of Formula I. 18. Any uncontrolled medical condition that, in the opinion of the investigator, would prevent participation in this study, including but not limited to, history of malignancy within the past 3 years (except non-facial, basal cell carcinoma is permitted), history of myocardial infarction within the past 6 months, or concomitant therapy.

[0093] Example 4: Comparing the ocular pharmacokinetics and tolerability of two salt forms following IVT injection in New Zealand White rabbits An evaluation of the ocular pharmacokinetics (PK) and tolerability of two salt forms of the compound of formula I (sodium salt and meglumine salt) following a single IVT injection in New Zealand White rabbits (non-GLP) was performed to understand whether the meglumine salt form (compound meglumine) behaved similarly or differently to the sodium salt form.

[0094] Two groups of 32 New Zealand White rabbits (total of 64 animals) received a single IVT injection of either the sodium salt form or the meglumine salt form (compound meglumine) of the compound of formula I at 8 μg / eye. The animals were sacrificed at various time points after IVT injection (2 hours, 24 hours, 72 hours, 120 hours, 168 hours, 336 hours, 504 hours, and 672 hours). The eyes were enucleated and plasma was collected from the auricular vein. The retina, lens, and vitreous humor along with the plasma were cut or collected and stored at −20° C. until use.

[0095] Tissue and fluid samples collected were analyzed by LC-MS / MS. Table 1 summarizes the PK findings. Similar exposure was observed between the two salt forms in the vitreous humor and lens. The concentration of the compound in the retina was primarily below the limit of quantification (BLQ) for both salt forms tested (as indicated as "NC"), and therefore no difference in retinal exposure between both salt forms was expected. The compound was at BLQ in plasma at all time points. Similar distribution of the sodium and meglumine salt forms was observed in each of the ocular tissues tested. The highest exposure observed was in the vitreous humor for both salt forms. No systemic exposure was found for either salt form. See Figure 15.

[0096] [Table 1]

[0097] The foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, but the descriptions and examples should not be construed as limiting the scope of the invention. The disclosures of all patent and scientific literature cited herein are expressly incorporated by reference in their entirety.

Claims

1. Compounds of Formula I: (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid 1. A pharmaceutical composition for use in a method for treating retinal vasculopathy comprising a crystalline solid meglumine salt (compound-meglumine) of The method comprises administering to a patient suffering from membrane vasculopathy a therapeutically effective dose of a compound-meglumine; A pharmaceutical composition, wherein the therapeutically effective dose is up to 25 μg of the compound-meglumine per eye.

2. 2. The pharmaceutical composition of claim 1, wherein the meglumine in the crystalline solid meglumine salt of the compound of formula I is present in a stoichiometric ratio of 1 to 3, and optionally the crystalline solid meglumine salt of the compound of formula I is stable at a temperature of 2°C to 8°C for 12 months or more.

3. The patient has a baseline best corrected visual acuity (BCVA) of 70 to 20 letters on the Early Treatment of Diabetic Retinopathy Study (ETDRS) or a baseline value of 20 / 40 to 20 / 400 on a Snellen chart. and / or the patient had been previously treated with an anti-vascular endothelial growth factor (anti-VEGF) therapy at baseline, and optionally the prior treatment with the anti-VEGF therapy had occurred within the preceding 6 month period, and optionally the patient also exhibited a central subfield thickness (CST) of 350 μm or greater as measured by SD-OCT at baseline, 150 μm or greater as measured by SD-OCT at baseline, 200 μm or greater as measured by SD-OCT at baseline, 250 μm or greater as measured by SD-OCT at baseline, 300 μm or greater as measured by SD-OCT at baseline, or 350 μm or greater as measured by SD-OCT at baseline; 2. The pharmaceutical composition of claim 1.

4. The patient, hemoglobin A1C (HbA1C) less than 12% at baseline, less than 11% at baseline, less than 10% at baseline, less than 9% at baseline, less than 8% at baseline, less than 7% at baseline, less than 6% at baseline, less than 5% at baseline, less than 4% at baseline, less than 3% at baseline, less than 2% at baseline, less than 1% at baseline; and / or Intraocular pressure (IOP) of 23 mmHg or less at baseline, 22 mmHg or less at baseline, 21 mmHg or less at baseline, 20 mmHg or less at baseline, 19 mmHg or less at baseline, 18 mmHg or less at baseline, 17 mmHg or less at baseline, 16 mmHg or less at baseline, 15 mmHg or less at baseline, 14 mmHg or less at baseline, 13 mmHg or less at baseline, 12 mmHg or less at baseline, 11 mmHg or less at baseline, 10 mmHg or less at baseline, 9 mmHg or less at baseline, 8 mmHg or less at baseline, 7 mmHg or less at baseline, 6 mmHg or less at baseline, 5 mmHg or less at baseline, 4 mmHg or less at baseline, 3 mmHg or less at baseline, 2 mmHg or less at baseline, 1 mmHg or less at baseline; and / or - A 2-point improvement in the Diabetic Retinopathy Severity Scale (DRSS) compared to baseline 2. The pharmaceutical composition of claim 1, having the formula:

