Methods of treating diabetic retinopathy

Abstract

Methods of slowing disease progression in a subject having or at risk of having diabetic retinopathy; methods involve administering an Edonentan composition.

Description

Attorney Docket No.: PFT-019WOMETHODS OF TREATING DIABETIC RETINOPATHYCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 756,762 (filed February 10, 2025), U.S. Provisional Application No. 63 / 783,729 (filed April 4, 2025), and U.S. Provisional Application No. 63 / 827,793 (filed June 20, 2025), the contents of each of which are incorporated by reference herein.BACKGROUND

[0002] Diseases of the eye have an enormous impact on the quality of human life and yet remain largely elusive to effective treatment. It is estimated that an annual economic burden of over $100 billion results from vision loss, eye diseases, and vision disorders in the United States.

[0003] Diabetic retinopathy (DR) is the most common complication of diabetes and the leading cause of decreased visual acuity and blindness in the working-age population in developed countries. The incidence of DR increases with the time of evolution of diabetes. Thus, 90% of patients with type 1 diabetes and 60% of patients with type 2 diabetes have some degree of DR after 20 years of evolution of diabetes. The prevalence of DR in Western countries is around 30%; in 10% of cases, the DR is in advanced stages that seriously threaten vision.

[0004] DR occurs when changes in blood glucose levels cause changes in retinal blood vessels. In some cases, these vessels will swell up and leak fluid into the rear of the eye (macular edema). In other cases, abnormal blood vessels will grow on the surface of the retina (proliferative DR). Unless treated, DR can gradually become more serious and progress from ‘background retinopathy’ to seriously affecting vision and can lead to blindness.

[0005] There remains a need to more effectively reduce the incidence of, treat, or otherwise ameliorate diabetic retinopathy.SUMMARY

[0006] The present disclosure addresses this need with methods of slowing disease progression.1IPTS / 200316898.1Attorney Docket No.: PFT-019WO

[0007] In one aspect, provided are methods for maintaining or improving the Diabetic Retinopathy Severity Score (DRSS) in a subject in need thereof, the methods comprising a step of: implanting, into the vitreous cavity of the subject’s eye, a sustained release bio-erodible device having a total amount of between about 150 pg and about 650 pg of a crystalline form of Edonentan, wherein the subject exhibits: a) no change in the DRSS at three months or six months after implanting, b) an improvement of at least one step in the DRSS at three months or six months after implanting, or c) an improvement of at least two steps in the DRSS at six months after implanting.

[0008] In one aspect, provided are a methods for slowing vision loss or improving vision in a subject having diabetic retinopathy, the methods comprising a step of: implanting, into the vitreous cavity of the subject’s eye, a sustained release bio-erodible device having a total amount of between about 150 pg and about 650 pg of a crystalline form of Edonentan, wherein the subject exhibits a visual field mean deviation (VF MD) slope of at least 0.50 dB / yr, at least 0.75 dB / year, at least 1.0 dB / year, at least 1.25 dB / year, at least 1.50 dB / year, or at least 1.75 dB / year as determined by a Frequency Doubling Perimetry (FDP) over a period of at least three months after implanting.

[0009] In one aspect, provided are methods for maintaining vision in a subject having diabetic retinopathy, the methods comprising a step of: implanting, into the vitreous cavity of the subject’s eye, a sustained release bio-erodible device having a total amount of between about 150 pg and about 650 pg of a crystalline form of Edonentan, wherein the subject maintains a visual field mean deviation (VF MD) slope of greater than -2.0 dB or greater than -1.0 dB as determined by a Frequency Doubling Perimetry (FDP) test for at least three months, at least four months, at least five months, at least six months, or about six months after implanting.

[0010] In one aspect, provided are methods for maintaining or improving visual acuity in a subject having diabetic retinopathy, the method comprising a step of: implanting, into the vitreous cavity of the subject’s eye, a sustained release bio-erodible device having a total amount of between about 150 pg and about 650 pg of a crystalline form of Edonentan, wherein the subject exhibits: a) a detectable decrease relative to baseline in foveal avascular zone (FAZ) area as determined by optical coherence tomography angiography (OCTA) at three months after implanting, b) a decrease of at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, or at least 8%, at least 8% relative to baseline in FAZ area as determined by OCTA at three months or six months after implanting, or c) a score improvement of at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at 2IPTS / 200316898.1Attorney Docket No.: PFT-019WOleast eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, or at least twenty Early Treatment Diabetic Retinopathy Study (ETDRS) letters as assessed by the Best Corrected Visual Acuity (BCVA) test using an ETDRS letter scoring protocol at three months after implanting, at six months after implanting, or as determined as the average of values at two, three, and four months after implanting.

[0011] In one aspect, provided are methods for maintaining or improving contrast sensitivity in a subject having diabetic retinopathy, the methods comprising a step of: implanting, into the vitreous cavity of the subject’s eye, a sustained release bio-erodible device having a total amount of between about 150 pg and about 650 pg of a crystalline form of Edonentan, wherein the subject exhibits: a) no change relative to baseline as determined by the quick contrast sensitivity function (qCSF) method on the Adaptive Sensory Technology (AST) Platform at 1.5 cycles per degree (CPD) measured at eight weeks or three months after implanting, b) an increase of about or at least 1.0 dB relative to baseline as determined by the qCSF method on the AST Platform at 1.5 CPD measured at 20 weeks or six months after implanting, c) no change relative to baseline as determined by the qCSF method on the AST Platform at 3.0 CPD measured at eight weeks, 20 weeks, three months, or six months after implanting, d) an increase of about or at least 0.5 dB relative to baseline as determined by the qCSF method on the AST Platform at 3.0 CPD measured at eight weeks, 20 weeks, three months, or six months after implanting, e) no change relative to baseline as determined by the qCSF method on the AST Platform at 6.0 CPD measured at eight weeks, twenty weeks, three months, or six months after implanting, or f) an increase of about or at least 0.5 dB baseline as determined by the qCSF method on the AST Platform at 6.0 CPD measured at eight weeks or three months after implanting.

[0012] In one aspect, provided are methods for slowing or reversing disease progression in a subject having diabetic retinopathy, the methods comprising a step of: implanting, into the vitreous cavity of the subject’s eye, a sustained release bio-erodible device having a total amount of between about 150 pg and about 650 pg of a crystalline form of Edonentan, wherein the subject exhibits: a) no change relative to baseline in the macular ischemic index as determined by ultra wide field fluorescein angiography (UWFA) measured at three months or six months after implanting, b) a decrease of at least or about 0.3%, at least or about 0.4%, or at least or about 0.5% relative to baseline in the macular ischemic index as determined by UWFA measured at three months or six months after implanting, c) no change relative to baseline in the macular total leakage index as determined by UWFA measured at three months 3IPTS / 200316898.1Attorney Docket No.: PFT-019WOor six months after implanting, d)a decrease of at least or about 2%, at least or about 3%, at least or about 4%, or at least or about 5% relative to baseline in the macular total leakage index as determined by UWFA measured at three months or six months after implanting, e) no change relative to baseline in the macular microaneurysm count as determined by UWFA measured at three months or six months after implanting, f) a decrease of at least or about 2, at least or about 3, at least or about 4, or at least or about 5, relative to baseline in the macular microaneurysm count as determined by UWFA measured at three months or six months after implanting, g) no change relative to baseline in the posterior pole ischemic index as determined by UWFA measured at three months or six months after implanting, h) a decrease of at least or about 0.3%, at least or about 0.4%, or at least or about 0.5% relative to baseline in the macular ischemic index as determined by UWFA measured at three months or six months after implanting, i) no change relative to baseline in the posterior pole total leakage index as determined by UWFA measured at three months or six months after implanting j) a decrease of at least or about 1%, at least or about 2%, or at least or about 3% relative to baseline in the macular total leakage index as determined by UWFA measured at three months or six months after implanting, k) no change relative to baseline in the posterior pole microaneurysm count as determined by UWFA measured at three months or six months after implanting, or 1) a decrease of at least or about 2, at least or about 3, at least or about 4, at least or about 5, at least or about 6, at least or about 7, at least or about 8, at least or about 9, at least or about 10, at least or about 11, at least or about 12, at least or about 13, at least or about 14, at least or about 15, at least or about 16, at least or about 17, at least or about 18, at least or about 19, or at least or about 20, relative to baseline in the posterior pole microaneurysm count as determined by UWFA measured at three months or six months after implanting.

[0013] In one aspect, provided are methods for slowing disease progression in a subject having or at risk of having diabetic retinopathy, the method comprising a step of administering to the subject a composition comprising a therapeutically effective amount of Edonentan, a pharmaceutically acceptable salt thereof, a crystalline form thereof, or an amorphous form thereof.

[0014] In some embodiments, slowing disease progression comprises slowing vision loss or improving vision (e.g., peripheral vision, maintaining or improving contrast sensitivity, and / or maintaining or improving visual acuity). For example, in some embodiments, improving peripheral vision loss comprise improving peripheral vision over a period of at least 3 months after the step of administration.4IPTS / 200316898.1Attorney Docket No.: PFT-019WO

[0015] In some embodiments, slowing disease progression comprises maintaining or improving a clinical score associated with severity of diabetic retinopathy. The clinical score may be maintained or improved, for example, over a period of at least three months from the step of administering. In some embodiments, the clinical score is the Diabetic Retinopathy Severity Score.

[0016] In some embodiments, the subject is a mammal, e.g., a human.

[0017] In some embodiments, administration comprises intravitreal administration, for example, by implanting, into the vitreous cavity of the eye, a sustained release, bio-erodible device which comprises the composition. In some embodiments, the bio-erodible device comprises a poly(lactic-co-glycolic acid) (PLGA) polymer. In some embodiments, the bio-erodible device contains a total dose of about 200 ptg, about 400 ptg, about 500 ptg, or about 600 ptg of Edonentan.

[0018] In some embodiments, the composition is administered at a regular interval, e.g., a regular interval of about three months, at least three months, about four months, or about six months.BRIEF DESCRIPTION OF THE DRAWINGS

[0019] FIG. 1 depicts drug release profiles of Edonentan in disk punches of exemplary formulations each containing a polymer matrix incorporating Edonentan. Up to 70% of Edonentan was released from most formulations within 100 days as determined by high-performance liquid chromatography (HPLC). The in vitro release results show that the amount of Edonentan released decreases with the increase of the ratio of poly-lactic acid (PLA) to poly-glycolic acid (PGA) as well as the increase of molecular weight of the polymer. Formulation 1 (50 / 50 RG503 / RG503H) has a faster release compared to Formulation 2 (65 / 35 PLA / PGA) due to the lower ratio of PLG to PGA. Formulation 4 (50 / 50 502 / 502H) has a faster release compared to Formulation 1 (50 / 50 503 / 503H) due to the lower molecular weight of the polymer. The results also showed that RG753S has the slowest release profile among the formulations tested, and the mixtures of RG753S with other faster-releasing formulations provide a long period of sustained drug release while maintaining sufficient drug release at earlier time points.

