Methods of treating glaucoma

Abstract

Methods of ameliorating a symptom (e.g., vison loss) associated with glaucoma impairment in a subject in need thereof; methods involve administering an Edonentan composition.

Description

Attorney Docket No.: PFT-018WOMETHODS OF TREATING GLAUCOMACROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 756,759 (filed February 10, 2025) and U.S. Provisional Application No. 63 / 827,799 (filed June 20, 2025), the contents of each of which are incorporated by reference herein in their entirety.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] Glaucoma is a leading cause of global blindness characterized by visual field defects and excavation of the optic nerve head. High intraocular pressure is the only known modifiable risk factor. However, even with normal intraocular pressure, there is gradual loss of vision over time. The pathophysiological mechanism of glaucoma is still largely unknown.

[0004] There are three basic types of glaucoma: primary, secondary, and congenital. Primary glaucoma is the most common type and can be divided into open-angle and closedangle glaucoma. Primary open angle glaucoma (“POAG”) is the most frequent type of glaucoma observed in the United States. POAG is usually detected in its early stages during routine eye examinations. Primary closed angle glaucoma, also called acute glaucoma, usually has a sudden onset and is characterized by eye pain and blurred vision. Secondary glaucoma occurs as a complication of a variety of other conditions, such as injury, inflammation, generalized vascular disease, and diabetes. Congenital glaucoma is due to a developmental defect in the eye’s drainage mechanism.

[0005] There remains a need to more effectively reduce the incidence of, treat, or otherwise ameliorate glaucoma and glaucoma-related impairment.1IPTS / 200315815.1Attorney Docket No.: PFT-018WOSUMMARY

[0006] The present disclosure addresses this need with methods of ameliorating a symptom associated with glaucoma impairment in a subject in need thereof.

[0007] In one aspect, provided are methods for ameliorating impaired blood flow to the optic nerve head in a subject having glaucoma, 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: an increase relative to baseline of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, or at least 30% in the mean blur rate (MBR) as determined by laser speckle flowgraphy at seven days, one month, two months, three months, four months, five months, or six months after implanting.

[0008] In one aspect, provided are methods for maintaining or improving vision in a subject having glaucoma, 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) an increase relative to baseline of at least or about 0.25 dB, at least or about 0.50 dB, at least or about 0.75 dB, at least or about 1.0 dB, at least or about 1.25 dB, at least or about 1.50 dB, at least or about 1.75 dB, or at least about 2.00 dB in the visual field mean deviation (VF MD) as determined by a Humphrey Field Analyser at three months after implanting, six months after implanting, or as determined as the average of values at two, three, and four months after implanting, (b) an improvement relative to baseline of at least 7 dB in visual field sensitivity in predefined areas based on Garway-Heath sectors that include a minimum of 5 measurable visual field test point, as determined by a Humphrey Field Analyser at six months after implanting, or (c) an improvement in visual acuity comprising 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.

[0009] In one aspect, provided are methods for ameliorating disease progression in a subject having glaucoma, the method comprising a step of: implanting, into the vitreous cavity of the 2IPTS / 200315815.1Attorney Docket No.: PFT-018WOsubject’s eye, a sustained release bio-erodible device having a total amount of between about 150 pg and about 650 µg of a crystalline form of Edonentan, wherein the subject exhibits: an increase relative to baseline of at least or about 0.25 µm, at least or about 0.50 µm, at least or about 0.75 µm, at least or about 1.0 µm, at least or about 1.25 µm, at least or about 1.50 µm, at least or about 1.75 µm, at least or about 2.00 µm, at least or about 2.25 µm, at least or about 2.50 µm, at least or about 2.75 µm, at least or about 3.00 µm, at least or about 3.25 µm, at least or about 3.50 µm, at least or about 3.75 µm, at least or about 4.00 µm, at least or about 4.25 µm, at least or about 4.50 µm, at least or about 4.75 µm, at least or about 5.00 µm, at least or about 5.25 µm, at least or about 5.50 µm, at least or about 5.75 µm, at least or about 5.00 µm, in the retinal nerve fiber layer (RNFL) as determined by optical coherence tomography at three months or six months after implanting.