5. The therapeutically effective dose of the compound-meglumine is - 0.5 μg, 1 μg, 2 μg, 2.5 μg, 3 μg, 4 μg, 5 μg, 6 μg, 7 μg, 8 μg, 9 μg, 10 μg, 11 μg, 12 μg, 13 μg, 14 μg, 15 μg, 16 μg, 17 μg, 18 μg, 19 μg, 20 μg, 21 μg, 22 μg, 23 μg, 24 μg, or 25 μg per eye, or - 0.5μg to 1μg per eye, 1μg to 2μg per eye, 2μg to 2.5μg per eye, 2.5μg to 3μg per eye, 3μg to 4μg per eye, 4μg to 5μg per eye, 5μg to 6μg per eye, 6μg to 7μg per eye, 7μg to 8μg per eye, 8μg to 9μg per eye, 9μg to 10μg per eye, 10μg to 11μg per eye, 11μg to 12μg per eye, 12μg per eye 13 μg to 14 μg per eye, 14 μg to 15 μg per eye, 15 μg to 16 μg per eye, 16 μg to 17 μg per eye, 17 μg to 18 μg per eye, 18 μg to 19 μg per eye, 19 μg to 20 μg per eye, 20 μg to 21 μg per eye, 21 μg to 22 μg per eye, 22 μg to 23 μg per eye, 23 μg to 24 μg per eye, or 24 μg to 25 μg per eye, or - 0.5 to 2 μg per eye, 2 to 4 μg per eye, 3 to 5 μg per eye, 4 to 6 μg per eye, 5 to 7 μg per eye, 6 to 8 μg per eye, 7 to 9 μg per eye, 8 to 10 μg per eye, 9 to 11 μg per eye, 10 to 15 μg per eye, 15 to 20 μg per eye, 20 to 25 μg per eye 2. The pharmaceutical composition of claim 1, wherein

6. The compound-meglumine is first administered to the patient's eye as a loading dose prior to administering the therapeutically effective dose, and optionally the loading dose of the compound-meglumine is - 0.5μg to 1μg per eye, 1μg to 2μg per eye, 2μg to 2.5μg per eye, 2.5μg to 3μg per eye, 3μg to 4μg per eye, 4μg to 5μg per eye, 5μg to 6μg per eye, 6μg to 7μg per eye, 7μg to 8μg per eye, 8μg to 9μg per eye, 9μg to 10μg per eye, 10μg to 11μg per eye, 11μg to 12μg per eye, 12μg per eye 13 μg to 14 μg per eye, 14 μg to 15 μg per eye, 15 μg to 16 μg per eye, 16 μg to 17 μg per eye, 17 μg to 18 μg per eye, 18 μg to 19 μg per eye, 19 μg to 20 μg per eye, 20 μg to 21 μg per eye, 21 μg to 22 μg per eye, 22 μg to 23 μg per eye, 23 μg to 24 μg per eye, or 24 μg to 25 μg per eye, or - 0.5 to 2 μg per eye, 2 to 4 μg per eye, 3 to 5 μg per eye, 4 to 6 μg per eye, 5 to 7 μg per eye, 6 to 8 μg per eye, 7 to 9 μg per eye, 8 to 10 μg per eye, 9 to 11 μg per eye, 10 to 15 μg per eye, 15 to 20 μg per eye, 20 to 25 μg per eye 2. The pharmaceutical composition of claim 1, wherein

7. the total volume of the loading dose of the compound-meglumine per eye is 50 μl; and / or The loading dose of the compound-meglumine is administered intravitreally to the patient's eye. The pharmaceutical composition of claim 6.

8. The therapeutically effective dose of the compound-meglumine is administered intravitreally to the patient's eye, and optionally, the intravitreal administration Every 2 months, every 3 months, every 4 months, every 5 months, every 6 months, every 7 months, every 8 months, every 9 months, every 10 months, every 11 months, every 12 months, or Every 2-3 months, every 3-4 months, every 5-6 months, every 6-7 months, every 8-9 months, every 9-10 months, every 11-12 months 2. The pharmaceutical composition of claim 1, wherein

9. the therapeutically effective dose of the compound-meglumine is administered intravitreally to the patient's eye as a single dose every 2 months, as a single dose every 3 months, as a single dose every 4 months, as a single dose every 5 months, as a single dose every 6 months, as a single dose every 7 months, as a single dose every 8 months, as a single dose every 9 months, as a single dose every 10 months, as a single dose every 11 months, or as a single dose every 12 months; or the therapeutically effective dose of the compound-meglumine is administered intravitreally to the patient's eye as a single dose every 2-3 months, as a single dose every 3-4 months, as a single dose every 5-6 months, as a single dose every 6-7 months, as a single dose every 8-9 months, as a single dose every 9-10 months, or as a single dose every 11-12 months; The pharmaceutical composition of claim 5.