[0020] FIG. 2 depicts elution rate profiles of Edonentan in disk punches of exemplary formulations each containing a polymer matrix incorporating Edonentan. The in vitro release results show that for each polymer matrix there is a peak Edonentan release from 10 to 35 days5IPTS / 200316898.1Attorney Docket No.: PFT-019WOfollowed by a decrease in elution rate, with a sustained steady-state release for some matrices as determined by HPLC.

[0021] FIG. 3 depicts drug release profiles of Edonentan in implants of exemplary formulations each containing a polymer matrix incorporating Edonentan. The in vitro release results show that the combination of polymer matrix with Edonentan provides sustained release of active as determined by HPLC.

[0022] FIG. 4 depicts elution rate profiles of Edonentan in implants of exemplary formulations each containing a polymer matrix incorporating Edonentan. The in vitro release results show that the polymer matrix controls the initial release of Edonentan with the peak release ranging from day 17 to day 92, as determined by HPLC. The in vitro release results show that the amount of Edonentan released decreases with the increase of the ratio of polylactic acid (PLA) to poly-glycolic acid (PGA) as well as the increase of molecular weight of the polymer. The mixtures of RG753S with other faster-releasing formulations provide a long period of sustained drug release while maintaining sufficient drug release at earlier time points.

[0023] FIG. 5 is a graph depicting Visual Field (VF) Mean Deviation (MD) rate of change from baseline over a 6-month period for patients enrolled in the Phase 2a Diabetic Retinopathy study with Edonentan Implant 1. VF MD slope measurements for low dose (n=8), high dose (n=7) and sham control (n=7) groups are plotted. The calculated slopes were 1.8308 dB / year for the low dose group (middle lnie sloping upward), -0.1100 dB / yr for the high dose group (top-most line), and 0.0107 dB / year for the contro dose group (lower-most line). The y-axis is marked at -6, -4, -2, and 0. The x-axis is marked at 0.0, 0.1, 0.2, 0.3, 0.4, and 0.5 (years). See Example 9.

[0024] FIGs. 6 -6C depict diabetic retinopathy severity score (DRSS) changes for patients enrolled in a Phase 2a Diabetic Retinopathy study with Edonentan Implant 1 in low dose (Figure 6A), high dose (FIG. 6B), and sham control (FIG. 6C) groups at 3 months after administration of Edonentan Implant 1. See Example 9.

[0025] FIGs. 7A and 7B depict diabetic retinopathy severity score (DRSS) changes for patients enrolled in a Phase 2a Diabetic Retinopathy study with Edonentan Implant 1 in low dose (FIG. 7A), high dose (FIG. 7B) and sham control (FIG. 7C) groups at 6 months after administration of Edonentan Implant 1. See Example 9.

[0026] FIG. 8 depicts Foveal Avascular Zone (FAZ) area changes from baseline at 3 months or 6 months for patients enrolled in a Phase 2a Diabetic Retinopathy study with Edonentan Implant 1 in low dose, high dose, and control groups. See Example 10.6IPTS / 200316898.1Attorney Docket No.: PFT-019WO

[0027] FIGs. 9A, 9B, and 9C depict macular ischemic index (%) (FIG. 9A), macular total leakage index (%) (FIG. 9B), and macular microaneurysm count (FIG. 9C) changes from baseline at 3 months or 6 months after implantation with Edonentan Implant 1 in patients in low dose, high dose, and control groups in a Phase 2a diabetic retinopathy study. Error bars indicate standard deviation. See Example 11.

[0028] FIGs. 10A, 10B, and 10C depict posterior pole ischemic index (%) (FIG. 10A), posterior pole leakage index (%) (FIG. 10B), and posterior pole microaneurysm count (FIG.10C) changes from baseline at 3 months or 6 months after implantation with Edonentan Implant 1 in patients in low dose, high dose, and control groups in a Phase 2a diabetic retinopathy study. Error bars indicate standard deviation. See Example 11.

[0029] FIGs. 11A-11D depict low luminance contrast sensitivity changes from baseline at 8 weeks or 20 weeks after implantation with Edonentan Implant 1 in patients in low dose, high dose, or control groups in a Phase 2a diabetic retinopathy study. FIGs. 11A-11C depict single frequency contrast sensitivity changes at 1.5 (FIG. 11A), 3.0 (FIG. 11B), and 6.0 (FIG. 11C) cycles per degree (CPD). FIG. 11D depicts contrast sensitivity changes from baseline in a predefined region of interest (ROI) encompassing the spatial frequencies of 1.25 CPD, 2.50 CPD, and 5.0 CPD).

[0030] FIG. HE depicts low luminance low contrast visual acuity changes from baseline over time at two months or five months after implantation with Edonentan Implant 1 in low dose, high dose, or control groups. See Example 12.

[0031] FIG. 12 depicts a correlation fit plot for the macular leakage rate of change (y-axis) vs. the low luminance contrast sensitivity (dB) (x-axis). The solid line indicates the fit plot, the shaded area indicates 95% confidence limits, and the dotted lines indicate the boundaries for the 95% prediction limits. The y-axis is labeled at -10, 9, 10, and 20. The x-axis is labeled at -7.5, -5.0, -2.5. 0.0, 2.5, and 5.0 See Example 12.DETAILED DESCRIPTION OF CERTAIN EMBODIMENTSDefinitions

[0032] As used herein, the terms “about” or “approximately” when used herein in reference to a value, are used interchangeably and refer to a value that is similar to the referenced value. In general, those skilled in the art and familiar with the context will appreciate the relevant degree of variance encompassed by “about” in that context. For example, in some embodiments, the term “about” may encompass a range of values that fall within 25%, 20%,7IPTS / 200316898.1Attorney Docket No.: PFT-019WO19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the referred value. In some embodiments, “about” refers to a range of values that fall within 10% of the referred value.

[0033] As used herein, the term “amorphous” refers to a solid material having no long range order in the position of its molecules. Amorphous solids are generally supercooled liquids in which the molecules are arranged in a random manner so that there is no well-defined arrangement, e.g., molecular packing, and no long range order. Amorphous solids are generally isotropic, i.e. exhibit similar properties in all directions and do not have definite melting points. For example, an amorphous material is a solid material having no sharp characteristic crystalline peak(s) in its X-ray power diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or several broad peaks (e.g., halos) appear in its XRPD pattern.

[0034] As used herein, the terms “baseline” refers to a level used for comparison. For example, a baseline level may refer to the level for the same indicator being measured before a treatment is administered, or at approximately the same time as the beginning of a treatment, in the same subject who is being evaluated at later timepoints.

[0035] As used herein, the terms “biodegradable,” and like terms generally describes a device and refers to a biologically assisted degradation process that the substance, e.g., polymer, making-up the device undergoes in a biological environment, such as within the body of a subject. Biodegradation encompasses within the scope the processes of absorption, dissolution, breaking down, degradation, assimilation, or otherwise removal of the device from the body, a biological environment. For example, a biodegradable polymer is liable to hydrolysis under physiological conditions due to the presence of hydrolytically and / or enzymatically susceptible functional groups.

[0036] As used herein, the term “bio-erodible” in reference to a material, e.g., a device or an implant, refers to a characteristic of the material in that the material erodes mechanically via a biological process, e.g., for polymer-based bio-erodible materials, the biological process may solubilize the polymer an enable absorption of the polymer into surrounding tissue.

[0037] As used herein, a “carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.

[0038] As used herein, a “diluent” refers to an ingredient in a composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable which may be 8IPTS / 200316898.1Attorney Docket No.: PFT-019WOused (1) to increase the bulk of a potent drug whose mass is too small for manufacture and / or administration or (2) for the dissolution of a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the composition of human blood.

[0039] As used herein, an “excipient” refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability, retarded dissolution etc., to the composition. A “diluent” is a type of excipient.

[0040] As used herein, the phrase “pharmaceutically acceptable” is used to describe a carrier, diluent, excipient, salt or composition that is safe and effective for its intended use and possesses the desired biological and pharmacological activity.

[0041] As used herein, the term “pharmaceutical composition” refers to a mixture of a compound or other agent with other chemical components, such as diluents or carriers, and is suitable for pharmaceutical use, e.g., administration to an organism.

[0042] As used herein, the term “polymer” encompasses both homopolymers (polymers having only one type of repeating unit) and copolymers (a polymer having more than one type of repeating unit). The term “biodegradable polymer” as used herein refers to a polymer or polymers, which degrade in vivo, under physiological conditions. The release of a therapeutic agent occurs concurrent with, or subsequent to, the degradation of a biodegradable polymer over time.

[0043] As used herein, the phrases “therapeutically effective amount” and “effective amount” are used interchangeably and refer to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result. A therapeutically effective amount may vary according to factors such as the type of disease e.g., disease state, age, sex, and / or weight of the individual, and the ability of a compound (or a composition thereof) to elicit a desired response in the individual. An effective amount may also be an amount for which any toxic or detrimental effects of a composition (e.g., a composition comprising Edonentan or a form thereof) are outweighed by therapeutically beneficial effects.

[0044] As used herein, the term “reference” describes a standard or control relative to which a comparison is performed, and a “reference level” refers to a level from such a standard or control. For example, in some embodiments, an agent, animal, subject, population, sample, sequence or value of interest is compared with a reference or control agent, animal, subject, population, sample, sequence or value. In some embodiments, a reference or control is tested and / or determined substantially simultaneously with the testing or determination of interest. In 9IPTS / 200316898.1Attorney Docket No.: PFT-019WOsome embodiments, a reference or control is a historical reference or control, optionally embodied in a tangible medium. Typically, as would be understood by those skilled in the art, a reference or control is determined or characterized under comparable conditions or circumstances to those under assessment. Those skilled in the art will appreciate when sufficient similarities are present to justify reliance on and / or comparison to a particular possible reference or control.

[0045] As used herein, the term “subject” refers to an organism, typically a mammal (e.g., a human). In some embodiments, a subject is suffering from or susceptible to a relevant disease, disorder or condition. In some embodiments, a subject displays one or more symptoms or characteristics of a disease, disorder or condition. In some embodiments, a subject is someone with one or more features characteristic of susceptibility to or risk of a disease, disorder, or condition. In some embodiments, a subject is a patient. In some embodiments, a subject is a subject to whom diagnosis and / or therapy is and / or has been administered.Methods of slowing disease progression

[0046] Methods provided herein generally comprise a step of administering to a subject in need thereof a composition comprising a therapeutically effective amount of Edonentan, a pharmaceutically acceptable salt thereof, a crystalline form thereof, or an amorphous form thereof, as described further herein. Administration may be achieved, in some embodiments, by use of a delivery device such as a bio-erodible device comprising a biodegradable polymer (e.g., Poly(lactic-co-glycolic acid) (PLGA)) as further described herein.

[0047] In many embodiments, the subject is a mammal, e.g., a human.