[0010] In one aspect, provided are methods of ameliorating a symptom associated with glaucoma impairment in a subject, comprising a step of administering to the subject a composition comprising Edonentan, a pharmaceutically acceptable salt thereof, a crystalline form thereof, or an amorphous form thereof.

[0011] In some embodiments, the symptom comprises vision loss, e.g., peripheral vision loss.

[0012] In some embodiments, administration results in maintenance or improvement of the visual field. For example, in some embodiments, the method results in an improvement of the visual field comprising an increase of at least 0.25 dB in the visual field mean deviation (VF MD) as determined by a Humphrey Field Analyser at three months after administration or at six months after administration.

[0013] In some embodiments, the symptom comprises impaired blood flow to the optic nerve head. In some embodiments, administration results in an increase in optic nerve head (ONH) capillary blood flow, for example, an increase in the Mean Blur Rate (MBR) as determined by laser speckle flowgraphy. In some embodiments, the increase in MBR represents an increase of at least a 5% increase from baseline for three months or for six months after administration.

[0014] In some embodiments, administration results in reduction of thinning or maintenance of or increase in retinal nerve fiber layer (RNFL) thickness after administration of the composition. For example, in some embodiments, administration results in maintenance of or an increase in RNFL thickness which comprises an increase of at least 0.5 µm from a baseline level at three months after administration.

[0015] In some embodiments, the subject is a mammal, e.g., a human.3IPTS / 200315815.1Attorney Docket No.: PFT-018WO

[0016] In some embodiments, the subject is at risk for developing glaucoma, or is diagnosed with or suffering from glaucoma.

[0017] In some embodiments, the 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.

[0018] In some embodiments, the bio-erodible device contains a total dose of about 200 pg, about 400 pg, or about 500 pg of Edonentan.

[0019] In some embodiments, administration comprises administering the composition 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

[0020] 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.

[0021] 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 days followed by a decrease in elution rate, with a sustained steady-state release for some matrices as determined by HPLC.

[0022] FIG. 3 depicts drug release profiles of Edonentan in implants of exemplary formulations each containing a polymer matrix incorporating Edonentan. The in vitro release4IPTS / 200315815.1Attorney Docket No.: PFT-018WOresults show that the combination of polymer matrix with Edonentan provides sustained release of active as determined by HPLC.

[0023] 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.

[0024] FIG. 5 depicts percent Mean Blur Rate (MBR), indicative of optic nerve head (ONH) blood flow, changes from baseline at various timepoints after administration of Edonentan Implant 1 (a bio-erodible sustained release intravitreal implant comprising Edonentan) in a 6-month Phase 1 and 2a glaucoma study. “Low dose” refers to a total dose of approximately 200 ptg; “high dose” refers to a total dose of approximate 400 ptg. See Example 7.

[0025] FIGs. 6A-6D depict Visual Field (VF) Mean Deviation (MD) changes from baseline (in dB; decibels) in treatment and control groups in a Phase 1 or Phase 2a glaucoma study. FIG. 6A and 6B depict results from a Phase 1 study at three months and six months, respectively, after administration of Edonentan Implant 1. “FE” refers to the fellow eye; “SE” refers to the study eye with advanced glaucoma. The number of eyes for each group for FIG.6A (three-month timepoint) were 4 for “combined doses fellow eye,” 3 for “low dose study eye,” and 2 for “high dose study eye.” The number of eyes for each group for FIG. 6B (six-month time-point) were 5 for “combined doses fellow eye,” 3 for “low dose study eye,” and 1 for “high dose study eye.” FIG.6C depicts results from a Phase 2a study at mid-study (two to four months) and six months after administration of Edonentan Implant 1 for control (n=8), low dose (n=9), and high dose (n=8) treatment groups. FIG.6D depicts VF MD changes (dB) from baseline over a 6-month (24 weeks) period after administration of Edonentan Implant 1. “Low dose” refers to a total dose of approximately 200 ptg (n=9); “high dose” refers to a total dose of approximate 400 ptg (n=8). “Control” refers to sham control groups (n=8). The slopes for the control, low dose, and high dose groups were about -1.1606 dB / year, +1.1074 dB / year, and +1.5225 dB / year, respectively. See Example 9.5IPTS / 200315815.1Attorney Docket No.: PFT-018WO

[0026] FIG. 7 depicts Visual Field (VF) Mean Deviation (MD) changes from baseline (in dB; decibels) over a 6-month (24 weeks) period after administration of Edonentan Implant 1, with a separate line shown for individual patients in treatment or control groups in a Phase 1 / 2a glaucoma study. “Low dose” refers to a total dose of approximately 200 ptg (n=9); “high dose” refers to a total dose of approximate 400 ptg (n=8). “Control” refer to sham control groups (n=8). See Example 9.