10. the therapeutically effective dose of the compound-meglumine is administered intravitreally to the patient's eye once as a single dose, and optionally the therapeutically effective dose of the compound-meglumine is administered intravitreally to the patient's eye once as a single dose without being combined with a prior loading dose; The pharmaceutical composition of claim 5.

11. the loading dose administered intravitreally to the patient's eye is administered as a monthly IVT injection for two months, or as a monthly IVT injection for three months, or as at least one IVT injection in two months, or as at least two IVT injections in two months, or as at least three IVT injections in two months, or as at least three IVT injections in three months, or as at least two IVT injections in three months, and optionally the loading dose is followed by a cessation of treatment of at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months prior to administration of the therapeutically effective dose. The pharmaceutical composition of claim 6.

12. the patient exhibits a CST reduction of at least 40 μm from baseline, at least 50 μm from baseline, at least 60 μm from baseline, at least 70 μm from baseline, at least 80 μm from baseline, or at least 90 μm from baseline as measured by SD-OCT; and / or The patient, further demonstrates the absence of macular fluid compared to baseline as assessed by SD-OCT; or Further demonstrates the absence of exudation compared to baseline as assessed by SD-OCT; 2. The pharmaceutical composition of claim 1.

13. 2. The pharmaceutical composition of claim 1, wherein the patient does not require more than two anti-VEGF therapeutic rescues, or does not require more than three anti-VEGF therapeutic rescues, or does not require more than four anti-VEGF therapeutic rescues, or does not require more than five anti-VEGF therapeutic rescues, and optionally the patient does not require any anti-VEGF therapeutic rescues.

14. The patient, - demonstrating an improvement in BCVA of at least 5 ETDRS letters compared to baseline, or an improvement in BCVA of at least 6 ETDRS letters compared to baseline, or an improvement in BCVA of at least 7 ETDRS letters compared to baseline, or an improvement in BCVA of at least 8 ETDRS letters compared to baseline, or an improvement in BCVA of at least 9 ETDRS letters compared to baseline, or an improvement in BCVA of at least 10 ETDRS letters compared to baseline, an improvement in BCVA of at least 15 ETDRS letters compared to baseline, or an improvement in BCVA of at least 20 ETDRS letters compared to baseline; and / or demonstrating a BCVA improvement of 5-7 ETDRS letters compared to baseline, a BCVA improvement of 6-8 ETDRS letters compared to baseline, a BCVA improvement of 7-9 ETDRS letters compared to baseline, a BCVA improvement of 10-15 ETDRS letters compared to baseline, a BCVA improvement of 15-20 ETDRS letters compared to baseline, a BCVA improvement of 20-25 ETDRS letters compared to baseline, and a BCVA improvement of 25-30 ETDRS letters compared to baseline; and / or A reduction in the avascular area of ​​the eye of at least 0.10 mm compared to baseline, or at least 0.20 mm compared to baseline, all as measured by fluorescein angiography (FA) or optical coherence tomography angiography (OCT-A) ２ or a reduction in the avascular area of ​​the eye of at least 0.30 mm compared to baseline ２ or a reduction in the avascular area of ​​the eye of at least 0.40 mm compared to baseline ２ or a reduction in the avascular area of ​​the eye of at least 0.50 mm compared to baseline ２ or a reduction in the avascular area of ​​the eye of at least 0.60 mm compared to baseline ２ or a reduction in the avascular area of ​​the eye of at least 0.70 mm compared to baseline ２ or a reduction in the avascular area of ​​the eye of at least 0.80 mm compared to baseline ２ or a reduction in the avascular area of ​​the eye of at least 0.90 mm compared to baseline ２ or a reduction in the avascular area of ​​the eye of at least 1.0 mm compared to baseline ２ 10. The method of claim 1, further comprising: and / or - exhibit regression compared to baseline of neovascularization as measured by FA or OCT-A; 2. The pharmaceutical composition of claim 1.

15. The retinal vasculopathy is ・Diabetic macular edema (DME), Diabetic retinopathy (DR), and optionally said patient also presented with non-proliferative diabetic retinopathy at baseline or also presented with proliferative diabetic retinopathy at baseline; Age-related macular degeneration (AMD), or Geographic atrophy (GA) The pharmaceutical composition according to any one of claims 1 to 14,

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