[0048] In certain embodiments, the subject has or is at risk of having diabetic retinopathy, and / or exhibits one or more signs of having or being at risk of having diabetic retinopathy.Slowing disease progression

[0049] Provided methods result, in some embodiments, in slowing of disease progression, such as of diabetic retinopathy. “Slowing disease progression” may include 1) slowing the rate of deterioration or worsening with respect to at least one aspect of a disease; 2) maintaining a function with respect to at least one aspect of a disease; and / or 3) improving a function or outcome with respect to at least one aspect of a disease. Thus, in some embodiments, slowing disease progression means extending the amount of time a subject with a given state of a disease reaches an advanced (e.g., more deteriorated, more severe, and or more complicated) state of the disease as compared to a reference level or as compared to the level from a comparable 10IPTS / 200316898.1Attorney Docket No.: PFT-019WOsubject who has not been administered a composition in accordance with disclosed methods. The amount of time may be extended, in some embodiments, by 10%, by 15%, by 20%, by 25%, by 30%, by 35%, by 40%, by 45%, by 50%, by 55%, by 60%, by 65%, by 70%, by 75%, by 80%, by 85%, by 90%, by 95%, by 100%, by 125%, by 150%, by 175%, by 200%, by 250%, by 300%, by 350%, by 400%, by 450%, by 500%, or by more than 500%.

[0050] In some embodiments, provided methods result in the slowing or preventing of vision loss (e.g., central and / or peripheral vision loss), which would normally be expected in a diabetic retinopathy patient over time, the maintenance of vision (e.g., central and / or peripheral vision), or an improvement of vision (e.g., central and / or peripheral vision), over a period of time. For example, in some embodiments, methods result in maintained or improved peripheral vision, maintained or improved contrast sensitivity, maintained or improved low contrast visual acuity, and / or maintained or improved visual acuity over a period of least one, at least two, at least three, at least four, at least five, or at least six months after the step of administration. In some embodiments, methods result in maintained or improved contrast sensitivity and / or visual acuity.

[0051] In some embodiments, provided methods result in the slowing or preventing of a vision-threatening complication, such as macular edema.

[0052] In some embodiments, provided methods result in maintenance or improvement of visual acuity, e.g., maintenance of visual acuity over a period of at least one, at least two, at least three, at least four, at least five, or at least six months after the step of administration.

[0053] The ability to see delicate objects does not guarantee the ability to see large or medium-sized objects of low contrast. Contrast sensitivity (CS) is a measure of visual ability to distinguish an object from its background. Contrast sensitivity function (CSF) acquired with the quick CSF (qCSF) is a metric that incorporates both visual acuity (e.g., spatial resolution) and CS.

[0054] Contrast sensitivity can be evaluated using the qCSF (quick contrast sensitivity function) method on the AST Platform (Adaptive Sensory Technology, San Diego, CA, USA), a computerized method for evaluating the contrast thresholds over a wide range of contrast (0.002% - 100%) and spatial frequency (approximately 1 to 27 cycles per degree (CPD)). Subjects can be asked to read presented optotypes, and their responses can be registered (as correct, incorrect, or optotype not seen) on a tablet computer by a trained study nurse. All participants were tested monocularly for approximately 2 minutes. Sensitivities at various spatial frequencies (e.g., 1.5, 3.0, 5.0, or 6.0 CPD) can serve as a metric of constrast sensitivity11IPTS / 200316898.1Attorney Docket No.: PFT-019WOfunction and used for statistical analyses. Low luminance low contrast visual acuity can be assessed in reduced light conditions, using, e.g., a neutral density filter.

[0055] For example, in some embodiments, provided methods result in maintenance or improvement of the visual field, e.g., an improvement represented by an increase of at least 0.25 dB, at least 0.50 dB, at least 0.75 dB, at least 1.00 dB, at least 1.25 dB, at least 1.50 dB, at least 1.75 dB, or at least 2.00 dB in the visual field mean deviation (VF MD) as determined by a Humphrey Field Analyser at or for three months after administration. In some embodiments, provided methods result in an improvement represented by an increase of at least 0.25 dB, at least 0.50 dB, at least 0.75 dB, at least 1.00 dB, at least 1.25 dB, at least 1.50 dB, at least 1.75 dB, or at least 2.00 dB in the visual field mean deviation (VF MD) as determined by a Humphrey Field Analyser at or for six months after administration.

[0056] For example, in some embodiments, provided methods result in maintenance or improvement of contrast sensitivity, e.g., no change relative to baseline, or an improvement represented by an increase of at least 0.25 dB, at least 0.50 dB, at least 0.75 dB, at least 1.00 dB, at least 1.25 dB, at least 1.50 dB, at least 1.75 dB, or at least 2.00 dB in the quick contrast sensitivity function (qCSF) method on the Adaptive Sensory Technology (AST) Platform at 1.5 CPD, 3.0 CPD, or 6.0 CPD at or for three months, six months, eight weeks, or twenty weeks, after co-administration.

[0057] Best Corrected Visual Acuity (BCVA) can be measured using an Early Treatment of Diabetic Retinopathy Study (ETDRS) chart (5 letters per row, with standardized spacing between letters and rows, having a total of 14 rows (70 letters). The letter score is calculated when 20 or more letters are read correctly at 4.0 meters. The visual acuity letter score is equal to the total number of letters read correctly at 4.0 meters plus 30 (allowing a maximum score of 100). If fewer than 20 letters are read correctly at 4.0 meters, the visual acuity letter score is equal to the total number of letters read correctly at 4.0 meters (number of letters recorded on line 1.0), plus the total number of letters in the first six lines read correctly at 1.0 meter.

[0058] When visual acuity is assessed by BCVA, in some embodiments, provided methods result in a score improvement of at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, and Early Treatment Diabetic Retinopathy (ETDRS) letters on the BCVA at a given timepoint after administration, for example, a timepoint of at least one, at least two, at least three, at least four, at least five, or at least six months after administration.12IPTS / 200316898.1Attorney Docket No.: PFT-019WO

[0059] In some embodiments, slowing disease progression comprises preventing or slowing progression from a non-proliferative state (e.g., non-proliferative diabetic retinopathy) to a proliferative state (e.g., proliferative diabetic retinopathy).

[0060] In some embodiments, slowing disease progression comprises maintaining or improving a clinical status or score associated with the disease, for example, a clinical status or score associated with severity of diabetic retinopathy. For example, a clinician may assess diabetic retinopathy as mild, moderate, or severe with non-proliferative or proliferative disease without using a quantitative score.

[0061] In some embodiments, slowing disease progression comprises maintaining or improving a clinical score in the Diabetic Retinopathy Severity Score (DRSS) described in Example 7. For example, in the DRSS (in which a higher score represents increased severity), an improvement may comprise a one-step or a two-step decrease in the DRSS score. (An example of a one- step decrease is moving from moderate proliferative diabetic retinopathy (level 65) to mild proliferative DR (levels 60 and 61; see Example 7.)

[0062] In some embodiments, the clinical score is maintained or improved over a period of time after the step of administration, e.g., at least one, at least two, at least three, at least four, at least five, or at least six months after the step of administration. In some embodiments, the clinical score is maintained or improved over a period of at least three, at least four, or at least six months after the step of administration.Compositions comprising Edonentan and / or forms thereofEdonentan

[0063] Edonentan is a highly selective and very potent endothelin A receptor antagonist with the chemical name: N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[l,l'-biphenyl]-2-yl]methyl]-N,3,3-trimethylbutanamide. Edonentan has a molecular weight of 536.6 g / mol and the following structure:Edonentan (Compound I)13IPTS / 200316898.1Attorney Docket No.: PFT-019WO

[0064] Methods of preparing Edonentan are well known to a person of skill in the art. Suitable methods are disclosed, for example, in U. S. Patent No. 6,043,265.

[0065] Compositions used in methods disclosed herein can include therapeutically effective amount of Edonentan or of any form thereof, such as a pharmaceutically acceptable salt for, a crystalline form, an amorphous form, or a combination of any of the foregoing.

[0066] Crystalline forms of Edonentan are substantially more stable compared to the amorphous form of Edonentan. For example, crystalline “Form 4” of Edonentan, disclosed in International Patent Publication WO 2021 / 158663 Al, may be stored under practical and economical storage conditions, while retaining physical properties so that it may be manufactured into a dosage form. A given crystalline form (e.g., Form 1, Form 2, or Form 3 disclosed in WO 2021 / 158663 Al) may be converted to another crystalline form (e.g., Form 4 disclosed in WO 2021 / 158663 Al), as further explained in WO 2021 / 158663 Al and below.

[0067] In some embodiments, a given crystalline form, together with any other forms of Edonentan present in the composition, are present in amounts that are therapeutically effective together. In some embodiments, the composition comprises a therapeutically effective amount of a given crystalline form. In some embodiments, the composition comprises crystalline Form 4 of Edonentan (as described in WO 2021 / 158663 Al).

[0068] In some embodiments, the composition comprises a hydrate form of crystalline Edonentan, e.g., Edonentan · (H₂O)m, where m is a fractional or whole number between about 0 and about 4 inclusive. For example, anhydrate or monohydrate forms of crystalline Edonentan may be included in the composition. In some embodiments, a crystalline form of Edonentan may have a water level of about 1 to 10% by weight (e.g., 3 to 9% or 5 to 8% by weight).Crystalline forms

[0069] In certain embodiments, compositions comprise a crystal form of the compound of Formula I:14IPTS / 200316898.1Attorney Docket No.: PFT-019WO

[0070] In some embodiments, the compound of Formula I is in an anhydrous crystalline form (Form 4), having an X-ray powder diffraction pattern as determined by Cu Ka radiation comprising at least three characterization peaks, in terms of 29, selected from peaks at 5.6+0.2°, 11.4+0.2°, 14.4+0.2°, 15.7+0.2°, 16.8+0.2°, 17.7+0.2°, 19.3+0.2°, 21.1+0.2°, 21.9+0.2°, 23.9+0.2°, and 24.6+0.2°.

[0071] In some embodiments, Form 4 has an X-ray powder diffraction pattern as determined by Cu Ka radiation comprising the following peaks expressed in terms of diffraction angles (29): 5.6±0.2°, 11.4+0.2°, 17.7+0.2°, 19.3+0.2°, 21.1+0.2°, and 21.9+0.2°. In some embodiments, Form 4 has an X-ray powder diffraction pattern as determined by Cu Ka radiation comprising the following peaks expressed in terms of diffraction angles (29): 5.6+0.2°, 11.4+0.2°, 17.7+0.2°, 19.3+0.2°, and 21.9+0.2°. In some embodiments, Form 4 has an X-ray powder diffraction pattern as determined by Cu Ka radiation comprising the following peaks expressed in terms of diffraction angles (29): 11.4+0.2°, 17.7+0.2°, and 19.3+0.2°. In some embodiments, Form 4 has an X-ray powder diffraction pattern as determined by Cu Ka radiation comprising the following peaks expressed in terms of diffraction angles (29): 5.6+0.2°, 11.4+0.2°, 14.4+0.2°, 15.7+0.2°, 16.8+0.2°, 17.7+0.2°, 19.3+0.2°, 21.1+0.2°, 21.9+0.2°, 23.9+0.2°, and 24.6+0.2°.

[0072] In some embodiments, Form 4 has a Tmof about 163 °C by DSC analysis.

[0073] In some embodiments, at least 90% by weight (e.g., at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% by weight) of the total amount of the compound of Formula I in the composition is in the form of Form 4.