[0027] FIGs. 8A-8C depicts retinal nerve fiber layer (RNFL) changes (as measured by optical coherence tomography (OCT)) (mean ± SD) from baseline at 3 months and 6 months (FIG. 8A) or over time (FIG. 8B) after administration of Edonentan Implant 1 in a Phase 2a glaucoma study. In FIG. 8B, the slopes for the control, low dose, and high dose groups were about −5.4363 µm / year, + 7.7228 µm / year, and +2.0985 µm / year, respectively. FIG. 8C shows the RNFL thickness over time, with a separate line shown for individual patients in combined control, low dose, or high dose groups. “Low dose” refers to a total dose of approximately 200 pg (n=7); “high dose” refers to a total dose of approximate 400 pg (n=6). “Combined Control” refer to sham control groups (n=7). See Example 9.

[0028] FIGs. 9A and 9B are a scatter plot and a fit plot, respectively, depicting correlations between retinal nerve fiber layer (RNFL) changes and Visual Field (VF) Mean Deviation (MD) changes from baseline to month 6 (24 weeks) in a Phase 1 / Phase 2a glaucoma study with Edonentan Implant 1. In FIG. 9A, each point represents measurements from a patient, with orange dots representing patients in the low dose group (200 µg Edonentan), blue dots representing patients in the high dose group (400 µg Edonentan), and gray dots representing patients in the sham control group. See Example 9.

[0029] FIGs. 10A and 10B depicts the percentage of patients with a > 7 dB visual field change improvement (FIG. 10A) or worsening (FIG. 10B) in a pre-defined retinal area of > 5 measurable points from baseline at 6 months from time of administration with Edonentan Implant 1. In Figure 10A, 0 / 8 Control, 2 / 9 low dose, and 3 / 8 high dose patients exhibited a > 7 dB visual field change improvement, n Figure 10B, 1 / 8 Control, 0 / 9 low dose, and 0 / 8 high dose patients exhibited a > 7 dB visual field change worsening.

[0030] FIG. 10C depicts the percentage of patients with a > 7 dB visual field change in a pre-defined retinal area of > 5 measurable points from baseline over time (within 6 months, 12 months, 18 months, and 66 months) in a natural history study. Worsening of > 7 dB (left-hand in each set of bars) or improvement of > 7 dB (right-hand bar witin each set of bars) are shown in separate bars. Values shown at month 6 are 13.2% worsening and 2.7 improvement at month 6IPTS / 200315815.1Attorney Docket No.: PFT-018WO6, 16.4% worsening and 2.9% improving at month 12, 25% worsening and 1.8% improving at month 18, and 47.3% worsening and 3.6% improving at month 66.DETAILED DESCRIPTION OF CERTAIN EMBODIMENTSDefinitions

[0031] 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%, 19%, 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.

[0032] 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.

[0033] 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.

[0034] 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 to7IPTS / 200315815.1Attorney Docket No.: PFT-018WOhydrolysis under physiological conditions due to the presence of hydrolytically and / or enzymatically susceptible functional groups.

[0035] 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.

[0036] 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.

[0037] 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 used (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.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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 8IPTS / 200315815.1Attorney Docket No.: PFT-018WOof 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.

[0043] 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 some 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.

[0044] 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 ameliorating symptoms associated with glaucoma impairment

[0045] 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.

[0046] In many embodiments, the subject is a mammal, e.g., a human.9IPTS / 200315815.1Attorney Docket No.: PFT-018WO

[0047] In certain embodiments, the subject has or is at risk of having glaucoma, and / or exhibits one or more signs of having or being at risk of having glaucoma.Ameliorating a symptom

[0048] Provided methods result, in some embodiments, in amelioration of a symptom and / or slowing of disease progression, such as of glaucoma. “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 subject 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%.