[0074] In certain embodiments, the compound of Formula I is in an anhydrous crystalline form (Form 1), wherein the anhydrous crystalline Form 1 has an X-ray powder diffraction pattern as determined by Cu Ka radiation comprising at least three characterization peaks, in terms of 29, selected from peaks at 6.3+0.2°, 7.5+0.2°, 11.7+0.2°, 15.1+0.2°, and 17.3+0.2°; and 90% by weight or more of the total amount of the compound of Formula I in the composition is in the form of Form 1.

[0075] In certain embodiments, the compound of Formula I is in a monohydrate crystalline form (Form 2), wherein the monohydrate crystalline Form 2 has an X-ray powder diffraction pattern as determined by Cu Ka radiation comprising at least three characterization peaks, in terms of 29, selected from peaks at 9.6+0.2°, 10.4+0.2°, 19.6+0.2°, 19.7+0.2°, 22.0+0.2°, 22.9+0.2°, and 23.7+0.2°; and 90% by weight or more of the total amount of the compound of Formula I in the composition is in the form of Form 2.15IPTS / 200316898.1Attorney Docket No.: PFT-019WO

[0076] In certain embodiments, the compound of Formula I is in an anhydrous crystalline (Form 3), wherein the anhydrous crystalline Form 3 has an X-ray powder diffraction pattern as determined by Cu Ka radiation comprising at least three characterization peaks, in terms of 29, selected from peaks at 7.8+0.2°, 9.0+0.2°, 11.6+0.2°, 15.8+0.2°, and 19.1+0.2°; and 90% by weight or more of the total amount of the compound of Formula I in the composition is in the form of Form 3.

[0077] As used herein, the term “amorphous” refers to a solid material having no long range order in the position of its molecules. Amorphous solids are generally supercooled liquids in which the molecules are arranged in a random manner so that there is no well-defined arrangement, e.g., molecular packing, and no long range order. Amorphous solids are generally isotropic, i.e. exhibit similar properties in all directions and do not have definite melting points. For example, an amorphous material is a solid material having no sharp characteristic crystalline peak(s) in its X-ray power diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or several broad peaks (e.g., halos) appear in its XRPD pattern.

[0078] Hydrate forms of crystalline Edonentan are contemplated, e.g., Edonentan · (H₂O)m, where m is a fractional or whole number between about 0 and about 4 inclusive. For example, contemplated herein are anhydrate or monohydrate forms of crystalline Edonentan. In an embodiment, a disclosed crystalline form of Edonentan may have a water level of about 1 to 10% by weight (e.g., 3 to 9% or 5 to 8% by weight).Other components

[0079] In some embodiments, compositions comprise a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

[0080] Compositions for use in accordance with the presently disclosed methods can be administered to a human patient per se, or in compositions where they are mixed with other active ingredients (e.g., as in a combination therapy), or carriers, diluents, excipients or combinations thereof. Proper formulation may depend upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.

[0081] Compositions may be manufactured e.g., by means of mixing, dissolving, granulating, levigating, emulsifying, encapsulating or entrapping processes. Compositions for use in methods disclosed herein may also be formulated for particular delivery mechanisms and / or routes of administration, e.g., as further described herein.16IPTS / 200316898.1Attorney Docket No.: PFT-019WO

[0082] In some embodiments, the composition is an ophthalmic preparation comprising a therapeutically effective amount of Edonentan or a form thereof. As used herein, an “ophthalmic preparation” refers to a specialized dosage form designed to be instilled onto the external surface of the eye (topical), administered inside (intraocular) or adjacent (periocular) to the eye or used in conjunction with an ophthalmic device. In some embodiments, the ophthalmic preparation is in the form of a solution, suspension, or an ointment. In other embodiments, the ophthalmic preparation is in the form of a gel, a gel-forming solution, an ocular insert, a micro / nanoparticle preparations for topical or preferably intravitreal injection, or an implant, e.g., as further described herein.

[0083] In some embodiments, the ophthalmic preparation comprises a preservative. Examples of suitable preservatives include, but are not limited to, cationic wetting agents (e.g., benzalkonium chloride), organic mercurials (e.g., phenylmercuric nitrate, phenylmercuric acetate), organic acids or their esters (e.g., sorbic acid, esters of p-hydroxybenzoic acid such as methyl hydroxybenzoate, propylhydroxybenzoate), and alcohol substitutes (e.g., chlorobutanol, phenylethanol). The preservative can be present in the ophthalmic preparation in an amount in the range of about 0.002 % w / v to about 0.5 % w / v (e.g., 0.01 - 0.25 % w / v). The ophthalmic preparation can further comprise a preservative aid. Examples of suitable preservative aid include, but are not limited to, ethylenediaminetetraacetic acid (EDTA).

[0084] In some embodiments, the ophthalmic preparation comprises one or more additional excipients or agents to impart viscosity or lubrication, stabilize the active ingredients against decomposition, increase solubility of an active or inactive ingredient, adjust tonicity, or act as solvent. Examples of excipients or agents for imparting viscosity or lubrication include, but are not limited to, hypromellose, carbomer 974P, hydroxyethyl cellulose (HEC), polyvinyl alcohol, sodium hyaluronate, sodium carboxymethyl cellulose, Carbopol 940, hydroxypropylmethyl cellulose (HPMC), poloxamer, xyloglucan, alginic acid, sodium alginate, gellan gum, cellulose acetate phthalate, and xantham gum. Examples of excipients or agents as stabilizers include, but are not limited to, sodium bisulfite, sodium metabisulfite, sodium thiosulfate, and sodium sulfate / sulfuric acid, which can act as antioxidants. Examples of excipients or agents as solubilizers include, but are not limited to, providone, glycerol, polyethylene glycol (PEG), polypropylene glycol (PPG), PEG- stearate, poloxamer 407, tyloxapol, polysorbate 80, creatinine, cyclodextrin, and castor oil. Examples of excipients or agents for adjusting tonicity include sodium chloride, potassium chloride, calcium chloride dehydrate, magnesium chloride hexahydrate, sugars (e.g., sucrose, maltose, dextrose, etc.), glycerin, propylene glycol, mannitol, ascorbic acid, and acetylcysteine.17IPTS / 200316898.1Attorney Docket No.: PFT-019WO

[0085] In some embodiments, the ophthalmic preparation comprises one or more buffers to adjust pH. Examples of buffers for adjusting pH include, but are not limited to, sodium citrate, monobasic sodium phosphate, dibasic sodium phosphate, boric acid, hepatahydrate, sodium acetate trihydrate, sodium citrate dihydrate, histidine, and phosphate buffered saline (PBS). The resulting composition can have a pH value of 5.0-8.5 (e.g., 5.0-6.0, 5.2-5.8, 6.0-8.0, 6.6-7.8, 6.2-8.2, and 6.2-7.5)

[0086] In some embodiments, the ophthalmic preparation comprises one or more surfactants. Non-limiting examples of surfactants include sorbitan ether esters of oleic acid (e.g., polysorbate or Tween 20 and 80) and tyloxapol.Delivery mechanisms, administration, and dosing

[0087] In some embodiments, the step of administration comprises local administration, e.g., via a topical ophthalmic formulation and / or via injection of the compounds or compositions directly to the ocular tissue, for example, in a depot or sustained release formulation. Administration can be, e.g., intravitreal, suprachoroidal, periocular, topical, via subconjunctival injection of a formulation, via use of an implant technology, or any combination of the foregoing. In some embodiments, the step of administration comprises intravitreal administration.

[0088] In some embodiments, administration is achieved using a sustained release formulation or device which releases the Edonentan or form thereof over a period of time. In some embodiments, the sustained release formulation or device releases Edonentan or form thereof over a period of at least one month, at least two months, at least three months, at least four months, at least five months, or at least six months. In some embodiments, the sustained release formulation or device releases Edonentan or form thereof over a period of about one month, about two months, about three months, about four months, about five months, or about six months.

[0089] For example, liposomal preparations can be used to slowly release the Edonentan or form thereof, sustaining the desired pharmacological effects. Alternatively or additionally, polyvinyl alcohol nanoparticles can be prepared by well-known methods to afford a sustained or extended release-formulation for topical or intra-ocular applications.

[0090] In some embodiments, administration, e.g., intravitreal administration, is achieved via a sustained release bio-erodible device, such as an intravitreal bio-erodible device as described in International Patent Application No. WO 2022 / 232588 Al. The bio-erodible device (which may be referred to herein as a “bio-erodible implant,” “implant,” or like terms)18IPTS / 200316898.1Attorney Docket No.: PFT-019WOgenerally comprises Edonentan or a form thereof within a biodegradable substance, e.g., a biodegradable polymer.

[0091] Suitable polymeric materials or compositions for use in bio-erodible device include those materials which are biocompatible with the eye so as to cause no substantial interference with the functioning or physiology of the eye. Such polymeric materials may also be biodegradable, e.g., a biodegradable polymer.Biodegradable polymers

[0092] In some embodiments, the biodegradable polymer is a PLGA (poly(lactic-co-glycolic acid)), a copolymer of polylactic acid (PLA) and polyglycolic acid (PLG). PLGA polymers are known to degrade via backbone hydrolysis (bulk erosion), and the final degradation products are lactic and glycolic acids, which are non-toxic and considered natural metabolic compounds. Lactic and glycolic acids are eliminated safely via the Krebs cycle by conversion to carbon dioxide and water. Biocompatibility of PLGA polymers have been examined in both non-ocular and ocular tissues of animals and humans, and findings indicate that these polymers are well tolerated.

[0093] PLGA is synthesized through random ring-opening co-polymerization of the cyclic dimers of glycolic acid and lactic acid. Successive monomeric units of glycolic or lactic acid are linked together by ester linkages. The ratio of lactide to glycolide can be varied, altering the biodegradation characteristics of the product. By altering the ratio, it is possible to tailor the polymer degradation time. Importantly, drug release characteristics are affected by the rate of biodegradation, molecular weight, and degree of crystallinity in drug delivery systems. By altering and customizing the biodegradable polymer matrix, the drug delivery profile can be changed.

[0094] Examples of suitable PLGA polymers include, but are not limited to, the RESOMER® Product line from Evonik Industries identified as RG502, RG502H, RG503, RG503H, RG504, RG504H, RG505, RG653H, RG750S, RG752H, RG752S, RG753H, RG753S, RG755S, RG756S, RG757S, and RG858S. In some embodiments, the biodegradable polymer comprises a poly(lactic-co-glycolic acid) (PLGA), wherein the PLGA is selected from the group consisting of RG502, RG503, RG752S, RG753S, RG755S, RG756S, and RG858S. Compositions of each of the aforementioned PLGA polymers are known to those skilled in the art.19IPTS / 200316898.1Attorney Docket No.: PFT-019WO

[0095] In some embodiments, the bio-erodible comprises at least two types of PLGA. In some embodiments, the biodegradable polymer comprises at least three types of PLGA (e.g., three to six types of PLGA, three types of PLGA, four types of PLGA, or five types PLGA).

[0096] In some embodiments, the bio-erodible device comprises at least two PLGA, wherein each PLGA is independently selected from the group consisting of RG502, RG502H, RG503, RG503H, RG504, RG504H, RG505, RG653H, RG750S, RG752H, RG752S, RG753H, RG753S, RG755S, RG756S, RG757S, and RG858S.