[0049] In some embodiments, provided methods result in the amelioration of (e.g., slowing or preventing) of vision loss (e.g., central and / or peripheral vision loss), which would normally be expected in a glaucoma 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.

[0050] 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.

[0051] Contrast sensitivity can be evaluated using the qCSF (quick contrast sensitivity function) method on the AST Platform (Adaptive Sensory Technology, San Diego, CA, USA),10IPTS / 200315815.1Attorney Docket No.: PFT-018WOa 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 sensitivity function 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.

[0052] 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.

[0053] 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.

[0054] In some embodiments, provided methods result in amelioration of impaired blood flow to the optic nerve head, e.g., by increasing optic nerve head capillary blood flow. In some embodiments, provided methods result in an increase in the Mean Blur Rate (MBR) as determined by laser speckle flowgraphy. For example, the increase in the MBR can be, in some embodiments, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, or at least 30% over a baseline level. By “baseline level,” it is meant the level in the same subject at the time of administration or before administration, or a similar comparable reference level, such as a reference level from a control subject.

[0055] In some embodiments, provided methods result in an increase in retinal nerve fiber layer (RNFL) thickness after administration of the composition, e.g., as determined by a 11IPTS / 200315815.1Attorney Docket No.: PFT-018WOtechnique such as optical coherence tomography. For example, the increase in the RNFL thickness can be, in some embodiments, at least 0.5 μm at least 1.0 μm, at least 1.5 μm, at least 2.0 μm, at least 2.5 μm or at least 3.0 μm from a baseline level at or for three months after administration.

[0056] In some embodiments, provided methods result in the slowing or preventing of a vision-threatening complication, such as macular edema.

[0057] 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.

[0058] 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.

[0059] 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, or at least twenty Early Treatment of 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.

[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 glaucoma.

[0061] 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.12IPTS / 200315815.1Attorney Docket No.: PFT-018WOCompositions comprising Edonentan and / or forms thereofEdonentan

[0062] 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)

[0063] 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.

[0064] 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.

[0065] 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.

[0066] 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).

[0067] 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 13IPTS / 200315815.1Attorney Docket No.: PFT-018WO0 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

[0068] In certain embodiments, compositions comprise a crystal form of the compound of Formula I:

[0069] 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°.

[0070] 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°.

[0071] In some embodiments, Form 4 has a Tmof about 163 °C by DSC analysis.14IPTS / 200315815.1Attorney Docket No.: PFT-018WO

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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 an15IPTS / 200315815.1Attorney Docket No.: PFT-018WOembodiment, 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

[0078] In some embodiments, compositions comprise a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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).16IPTS / 200315815.1Attorney Docket No.: PFT-018WO

[0083] 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.

[0084] 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)

[0085] 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

[0086] 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.17IPTS / 200315815.1Attorney Docket No.: PFT-018WO

[0087] 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.

[0088] 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.

[0089] 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) generally comprises Edonentan or a form thereof within a biodegradable substance, e.g., a biodegradable polymer.

[0090] 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

[0091] 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.

[0092] 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 18IPTS / 200315815.1Attorney Docket No.: PFT-018WOare 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.

[0093] 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. 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).

[0094] 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.

[0095] 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.

[0096] 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 19IPTS / 200315815.1Attorney Docket No.: PFT-018WOto glycolide from approximately 1:99 to approximately 99:1, such as, but not limited to, 50:50, 65:35, 75:25, and 85:15.

[0097] 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)

[0098] 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.

[0099] Non-limiting examples of implant compositions include those disclosed in Examples 5 and 6 and / or in Tables 1 and 2 below.

[0100] 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.

[0101] In some embodiments, the biodegradable polymer containing about 45% of Edonentan, a form thereof, or a pharmaceutically acceptable salt thereof.

[0102] 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%.

[0103] 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 20IPTS / 200315815.1Attorney Docket No.: PFT-018WOcomprises Resomer® RG502 (“RG502”), Resomer® RG503 (“RG503”), and Resomer® RG753S (“R753S”), at a ratio of about 50% RG503: about 10% RG502: about 40% RG753S.

[0104] 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 polymer with an average Mwof between 18,000 and 28,000.

[0105] In some embodiments, the biodegradable polymer containing about 45% of Edonentan, a form thereof, or a pharmaceutically acceptable salt thereof.

[0106] 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%.

[0107] 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.)

[0108] 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

[0109] 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 pharmaceutical21IPTS / 200315815.1Attorney Docket No.: PFT-018WOcomposition 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.

[0110] 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 some embodiments, 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 pL 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

[0111] 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.

[0112] 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 delivered22IPTS / 200315815.1Attorney Docket No.: PFT-018WOtogether to the subject at the appropriate location in or around the eye, e.g., into the vitreous cavitli F Ntormaonouy..

[0113] In some embodiments, the composition is administered at a regular interval, e.g., at regular intervd % Etonenanals of at least one, at least two, at least three, at least four, at least five, at least six / wwmonths. In some embodiments, the regular interval is about one, about two, about three, about four, about five, or aboG502 Rut 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.G502 RHExemplary formulationsG503 R

[0114] By way of non-limiting example, Tables 1 and 2 provide examples of sustained delivery formulations and implantsG503 RHTable 1. Examples of Edonentan Containing Sustained Delivery Formulations (1 -7) for G504 Rthe production of film disksG504 RHPolymer % w / wG53 R7HG53S R71 30 50 5065 / 35A / PL 2 30 100G PL3 30 1004 30 50 505 30 50 506 30 40 40 207 30 50 10 4023IPTS / 200315815.1Attorney Docket No.: PFT-018WOTable 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 20EXAMPLESEXAMPLE 1: Compound Physicochemical and Biochemical Characterization

[0115] Provided in Table 3 below are physicochemical and biochemical data for Edonentan.24IPTS / 200315815.1Attorney Docket No.: PFT-018WOTable 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.

[0116] 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 25IPTS / 200315815.1Attorney Docket No.: PFT-018WOPharmacol., 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

[0117] 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

[0118] 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.

[0119] 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

[0120] 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 'Fable 4 below:26IPTS / 200315815.1Attorney Docket No.: PFT-018WOTable 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.

[0121] 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.

[0122] 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.27IPTS / 200315815.1Attorney Docket No.: PFT-018WOAfter 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

[0123] 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 4028IPTS / 200315815.1Attorney Docket No.: PFT-018WOEXAMPLE 6: Preparation and testing of additional Extended Release Formulations Containing Edonentan

[0124] 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.

[0125] 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.

[0126] 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.

[0127] 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 are29IPTS / 200315815.1Attorney Docket No.: PFT-018WOprovided in FIG. 4. The release medium was completely replaced with fresh medium during li Ftormaonueach sampling time point.No.Table 6. Exemd % Etonenanplary formulations. / wwEdonentan Containing Sustained Delivery Formulations (8 - 16)G502 Rfor the production of implantsG503 RH Polymer % w / wC / 3 ooG503 R ooo8 30 10 50 G52S R7 409 45 10 50 40G53S R710 45 20 40 4011 45 10 50 40G55S R712 45 20 60 2013 45 20 20 40 20G56S R714 45 10 50 4015 45 10 10 30 5016 45 20 20 20 4017 45 20 20 60203S R 18 45 10 50 4019 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

[0128] 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 30IPTS / 200315815.1Attorney Docket No.: PFT-018WOcomplete 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

[0129] 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 1 / 2a glaucoma study

[0130] A six-month Phase l / 2a study was conducted to evaluate the efficacy and safety of Edonentan in a bio-erodible sustained release intra vitreal (IVT) implant (Edonentan Implant 1 ) in patients with glaucoma. Both low dose (approximately 200 ug of Edonentan) and high dose (two implants; a total of approximately 400 pg of Edonentan) were evaluated in the studies. Edonentan Implant 1 releases Edonentan over a period of about six months.

[0131] The Phase 1 study, which included three patients per dose group, was an open-label, single ascending dose study in patients with advanced glaucoma. The Phase 2a study, which included twelve patients per dose group, was a randomized, sham-controlled, patient and reading center masked study in patients with progressive mild to moderate glaucoma who were already on current intra-ocular pressure (IOP) treatments.