[0097] PLGA copolymers can be an ester-terminated PLGA copolymer, as identified by the terminal ‘S’ in the product name, or an acid-terminated PLGA copolymer, as identified by the terminal ‘H’ in the product name. Inherent viscosities of PLGA copolymers range from approximately 0.14 to approximately 1.7 dL / g when measured at 0.1% w / v in CHCl₃ at 25 °C. with an Ubbelohde size 0c glass capillary viscometer. In some embodiments, polymers have a molar ratio of polyD, L-lactide (PLA) to polyglycolide (PLG) from approximately 50:50 to approximately 85:15, such as, but not limited to, 50:50, 65:35, 75:25, and 85:15. In some embodiments, the PLGA has a molar ratio of PLA and PLG of about 65:35.

[0098] Other examples of PLGA polymers include those produced by Lakeshore Biomaterials identified as, but not limited to, DLG 1A, DLG 3 A, or DLG 4A. Such DLG polymers include both acid (A) and ester (E) terminated polymers with inherent viscosities ranging from approximately 0.0.5 to approximately 1.0 dL / g when measured at 0.1% w / v in CHCl₃ at 25° C. with an Ubbelohde size 0c glass capillary viscometer. Example polymers used in various embodiments of the disclosure may include variation in the mole ratio of D, L-lactide to glycolide from approximately 1:99 to approximately 99:1, such as, but not limited to, 50:50, 65:35, 75:25, and 85:15.

[0099] RESOMERS® identified by an “RG” or “DLG” in the product name, such as RG752S, are poly(D, L-lactide-co-glycolide) (PLGA) having the general structure (Compound II):(Compound II)20IPTS / 200316898.1Attorney Docket No.: PFT-019WO

[0100] DLG can be synthesized with various D, L-lactide-glycolide ratios. In some embodiments, DLG, such as 1A, with an inherent viscosity of approximately 0.05 to approximately 0.15 dL / g is used. In some embodiment, DLGs, such as 2A, with an inherent viscosity of approximately 0.15 to approximately 0.25 dL / g is used.

[0101] Non-limiting examples of implant compositions include those disclosed in Examples 5 and 6 and / or in Tables 1 and 2 below.

[0102] In some embodiments, the Edonentan or form thereof is delivered via a bio-erodible ocular implant comprising a biodegradable polymer containing between 35% w / w and 45% of Edonentan, a form thereof, or a pharmaceutically acceptable salt thereof, and the biodegradable polymer comprises Resomer® RG502 (“RG502”), Resomer® RG503 (“RG503”), and Resomer® RG753S (“R753S”). RG502 and RG503 are both ester- terminated poly(D, L-lactide-co-glycolide) synthesized at about 50:50 ratio of lactide to glycolide. RG502 has an average Mwof between 7,000 and 17,000, and RG503 has an average Mwof between 24,000 and 38,000. RG753S is an ester-terminated poly(D, L-lactide-co-glycolide) synthesized at about 75:25 ratio of lactide to glycolide.

[0103] In some embodiments, the biodegradable polymer containing about 45% of Edonentan, a form thereof, or a pharmaceutically acceptable salt thereof.

[0104] The ratio of RG502: RG503: RG753S may vary depending on the embodiment, e.g., about 50%:about 10%:about 40% or about 20%:about 20%: about 60%.

[0105] In some embodiments, the Edonentan or form thereof is delivered via a bio-erodible ocular implant comprising a biodegradable polymer containing about 45% w / w of Edonentan, a form thereof, or a pharmaceutically acceptable salt thereof, and the biodegradable polymer comprises Resomer® RG502 (“RG502”), Resomer® RG503 (“RG503”), and Resomer® RG753S (“R753S”), at a ratio of about 50% RG503: about 10% RG502: about 40% RG753S.

[0106] In some embodiments, the Edonentan or form thereof is delivered via a bio-erodible ocular implant comprising a biodegradable polymer containing between 35% w / w and 45% of Edonentan, a form thereof, or a pharmaceutically acceptable salt thereof, and the biodegradable polymer comprises RG502, RG503, RG753S, and Resomer R203S (“R203S”). R203S is an ester-terminated lactide polymerwith an average Mwof between 18,000 and 28,000.

[0107] In some embodiments, the biodegradable polymer containing about 45% of Edonentan, a form thereof, or a pharmaceutically acceptable salt thereof.21IPTS / 200316898.1Attorney Docket No.: PFT-019WO

[0108] The ratio of RG502: RG503: RG753S: R203S may vary depending on the embodiment. A non-limiting example of a RG502: RG503: RG753S: R203S ratio is about 30%:about 20%:about 30%:about 20%.

[0109] Additional examples of PLGA polymers include the Viatel™ line of products supplied by Ashland (Wilmington, Delaware), such as the Viatel™ DLG5002A (Poly(D, L-Lactide-co-Glycolide) acid endcap LG 50:50), Viatel™ DLG5003A (Poly(D, L-Lactide-co-Glycolide) acid endcap LG 50:50), Viatel™ DLG5005A (Poly(D, L-Lactide-co-Glycolide) acid endcap LG 50:50), Viatel™ DLG5005E (Poly(D, L-Lactide-co-Glycolide) ester endcap LG 50:50), Viatel™ DLG7505A (Poly(D, L-Lactide-co-Glycolide) acid endcap LG 75:25), Viatel™ DLG8503E (Poly(D, L-Lactide-co-Glycolide) ester endcap LG 85:15), and Viatel™ (Poly(D, L-Lactide-co-Glycolide) ester endcap LG 85:15). (The ratios after “LG” signify the ratios of D, L-lactide to glycolide.)

[0110] Further examples of PLGA polymers include the Expansorb® line of products from SEQUENS (Ecully, France), such as Expansorb® PLGA 45:55, Expansorb® PLGA 50:50, Expansorb® PLGA 50:50 PEG, Expansorb® PLGA 55:45, Expansorb® PLGA 55:45-Glu, Expansorb® PLGA 50:50, Expansorb® PLGA 75:25, Expansorb® PLGA 75:25 PEG, Expansorb® PLGA 85:15, Expansorb® PLGA 90:10, and Expansorb® PLGA 95:5.Volumes

[0111] The volume that can be injected to a human eye at one time through the intravitreal route is typically up to or about 200 pL (e.g., up to or about 150 pL, up to or about 100 pL, up to or about 75 pL, or up to or about 50 pL.) In some embodiments, the volume of an injection pharmaceutical composition or an implant comprising the compound or pharmaceutical composition thereof is 50 pL or less, 45 pL or less, 40 pL or less, 35 pL or less, 30 pL or less, 25 pL or les, 20 pL or less, 15 pL or less, 10 pL or less, 7.5 pL or less, 5 pL or less, 4 pL or less, 3 pL or less, 2 pL or less, 1 pL or less, 0.5 pL or less, or 0.4 pL or less.

[0112] Suitable volumes for other routes may vary, e.g., about 0.3 to about 1.0 pL through a subre tinal route, and about 100 pL to about 200 pL via a suprachoroidal route. The needle used in these routes can be typically 23G to 30 G in size, e.g., 23G, 25G, 27G, 28G, 29G, or 30G. The dose depends on the concentration that can be formulated to fit this volume, potency, target efficacy and pharmacokinetic profile for each indication. Generally, the injections to the eye will not be administered at a frequency greater than once per month per eye. In some22IPTS / 200316898.1Attorney Docket No.: PFT-019WOembodiments, when a composition as described herein is administered in topical form (e.g., eye drop), the volume administered to a human eye at one time can be between about 25 p and 75 pL, e.g., about 50 pL. Concentrations of compound within an eye drop can vary depending on the embodiment. A non-limiting example of such a concentration is about 5 mg / mL).Dosing

[0113] In some embodiments, a formulation, e.g., an intravitreal formulation will comprise a dose of a composition comprising an Edonentan crystalline form in the range of about 1 pg to about 1 mg. A first exemplary formulation comprises about 1 pg to about 1 mg of a composition comprising an Edonentan crystalline form, about 10 mM histidine HC1, about 10% a, a- trehalose dihydrate, and about 0.01% polysorbate 20. A second exemplary formulation comprises about 1 pg to about 1 mg of a composition comprising an Edonentan crystalline form, about 10 mM sodium phosphate, about 40 mM sodium chloride, about 0.03% polysorbate 20, and about 5% sucrose.

[0114] In some embodiments, a total dose of about 100 pg, about 150 pg, about 200 pg, about 250 pg, about 300 pg, about 350 pg, about 400 pg, about 450 pg, about 500 pg, about 550 pg, about 600 pg, about 650 pg, about 700 pg, about 750 pg, or about 800 pg Edonentan is administered to the subject, e.g., via a sustained release formulation, e.g., a bio-erodible device, such as a bio-erodible device for intravitreal administration. In certain embodiments, the total dose comprises a therapeutically effective dose of the Edonentan or form thereof. In some embodiments in which a bio-erodible device is used, the total dose is contained in a single bio-erodible device. In some embodiments in which a bio-erodible device is used, the total dose is contained in multiple bio-erodible device, e.g., two bio-erodible devices, which are delivered together to the subject at the appropriate location in or around the eye, e.g., into the vitreous cavity.

[0115] In some embodiments, the composition is administered at a regular interval, e.g., at regular intervals of at least one, at least two, at least three, at least four, at least five, at least six months. In some embodiments, the regular interval is about one, about two, about three, about four, about five, or about six months. For example, in embodiments in which a bio-erodible device (e.g., an intravitreal bio-erodible device) is implanted into a subject, the subject may be re-implanted with another bio-erodible device at regular intervals.23IPTS / 200316898.1Attorney Docket No.: PFT-019WOExemplary formulations[011li F Nt6ormaonou.] By way of non-limiting example, Tables 1 and 2 provide examples of sustained delivery formulations and implantsd % Etonenan / wwTable 1. Examples of Edonentan Containing Sustained Delivery Formulations (1 -7) for the production of filmG502 R disksPolymer % w / wG502 RHG503 R1 30 50 5G503 RH02 30 100G504 R3 30 1004 30 50 50G504 RH5 30 50 506 30 40 40 20G53 R7H7 30 50 10 40G53S R765 / 35A / PL G PL24IPTS / 200316898.1Attorney Docket No.: PFT-019WOTable 2. Examples of Edonentan Containing Sustained Delivery Formulations for the li Ftormaonuproduction of implantsNo.d % Etonenan Polymer % w / w / wwC / 3 oo tnG502 R ooo8 30 1G503 RH0 50 409 45 10 50 4010 45 20 4G503 R0 4011 45 10 50 40G52S R712 45 20 60 2013 45 20 20 40 20G53S R714 45 10 50 4015 45 10 10 30 50G55S R716 45 20 20 20 4017 45 20 20 60G56S R718 45 10 50 4019 45 10 50 4020 45 20 30 30 2021 45 10 50 30 10 203S R 22 45 20 30 30 20EXAMPLES EXAMPLE 1: Compound Physicochemical and Biochemical Characterization

[0117] Provided in Table 3 below are physicochemical and biochemical data for Edonentan.25I PTS / 200316898.1Attorney Docket No.: PFT-019WOTable 3. Edonentan physicochemical and biochemical characterizationEdonentan(MW = 537)ETA IC5O = 1.54 nMFunctional Potency for ETAETB IC50 = 590 nMand ETB ReceptorsHigh potencyHigh specificity< 0.54 pg / mL;Solubility at pH 2< 1 pM326 pg / mL;Solubility at pH 7a607 pM8900 mg / mL; 16753 mMSolubility in Ethyl AcetateGoodStability in Solid StateStable(2h@125°C)LogD @pH 7.4 1.48log Pe = -5.9Permeability PSA = 109.66(PAMPA - log Pe) (PSAb) Mid-HighPermeabilityaThe data are from the amorphous form.bCalculated property that considers surface charge distributions (mainly O and N).Compounds with a PSA around 90 or below would be predicted to cross the blood-brain barrier.