[0132] Mean blur rate (MBR) change was used as an index of optic nerve head (ONH). Visual field (VF) tests were used to determine whether an eye shows progressive glaucomatous damage. Anatomical changes in RNFL thickness, which can predict glaucoma progression and visual field loss, was measured by optical coherence tomography (OCT).31IPTS / 200315815.1Attorney Docket No.: PFT-018WOMaterials and MethodsLaser Speckle Flowgraphy (LSFG) measurements

[0133] Measurements of ONH capillary blood flow were made using an LSFG instrument (Softcare, lizuka, Japan). In brief, the LSFG device was focused on an area centered on the ONH. The area is approximately 3.8 mm x 3.0 mm (width x height). The laser (1 = 830 nm, maximum output power, 1.2 mW) generates a speckle pattern whose contrast was reduced (‘blurred’) by motion within the tissue sample (e.g., of red blood cells passing through the vasculature). Images were acquired and recorded at a frequency of 30 frames per second for a total of 4 seconds to complete one LSFG scan. Three such scans of 4-second duration each were obtained for each eye at each time point and stored for offline analysis of blood flow parameters. From the average of the three scans (120 samples each, 30 frames / second x 4 seconds), the MBR - a parameter representing blood flow - was computed for each pixel of the composite using the LSFG Analyzer software (LSFG Analyzer, Ver 3.8.0.4, Softcare, lizuka, Japan) along with additional parameters representing the pulsatile flow through each cardiac cycle. Then, the ONH was outlined using an ellipse to create the region of interest (ROI). The area within the ONH ROI occupied by large vessels was thresholded and masked, leaving only the ONH tissue capillaries to contribute to the calculation of ONH capillary blood flow.Visual field measurements

[0134] A 700-series Humphrey Field Analyser (Carl Zeiss Meditec) was used to measure the photopic 24-2C visual field.RNFL measurements

[0135] All eyes were scanned with the SPECTRALIS HRA+OCT with the Glaucoma Module Premium Edition (GMPE) protocol, Topcon Healthcare Optical Coherene Tomography (OCT), or Zeiss OCT systems. By default, the GMPE protocol allows for the acquisition of a baseline series of scans, and then, at follow-up sessions, the scans are placed in the same location, using SPECTRALIS eye-tracking capabilities.

[0136] As part of the GMPE, 24 radial scans were acquired over the optic disc. Based on these radial scans, the average Bruch’s membrane opening-minimum rim width (B MO-MR W) was measured for a global (G) and six sectoral summary metrics. Next, three circumpapillary (circle) OCT scans were obtained centered on the disc with diameters of 3.5, 4.1, and 4.7 mm.32IPTS / 200315815.1Attorney Docket No.: PFT-018WOResults

[0137] In both the low dose and high dose cohorts, the mean blur rate (MBR) increased relative to baseline throughout most of the Phase l / 2a study (FIG. 5). (See Table 7 below.).Table 7: Number of subjects evaluated for Mean Blur Rate (MBR) changesTreatment Day 7 Month 1 Month 2 Month 3 Month 4 Month 5 Month 6 GroupLow Dose 3 3 3 3 3 3 3 High Dose 7 4 5 6 6 5 5

[0138] The visual field also improved after treatment in both low dose and high dose cohorts, (FIGs. 6A-6C), while the visual field declined for the sham control group over the same time periods. (See Table 8 below for the number of subjects for the data shown in FIG. 6C.)Table 8: Number of subjects evaluated for Visual Field (VF) Mean Deviation (MD) changes.Treatment Month 2 Month 3 Month 4 Month 6 GroupCombined 8 8 8 8ControlLow Dose 8 9 8 9High Dose 8 8 8 8

[0139] FIG. 7 depicts VF MD changes from baseline, with lines shown for each individual over the six-month period within each group.

[0140] A decline in ONH blood flow has been shown to strongly correlate with retinal nerve fiber layer (RNFL) thinning in experimental glaucoma studies. At three months after administration of Edonentan Implant 1, RNFL thickness increased in both the low dose and high dose cohorts, while it decreased in the sham control (FIG. 8A). An increase RNFL thickness was also observed in the low dose cohort at six months after administration (FIG.8A). FIG. 8B depicts the RNFL changes over time for the control, low dose, and high dose groups. Table 9 shows the number of subjects evaluated at each timepoint.33IPTS / 200315815.1Attorney Docket No.: PFT-018WOTable 9: Number of subjects evaluated for retinal nerve fiber layer (RNFL) changes from baseline to month 3 and 6 in the Phase 2a glaucoma study.Treatment Group Month 3 Month 6Sham Control 7 6Low Dose 5 7High Dose 5 5

[0141] All patients in treatment groups appeared to have improved blood flow. FIG. 8C depicts RNFL changes from baseline, with lines shown for each individual over the six-month period within each group.

[0142] In treated patients, visual field and ONH blood flow changes appeared correlated: VF MD change from baseline and OCT RNFL thickness were correlated in the Phase 2a (Pearson correlation coefficient = 0.673, p=0.0011; R2=0.453; FIGs. 9A and 9B).Demographic and comparative data (including baseline MD, historical progression slope, baseline intraocular pressure (IOP), and study IOP) from Phase 2a revealed no confounding factors that would give an advantage to the active group over the control group.

[0143] These results indicate that administering an intravitreal implant which releases Edonentan can improve vision, RNFL thickness, and ONH blood flow in glaucoma patients, whereas untreated patients typically experience vision loss and decreasing RNFL thickness.EXAMPLE 10: Treatment with Edonentan demonstrates > 7 dB Visual Field gains in a Phase 2a glaucoma study

[0144] In the phase 2a study mentioned in Example 9, visual field (VF) sensitivity changes were assessed in patients in six predefined areas based on Garway-Heath sectors that included a minimum of 5 measurable VF test points. Patients were randomized to low dose (n=9), high dose (n=8) Edonentan Implant 1 or a sham control (n=8) group. A clinically meaningful change was defined as a mean > 7 dB improvement or > 7 dB worsening from baseline in any predefined sector over the 6-month study.Materials and MethodsVisual field measurements

[0145] A 700-series Humphrey Field Analyser (Carl Zeiss Meditec) was used to measure the photopic 24-2C visual field.34IPTS / 200315815.1Attorney Docket No.: PFT-018WOResults. A mean > 7 dB improvement in at least one sector was observed in 3 / 8 subjects (37.5%) in the high dose group and 2 / 9 subjects (22.2%) in the low dose group compared to 0 / 8 subjects (0%) in the control group. In contrast, none of the treated patients in either the low or high dose groups exhibited a mean > 7 dB worsening, though 1 / 8 (12.5%) of the patients in the control group exhibited a mean > 7 dB worsening. (See FIGs. 10A and 10B.)

[0146] These results indicate that administering an intravitreal implant which releases Edonentan ) demonstrated > 7 dB Visual Field gains in patients with progressive glaucoma. A mean > 7 dB visual gain aligns with the FDA’s guidance on definition of clinical significance, supporting Edonentan’ s potential as a first-in class, IOP- independent, disease modifying treatment for patients with glaucoma.

[0147] For context, in a natural history study of glaucoma patients including several cohorts, the percentage of patients with a mean > 7 dB worsening from a similar sectoral analysis increased over time (during months 6 through month 66 of the study), while the percentage of patients with a mean > 7 improvement was consistently less than 5% over the course of the study. (See FIG. 10C.)OTHER EMBODIMENTS

[0148] 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.35IPTS / 200315815.1

Claims

Attorney Docket No.: PFT-018WOCLAIMS1. A method for ameliorating impaired blood flow to the optic nerve head in a subject having glaucoma, 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:an increase relative to baseline of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, or at least 30% in the mean blur rate (MBR) as determined by laser speckle flowgraphy at seven days, one month, two months, three months, four months, five months, or six months after implanting.