[0118] In the above table, the physicochemical data, e.g., solubility, were obtained following standard protocols known in the field (see, e.g., Reis et al., Mini Rev Med Chem., 2010, 10(11): 1071-6; Avdeef et al., Expert Opin Drug Metab Toxicol., 2005, l(2):325-42; Bharate et al., Comb Chem High Throughput Screen., 2016, 19(6):461-9; and Jain et al., J Pharm Biomed Anal., 2013, 86:11-35.); and the biochemical data, i.e., potency for ETA / ETB, were obtained following the protocols known in the field (see, e.g., Kirkby et al., Br J 26IPTS / 200316898.1Attorney Docket No.: PFT-019WOPharmacol., 2008, 153(6): 1105- 19; and Maguire et al., Br J Pharmacol., 2014, 171(24):5555-72.).EXAMPLE 2: Formulation of Edonentan for Intravitreal Use in Rabbit

[0119] An appropriate amount of Edonentan is dissolved in neat PEG400, followed by addition of a 15% CD (HP-|3-cyclodextrin) solution. The final concentration of PEG400 is measured to be 20%. Target concentrations are 5 mg / ml and 0.5 mg / ml based on the amount of Edonentan. The resulting solution is filtered using a 0.25 micron filter.EXAMPLE 3: Effects of Edonentan and Endothelin 1 (ET-1) in a Rabbit Model

[0120] Adult, male Dutch-belted rabbits were given a 20 pl intravitreal injection (IVT) of 0.5 pg of Endothelin 1 ( ET-1) followed by a 20 pl intravitreal injection of 10-100 pg Edonentan given 30 min after the ET-1 administration. IOP, optical coherence tomography -angiography (OCT-A), and fluorescein angiograms (FA) were performed at pre-specified time points (30, 45, 60, and 75 min) following ET-1 and Edonentan administration to assess retinal blood flow changes induced by ET-1 + / - Edonentan.

[0121] Based in optical coherence tomography - angiography (OCT-A), ET-1 administration effectively induced a clear vasoconstriction in the retinal vascular beds within 45 min. Based on fluorescein angiography, the effect of ET-1 was then reversed with 10 pg of Edonentan administration within 90 min (60 min after Edonentan administration).EXAMPLE 4: Preparation of an Extended Release Formulation Containing Edonentan

[0122] A concentrated Edonentan dispersion is made by combining Edonentan with water, Vitamin E-TPGS and y-cyclodextrin. These ingredients are mixed to disperse the Edonentan, and then autoclaved. Sodium hyaluronate may be purchased as a sterile powder or sterilized by filtering a dilute solution followed by lyophilization to yield a sterile powder. The sterile sodium hyaluronate is dissolved in water to make an aqueous concentrate. The concentrated Edonentan dispersion is mixed and added as a slurry to the sodium hyaluronate concentrate. Water is added in sufficient quaintly (q.s„ as much as suffices, in this case as much as is required to prepare the homogenous mixture, dispersion, gel or suspension) and the mixture is mixed until homogenous. Examples of these compositions are provided in Table 4 below:27IPTS / 200316898.1Attorney Docket No.: PFT-019WOTable 4. Compositions of extended release formulation containing Edonentan Composition A Composition B Edonentan 2.0% (w / v) 8.0% (w / v)Sodium hyaluronate (polymeric) 2.5% (w / v) 2.3% (w / v)Sodium chloride 0.63% (w / v) 0.63% (w / v) dibasic sodium phosphate,0.30% (w / v) 0.30% (w / v) heptahydrateMonobasic sodium phosphate,0.04% (w / v) 0.04% (w / v) monohydrateWater for injection q.s. q.s.

[0123] These exemplary compositions contain a sufficient concentration of high molecular weight (i.e. polymeric) sodium hyaluronate so as to form a gelatinous plug or drug depot upon intravitreal injection into a human eye. Preferably the average molecular weight of the hyaluronate used is less than 2 million, and more preferably the average molecular weight of the hyaluronate used is between about 1.3 million and 1.6 million. The Edonentan particles are, in effect, trapped or held within this viscous plug of hyaluronate, so that undesirable pluming does not occur upon intravitreal injection of the formulation. Thus, the risk of drug particles disadvantageous!}' settling directly on the retinal tissue is substantially reduced, for example, relative to using a composition with a water-like viscosity, such as Kenalog® 40. Since sodium hyaluronate solutions are subject to dramatic shear thinning, these formulations are easily injected via 25 gauge, 27 gauge or even 30 gauge needles.EXAMPLE 5: Preparation and testing of exemplary formulation punch disks.

[0124] Small disks of polymer matrix incorporating Edonentan were prepared for elution rate assessment. The polymers, in particular weight ratios such as 50% RG503 and 50% RG503H (50 / 50 RG503 / RG503H) as shown in Table 5, were dissolved in methylene chloride. Edonentan, at 30% w / w with respect to the total weight of the polymers and Edonentan, was then added to the polymer solution and dissolved. The methylene chloride solution was then evaporated in a polytetrafluoroethylene (PTFE) dish at room temperature for 72 to 120 hours.28IPTS / 200316898.1Attorney Docket No.: PFT-019WOAfter the methylene chloride was removed, a thin film of homogeneous mixture of polymer and Eli F Ntormaonoud. onentan remained. Disks were prepared by using a biopsy punch to cut a disk of 2 mm in diameter out of each film resulting in disks weighing from 900 pg up to 1500 pg resulting in drug loadd % f Etonenanrom 270 pg up to 450 pg per disk. / ww

[0125] For in vitro drug release testing, three film disks per each formulation were cut from films and incubated inG502 R 3 mL of PBS pH 7.4 in a shaking incubator set at 37 °C and 50 rpm. The drug release was sampled at designated time points and the released Edonentan content as a function of time was analyzed by an HPLC assay, as shown in Figure 1. Corresponding G502 RHelution rates of the Edonentan from the disks as a function of time are provided in Figure 2.Drug release samples were analyzed by reversed phase chromatography using an Agilent G503 RPolaris Amide-C18 column at 40°C and mobile phases consisting of water and acetonitrile modified with trifluoroacetic acid. Quantitation was performed using an external standard with G503 RHdetection at 275 nm. The release medium was completely replaced with fresh medium during each sampling time point.G504 RTable 5. Exemplary formulations.G504 RHEdonentan Containing Sustained Delivery Formulations (1 -7)G53 R7Hfor the production of film disksPolymer % w / wG53S R765 / 35A / PL G PL1 30 50 502 30 100 3 30 1004 30 50 505 30 50 506 30 40 40 207 30 50 10 4029IPTS / 200316898.1Attorney Docket No.: PFT-019WOEXAMPLE 6: Preparation and testing of additional Extended Release Formulations Containing Edonentan

[0126] Using the procedure to produce homogeneous films in Example 5, additional formulations comprising various polymer and drug ratios shown in Table 6 were produced. The formulations were either evaporated at room temperature for 72 - 120 hours, as described in Example 1, or dried under vacuum at 25°C and 20 mbar for 24 hours. The films were then milled to a powder using a cryogenic mill. Small portions of the film were added to stainless steel cryogenic milling vessels with 2 to 3 appropriately sized grinding balls and precooled using liquid nitrogen for 2 or 3 minutes at 5 Hz. The material was then milled for 1 minute from 20 Hz to 25 Hz with 1 minute of rest at 5 Hz. This milling / rest cycle was repeated from 2 to 5 times. The resulting material was coarse to fine powder of homogenous material.

[0127] Implants were formed by injection molding with a modified Haake MiniJet (ThermoFisher Scientific). The homogeneous powder was loaded and injected into a mold consisting of channels of an appropriate size, such as 300 pm x 12 mm or 325 pm x 12 mm. The powder was loaded into a barrel leading into the mold and the mold placed under vacuum. The mold temperature was held at 15 - 25 °C. The cylinder, surrounding the powder loaded barrel, was held from 145°C to 165°C for 12 to 15 minutes to melt the powder blend. The injection was performed using an injection pressure of 230 bar to 320 bar holding for 2 to 5 minutes. A post injection pressure was held at 50 bar from 2 to 5 minutes. The mold was then cooled to 15 to 23°C before removing the mold from the injection molder. The molded fibers were then removed from the mold, and they were then cut into 4-mm implants containing 165 pg to 220 pg of Edonentan per implant.

[0128] Implants of select formulations were also formed by ram extrusion using a modified Barrell Micro Extruder (Barrell Engineering). The homogeneous powder was loaded into a 3 mm barrel and extruded through a 0.30 pm die maintaining a temperature of 68°C to 80°C and a flow rate of 5 pL / min to 6 pl / min. Extruded filaments were then cut into 4-mm implants containing 165 pg to 220 pg of Edonentan per implant. Resulting implants have similar performance characteristics as those produced with injection molding.

[0129] For in vitro drug release testing, three implants per each formulation were randomly cut from fiber trees and incubated in 3 mL of PBS pH 7.4 in a shaking incubator set at 37°C and 50 rpm. The drug release profiles of the implants were sampled at designated time points and the released Edonentan content analyzed by an HPLC assay, as shown in FIG. 3.Corresponding elution rates of the Edonentan from the implants as a function of time are30IPTS / 200316898.1Attorney Docket No.: PFT-019WOprovided in FIG. 4. The release medium was completely replaced with fresh medium during li Ftormaonueach sampling time point.No.Table 6. Exemplary formulations.d % Etonenan / E wwdonentan Containing Sustained Delivery Formulations (8 - 16)for the production of implantsG502 RPolymer % w / wG503 RH C / 3oo oo oG503 R8 30 10 50 409 45 10 50 G52S R7 4010 45 20 40 40G53S R711 45 10 50 4012 45 20 60 20G55S R713 45 20 20 40 2014 45 10 50 40G56S R715 45 10 10 30 5016 45 20 20 20 4017 45 20 20 6018 45 10 50 40203S R 19 45 10 50 4020 45 20 30 30 2021 45 10 50 30 1022 45 20 30 30 20EXAMPLE 7: Preparation of a Topical Edonentan Formulation

[0130] A topical Edonentan formulation can be prepared following a known method (e.g., WO 2016156639 Al). More specifically, 20 g of Cremophor® RH40 is dissolved in 75 mL of deionized water by magnetic stirring, which is allowed to stir until completely dissolved. Then 1.5 g of trometamol is added to the resulting solution and stirred for 15 minutes, achieving complete dissolution. 0.5 g of Edonentan is added and allowed to stir for 15 minutes, ensuring 31IPTS / 200316898.1Attorney Docket No.: PFT-019WOcomplete dissolution. Then 2 g of glycine and 1 g of boric acid are added and allowed to stir until completely dissolved. The resulting solution is added 100 mL deionized water in sufficient quantity. The final solution is filtered with filter paper, and a clear, colorless solution with a pH of 8.06 is obtained. The solution in dropper bottles eyedrop with a volume of 5 mL is packed.EXAMPLE 8: Topical Ophthalmic Solution Nanoparticles Containing Edonentan

[0131] Nanoparticles were prepared by solvent evaporation technique. A solution of 120 mg of 50:50 PLGA in 60 mL of ethyl acetate was prepared. To this solution it was incorporated under turboagitation an aqueous solution of 50 ml of water with 12 mg of Edonentan and 0.5 mg of polyvinyl alcohol. The resulting mixture was left under continuous agitation and under vacuum for 2 hours. Then the resulting preparation was ultra-centrifuged and washed with water three times to remove the nanoparticles from the medium. The nanoparticles thus obtained were dried in a vacuum oven and after evaluation, dispersed in an isotonic aqueous solution enough for a concentration of 5 rng / 1 mL of Edonentan.EXAMPLE 9: Treatment with Edonentan ameliorates symptoms and severity in a Phase 2a diabetic retinopathy study

[0132] A six-month Phase 2a randomized, sham-controlled, patient and reading center masked study was conducted to evaluate the efficacy and safety of Edonentan in a bio-erodible sustained release intravitreal (IVT) implant, (Edonentan Implant 1), in patients with moderate to severe non-proliferative Diabetic Retinopathy (DR) with no macular edema at the start of the trial. Both low dose (approximately 200 pg of Edonentan) and high dose (two implants; a total of approximately 400 pg of Edonentan) were evaluated in the study. Edonentan Implant 1 releases Edonentan over a period of about six months. Twelve patients (randomized 2:1, 8 active, 4 Sham Control) were evaluated for each dose level for visual field loss and diabetic retinopathy severity score (DRSS).Materials and MethodsFrequency Doubling Perimetry (FDP) measurements.

[0133] The Matrix perimeter (Carl Zeiss Meditec, Dublin, California, USA) was used to measure the FDP 30-2 visual field. The Matrix stimulus is a 0.25 cycles per degree sinusoidal grating which is phase reversed at 18 Hz. The grating appears to have twice as many alternating light and dark bars than are actually present. The minimum contrast threshold of the 5.08- 32IPTS / 2OO316898.1Attorney Docket No.: PFT-019WOdiameter stimulus is measured at each of the 55 test locations. The frequency doubling illusion on which FDP is based is thought to arise in the magnocellular and be ganglion cell dependent.Diabetic Retinopathy Severity Score.

[0134] The Diabetic Retinopathy Severity Scale (DRSS), established by the Early Treatment Diabetic Retinopathy Study (ETDRS) research group, subdivides diabetic retinopathy severity into categories based on findings visible on color fundus photography (including intraretinal microvascular abnormalities (IrMAs)), hemorrhages, microaneurysms, venous beading, and hard exudates. This scale progresses through various “steps” of increasing severity as follows:absent DR: levels 10-12DR questionable: levels 14, 15, and 20mild non-proliferative DR (NPDR): level 35moderate NPDR: level 43moderately severe NPDR: level 47severe NPDR: level 53mild proliferative DR (PDR): levels 60, 61moderate PDR: level 65high-risk PDR: level 71high-risk PDR (2): level 75advanced PDR: level 81advanced PDR (2): level level 85

[0135] Severity which cannot be graded is assigned level 90.Results

[0136] To assess visual field (VF) loss, a Frequency Doubling Perimetry (FDP) test was used to assess flicker light response of retinal ganglion cells (RGCs). The visual field mean deviation (VF MD) slope was approximately +1.8 dB / yr for patients in the low dose cohort (indicative of improvement) and approximately 0.01 dB / yr for the control group (Figure 5).The high-dose cohort had near-normal FDP measurements at baseline, with little to no room for improvement, and this cohort exhibited maintenance of visual field function according to this analysis.33IPTS / 200316898.1Attorney Docket No.: PFT-019WO

[0137] To assess the severity of diabetic retinopathy, patients were scored on the DRSS scale at various time points after administration of Edonentan Implant 1. The DRSS score remained stable or improved in 62.5% of the patients in the control and low dose cohorts and in 100% of the patients in the high dose cohort at mid-study (three months), with no patient experiencing two steps or more worsening in control or active treatment groups (FIGs. 6A-6C). By the end of the study (six months), the DRSS score was stable or improved in 62.5% of control patients (FIG. 7C) and in 75% of the patients in the low and high dose cohorts (FIGs.7A and 7B, respectively). While there were no patients with two steps or more worsening in the low dose cohort, 1 out of 8 of the patients in the control cohort and the high dose cohort had two steps or more worsening at six months.

[0138] These results indicate that administering an intravitreal implant which releases Edonentan can improve vision and reduce disease progression in diabetic retinopathy patients.

[0139] These results represent, to the inventors’ knowledge, the first successful demonstration of a therapeutic intervention which achieves these results in human diabetic retinopathy patients.EXAMPLE 10: Treatment with Edonentan results in decreased foveal avascular zone area in a Phase 2a diabetic retinopathy study

[0140] Enlargement of the foveal avascular zone (FAZ) provides a measure of macular ischemia and correlates with visual acuity decline in diabetic retinopathy patients. FAZ enlargement (or decrease) can be used as a predictor of decline of (or improvement of) visual acuity.

[0141] In the Phase 2a study mentioned in Example 9, patients in both the low dose and high dose cohorts were also evaluated for Foveal Avascular Zone (FAZ) area changes at baseline, 3 months and 6 months.Materials and MethodsFoveal Avascular Zone (FAZ) area measurements.

[0142] FAZ area was measured by optical coherence tomography angiography (OCTA), scanning a 3 mm x 3 mm area centered on the macula.Results

[0143] FAZ area decreased in the low and high dose cohorts (correlating with and / or predictive of improved visual acuity) at both the 3 month- and 6 month- timepoints after 34IPTS / 200316898.1Attorney Docket No.: PFT-019WOadministration of Edonentan Implant 1 (FIG.8). In contrast, FAZ area increased in the control cohort.

[0144] These results indicate that administering an intravitreal implant which releases Edonentan results in further detectable changes (here, decreases in FAZ area) which correlate with improved visual acuity.EXAMPLE 11: Treatment with Edonentan results in decreased macular and posterior pole ischemic index, total leakage index, and microaneurysm count in a Phase 2a diabetic retinopathy study

[0145] Ultra wide field fluorescein angiography (UWFA) is an invasive but sensitive and reliable tool to assess retinal vascular disease. Leakage index, microaneurysm count and ischemic index measured by UWFA are associated with overall level of diabetic retinopathy (DR) severity.

[0146] In the Phase 2a study described in Example 9, patients in both the low dose and high dose cohorts were also evaluated for macular and posterior pole ischemic index, total leakage index, and microaneurysm count at baseline, 3 months, and 6 months.Materials and MethodsTotal leakage, microaneurysm and ischemia measurements.

[0147] UWFA from patients were reviewed by masked reading center for image quality and suitability for DR severity grading and quantitative analysis. A selected single axial image was utilized for the UWFA images. An optimal UWFA image was identified for an early-mid phase image (i.e., typically between 45 seconds to 2 minutes) and a late phase image (i.e., typically 5-7 min). The early phase image was used for ischemia and microaneurysm (MA) analysis, while both the early and late phase images were used for leakage assessment.Results

[0148] In the macula, treatment with Edonentan Implant 1 led to improvements in macular ischemia, vascular leakage, and microaneurysm count at months 3 and 6 compared to control. The control group had worsening from baseline in ischemia (+0.24%, +0.10%), leakage (+2.55%, +4.29%), and microaneurysm (+12.86, +5.60) at months 3 and 6, respectively. The low dose and high dose groups had improvement in ischemia with differences compared t control of -0.21% and -0.82% at month 3, and -0.07% and -0.47% at month 6, respectively.35IPTS / 200316898.1Attorney Docket No.: PFT-019WOThe low dose and high dose groups had improvement in leakage with differences compared to control of -3.84% and -7.9% at month 3, and -3.47%, -6.64% at month 6, respectively. The low dose and high dose groups had improvement in microaneurysm counts with differences compared to control of -16.43 and -19.48 at month 3, and -13.46, -13.10 at month 6, respectively. (FIGSs. 9A-9C).

[0149] In the posterior pole, at 3 months after administration of Edonentan Implant 1, average ischemic index, total leakage index, and microaneurysm counts decreased in the high dose cohort, and these values appeared to remain stable or decrease in the low dose cohort. In contrast, average ischemic index and microaneurysm counts increased in control cohorts. At 6 months after administration of Edonentan Implant 1, average ischemic index and microaneurysm counts appeared to decrease or remain stable in both low and high dose cohorts.(FIGs. 10A-10C).

[0150] These results indicate that administering an intravitreal implant which releases Edonentan results in stable or improved indicators, which, taken as a whole, correlate with an overall decrease in DR severity.EXAMPLE 12: Treatment with Edonentan results in an increased contrast sensitivity in a Phase 2a diabetic retinopathy study

[0151] The ability to see delicate objects does not guarantee the ability to see large or medium-sized objects of low contrast. Contrast sensitivity (CS) is a measure of visual ability to distinguish an object from its background. Contrast sensitivity function (CSF) acquired with the quick CSF (qCSF) is a metric that incorporates both visual acuity (e.g., spatial resolution) and CS.

[0152] In the Phase 2a study mentioned in Example 9, patients in both the low dose and high dose cohorts were evaluated for low luminance contrast sensitivity changes at baseline, 8 weeks, and 20 weeks.Materials and MethodsContrast Sensitivity (CS) measurements.

[0153] Contrast sensitivity was evaluated using the qCSF (quick contrast sensitivity function) method on the AST Platform (Adaptive Sensory Technology, San Diego, CA, USA), a computerized method for evaluating the contrast thresholds over a wide range of contrast (0.002% - 100%) and spatial frequency (approximately 1 to 27 cycles per degree (CPD)). Participants were asked to read the presented optotypes, and their responses were registered (as 36IPTS / 200316898.1Attorney Docket No.: PFT-019WOcorrect, incorrect, or optotype not seen) on a tablet computer by a trained study nurse. All participants were tested monocularly for approximately 2 minutes. Sensitivity at single spatial frequencies (1.5 CPD, 3.0 CPD, and 6.0 CPD) and an integrated contrast sensitivity function metric defined as the area under the curve (AUC) across a predefined region of interest (ROI) encompassing the spatial frequencies of 1.25 CPD, 2.50 CPD and 5.0 CPD both served as measures of contrast sensitivity function and were used for statistical analysis. Contrast sensitivity is measured under two luminance conditions, including a regular luminance condition and a low luminance condition. The regular luminance condition is performed under standard lighting conditions, where the ambient room illumination does not exceed approximately 161.4 lux. The low luminance condition is performed under the same ambient lighting conditions, with the addition of a neutral density filter having an optical density of approximately 2.0, producing an approximately 2-log unit reduction in light reaching the eye.Results

[0154] At the 20-week timepoint contrast sensitivity remained stable (at 6.0 CPD) or increased (at 1.5 CPD or 3.0 CPD) in the low and high dose cohorts, whereas contrast sensitivity decreased in a pronounced manner in the control cohort at the same timepoint (Figure 11A-11D). Low luminance contrast sensitivity (LLCS), assessed as area under the curve across was also improved across the predefined region of interest in both low and high dose groups, as compared to controls, at weeks 8 and 20. LLCS had declines of -0.12 dB at month 2 and -2.01 dB in the control group, whereas both treatment groups had improvements at both visits (month 2: + 0.37 dB (low dose) and +0.64 dB (high dose); month 5: +0.65 dB (low dose) and +0.89 dB (high dose), with a difference from control of + 2.99 dB in the high dose group and +2.75 in the low dose group at month 5 (FIG. 11D).

[0155] When low luminance low contrast (LLCS) visual acuity was assessed, treatment with either low or high dose Edonentan Implant 1 resulted in a stabilization of visual acuity, whereas a decline was observed in the control group. At month 5, the differences in change from baseline in low contrast visual acuity (LLLC-VA) increased by +6.2 letters for the low dose group and +5.2 letters for the high dose group compared to control. (See month 5 in FIG. HE). In addition, patients with peripheral vision deficits demonstrated an improvement of +1.8 dB / year in the treatment group vs. +0.01 dB / year in the control group.

[0156] Moreover, change in leakage (see Example 11) and LLCS were strongly inversely correlated (r=-0.81; p<0.0001), indicating that decreases in leakage were associated with improvements in LLCS. (See FIG. 12)37IPTS / 200316898.1Attorney Docket No.: PFT-019WO

[0157] These results indicate that administering an intravitreal implant which releases Edonentan results in further detectable changes (here, maintenance or increase in contrast sensitivity), which correlate with overall maintenance or improvement in vision in DR patients.OTHER EMBODIMENTS

[0158] While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features set forth herein.38IPTS / 200316898.1

Claims

Attorney Docket No.: PFT-019WOCLAIMS1. A method for maintaining or improving the Diabetic Retinopathy Severity Score (DRSS) in a subject in need thereof, the method comprising a step of:implanting, into the vitreous cavity of the subject’s eye, a sustained release bio-erodible device having a total amount of between about 150 pg and about 650 pg of a crystalline form of Edonentan, wherein the subject exhibits:a) no change in the DRSS at three months or six months after implanting, b) an improvement of at least one step in the DRSS at three months or six months after implanting, orc) an improvement of at least two steps in the DRSS at six months after implanting.

2. A method for slowing vision loss or improving vision in a subject having diabetic retinopathy, the method comprising a step of:implanting, into the vitreous cavity of the subject’s eye, a sustained release bio-erodible device having a total amount of between about 150 pg and about 650 pg of a crystalline form of Edonentan, wherein the subject exhibits a visual field mean deviation (VF MD) slope of at least 0.50 dB / yr, at least 0.75 dB / year, at least 1.0 dB / year, at least 1.25 dB / year, at least 1.50 dB / year, or at least 1.75 dB / year as determined by a Frequency Doubling Perimetry (FDP) over a period of at least three months after implanting.

3. A method for maintaining vision in a subject having diabetic retinopathy, the method comprising a step of:implanting, into the vitreous cavity of the subject’s eye, a sustained release bio-erodible device having a total amount of between about 150 pg and about 650 pg of a crystalline form of Edonentan, wherein the subject maintains a visual field mean deviation (VF MD) slope of greater than -2.0 dB or greater than -1.0 dB as determined by a Frequency Doubling Perimetry (FDP) test for at least three months, at least four months, at least five months, at least six months, or about six months after implanting.

4. A method for maintaining or improving visual acuity in a subject having diabetic retinopathy, the method comprising a step of:39IPTS / 200316898.1Attorney Docket No.: PFT-019WOimplanting, into the vitreous cavity of the subject’s eye, a sustained release bio-erodible device having a total amount of between about 150 pg and about 650 pg of a crystalline form of Edonentan, wherein the subject exhibits:a) a detectable decrease relative to baseline in foveal avascular zone (FAZ) area as determined by optical coherence tomography angiography (OCTA) at three months after implanting,b) a decrease of at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, or at least 8%, at least 8% relative to baseline in FAZ area as determined by OCTA at three months or six months after implanting, orc) a score improvement of at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, or at least twenty Early Treatment Diabetic Retinopathy Study (ETDRS) letters as assessed by the Best Corrected Visual Acuity (BCVA) test using an ETDRS letter scoring protocol at three months after implanting, at six months after implanting, or as determined as the average of values at two, three, and four months after implanting.

5. A method for maintaining or improving contrast sensitivity in a subject having diabetic retinopathy, the method comprising a step of:implanting, into the vitreous cavity of the subject’s eye, a sustained release bio-erodible device having a total amount of between about 150 pg and about 650 pg of a crystalline form of Edonentan, wherein the subject exhibits:a) no change relative to baseline as determined by the quick contrast sensitivity function (qCSF) method on the Adaptive Sensory Technology (AST) Platform at 1.5 cycles per degree (CPD) measured at eight weeks or three months after implanting,b) an increase of about or at least 1.0 dB relative to baseline as determined by the qCSF method on the AST Platform at 1.5 CPD measured at 20 weeks or six months after implanting,c) no change relative to baseline as determined by the qCSF method on the AST Platform at 3.0 CPD measured at eight weeks, 20 weeks, three months, or six months after implanting,40IPTS / 200316898.1Attorney Docket No.: PFT-019WOd) an increase of about or at least 0.5 dB relative to baseline as determined by the qCSF method on the AST Platform at 3.0 CPD measured at eight weeks, 20 weeks, three months, or six months after implanting,e) no change relative to baseline as determined by the qCSF method on the AST Platform at 6.0 CPD measured at eight weeks, twenty weeks, three months, or six months after implanting, orf) an increase of about or at least 0.5 dB baseline as determined by the qCSF method on the AST Platform at 6.0 CPD measured at eight weeks or three months after implanting.

6. A method for slowing or reversing disease progression in a subject having diabetic retinopathy, the method comprising a step of:implanting, into the vitreous cavity of the subject’s eye, a sustained release bio-erodible device having a total amount of between about 150 pg and about 650 pg of a crystalline form of Edonentan, wherein the subject exhibits:a) no change relative to baseline in the macular ischemic index as determined by ultra wide field fluorescein angiography (UWFA) measured at three months or six months after implanting,b) a decrease of at least or about 0.3%, at least or about 0.4%, or at least or about 0.5% relative to baseline in the macular ischemic index as determined by UWFA measured at three months or six months after implanting,c) no change relative to baseline in the macular total leakage index as determined by UWFA measured at three months or six months after implantingd) a decrease of at least or about 2%, at least or about 3%, at least or about 4%, or at least or about 5% relative to baseline in the macular total leakage index as determined by UWFA measured at three months or six months after implanting, e) no change relative to baseline in the macular microaneurysm count as determined by UWFA measured at three months or six months after implanting, f) a decrease of at least or about 2, at least or about 3, at least or about 4, or at least or about 5, relative to baseline in the macular microaneurysm count as determined by UWFA measured at three months or six months after implanting, g) no change relative to baseline in the posterior pole ischemic index as determined by UWFA measured at three months or six months after implanting,41IPTS / 200316898.1Attorney Docket No.: PFT-019WOh) a decrease of at least or about 0.3%, at least or about 0.4%, or at least or about 0.5% relative to baseline in the macular ischemic index as determined by UWFA measured at three months or six months after implanting,i) no change relative to baseline in the posterior pole total leakage index as determined by UWFA measured at three months or six months after implanting j) a decrease of at least or about 1%, at least or about 2%, or at least or about 3% relative to baseline in the macular total leakage index as determined by UWFA measured at three months or six months after implanting,k) no change relative to baseline in the posterior pole microaneurysm count as determined by UWFA measured at three months or six months after implanting, orl) a decrease of at least or about 2, at least or about 3, at least or about 4, at least or about 5, at least or about 6, at least or about 7, at least or about 8, at least or about 9, at least or about 10, at least or about 11, at least or about 12, at least or about 13, at least or about 14, at least or about 15, at least or about 16, at least or about 17, at least or about 18, at least or about 19, or at least or about 20, relative to baseline in the posterior pole microaneurysm count as determined by UWFA measured at three months or six months after implanting.

7. A method for slowing disease progression in a subject having or at risk of having diabetic retinopathy, the method comprising a step of administering to the subject a composition comprising a therapeutically effective amount of Edonentan, a pharmaceutically acceptable salt thereof, a crystalline form thereof, or an amorphous form thereof.

8. The method of claim 7, wherein slowing disease progression comprises slowing vision loss or improving vision.

9. The method of claim 8, wherein slowing vision loss comprises slowing peripheral vision loss or improving peripheral vision.

10. The method of claim 9, wherein improving peripheral vision loss comprise improving peripheral vision over a period of at least 3 months after the step of administration.42IPTS / 200316898.1Attorney Docket No.: PFT-019WO11. The method of any one of claims 7-10, wherein slowing disease progression comprises maintaining or improving a clinical score associated with severity of diabetic retinopathy.

12. The method of claim 11, wherein the clinical score is maintained or improved over a period of at least three months from the step of administering.

13. The method of claim 11, wherein the clinical score is the Diabetic Retinopathy Severity Score.

14. The method of any one of claims 7-13, wherein slowing disease progression comprises maintaining or improving contrast sensitivity.

15. The method of claim 14, wherein maintaining or improving contrast sensitivity comprises maintaining or improving contrast sensitivity over a period of at least 3 months after the step of administration.

16. The method of any one of claims 7-15, wherein slowing disease progression comprises maintaining or improving visual acuity.

17. The method of claim 16, wherein maintaining or improving visual acuity comprises maintaining or improving visual acuity over a period of at least 3 months after the step of administration.

18. The method of any one of claims 1-17, wherein the subject is a mammal.

19. The method of claim 18, wherein the mammal is a human.

20. The method of any one of claims 7-19, wherein the administration comprises intravitreal administration.

21. The method of claim 20, wherein intravitreal administration comprises implanting, into the vitreous cavity of the eye, a sustained release, bio-erodible device which comprises the composition.43IPTS / 200316898.1Attorney Docket No.: PFT-019WO22. The method of any one of claims 1-6 or 21, wherein the bio-erodible device comprises a poly(lactic-co-glycolic acid) (PLGA) polymer.

23. The method of any one of claims 1-6, 21, or 22, wherein the bio-erodible device contains a total amount of about 200 ptg, about 400 ptg, about 500 ptg, or about 600 ptg of Edonentan.

24. The method of any one of claims 1-23, wherein the administration comprises administering the composition at a regular interval.

25. The method of claim 24, wherein the regular interval is about three months.

26. The method of claim 24, wherein the regular interval is at least three months.

27. The method of claim 26, wherein the regular interval is about four months.

28. The method of claim 27, wherein the regular interval is about six months.44IPTS / 200316898.1

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