2. A method for maintaining or improving vision in a subject having glaucoma, 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) an increase relative to baseline of at least or about 0.25 dB, at least or about 0.50 dB, at least or about 0.75 dB, at least or about 1.0 dB, at least or about 1.25 dB, at least or about 1.50 dB, at least or about 1.75 dB, or at least about 2.00 dB in the visual field mean deviation (VF MD) as determined by a Humphrey Field Analyser at three months after implanting, six months after implanting, or as determined as the average of values at two, three, and four months after implanting,(b) an improvement relative to baseline of at least 7 dB in visual field sensitivity in predefined areas based on Garway-Heath sectors that include a minimum of 5 measurable visual field test point, as determined by a Humphrey Field Analyser at six months after implanting, or(c) an improvement in visual acuity comprising 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 36IPTS / 200315815.1Attorney Docket No.: PFT-018WOmonths after implanting, or as determined as the average of values at two, three, and four months after implanting.

3. A method for ameliorating disease progression in a subject having glaucoma, 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:an increase relative to baseline of at least or about 0.25 pm, at least or about 0.50 pm, at least or about 0.75 pm, at least or about 1.0 pm, at least or about 1.25 pm, at least or about 1.50 pm, at least or about 1.75 pm, at least or about 2.00 pm, at least or about 2.25 pm, at least or about 2.50 pm, at least or about 2.75 pm, at least or about 3.00 pm, at least or about 3.25 pm, at least or about 3.50 pm, at least or about 3.75 pm, at least or about 4.00 pm, at least or about 4.25 pm, at least or about 4.50 pm, at least or about 4.75 pm, at least or about 5.00 pm, at least or about 5.25 pm, at least or about 5.50 pm, at least or about 5.75 pm, at least or about 5.00 pm, in the retinal nerve fiber layer (RNFL) as determined by optical coherence tomography at three months or six months after implanting.

4. A method of ameliorating a symptom associated with glaucoma impairment in a subject, comprising a step of administering to the subject a composition comprising Edonentan, a pharmaceutically acceptable salt thereof, a crystalline form thereof, or an amorphous form thereof.

5. The method of claim 4, wherein the symptom comprises vision loss.

6. The method of claim 5, wherein the vision loss comprises peripheral vision loss.

7. The method of any one of claims 4-6, wherein administration results in maintenance of the visual field.

8. The method of any one of claims 4-6, wherein administration results in improvement of the visual field.

9. The method of claim 8, wherein the improvement of the visual field comprises an increase of at least 0.25 dB in the visual field mean deviation (VF MD) as determined by a Humphrey Field Analyser at three months after administration.37IPTS / 200315815.1Attorney Docket No.: PFT-018WO10. The method of claim 8 or 9, wherein the improvement of the visual field comprises an increase of at least 0.25 dB in the VF MD as determined by a Humphrey Field Analyser at six months after administration.

11. The method of any one of claims 4-10, wherein the symptom comprises impaired blood flow to the optic nerve head.

12. The method of claim 11, wherein administration results in an increase in optic nerve head (ONH) capillary blood flow.

13. The method of claim 12, wherein the increase in ONH capillary blood flow comprises an increase in the Mean Blur Rate (MBR) as determined by laser speckle flowgraphy.

14. The method of claim 13, wherein the increase in MBR represents an increase of at least a 5% increase from baseline for three months after administration.

15. The method of claim 13 or 14, wherein the increase in MBR represents an increase of at least a 5% increase from baseline for six months after administration.

16. The method of any one of claims 4-15, wherein administration results in maintenance of retinal nerve fiber layer (RNFL) thickness and / or reduced thinning of RNFL after administration of the composition.

17. The method of claim 16, wherein administration results in an increase in RNFL thickness after administration of the composition.

18. The method of claim 17, wherein the increase in RNFL thickness comprises an increase of at least 0.5 m from a baseline level at three months after administration.

19. The method of any one of claims 4-18, wherein the subject is a mammal.

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

21. The method of any one of claims 4-20, wherein the subject is at risk for developing glaucoma.

22. The method of any one of claims 4-21, wherein the subject is diagnosed with or suffering from glaucoma.

23. The method of any one of claims 4-22, wherein the administration comprises intravitreal administration.38IPTS / 200315815.1Attorney Docket No.: PFT-018WO24. The method of claim 23, wherein intravitreal administration comprises implanting, into the vitreous cavity of the eye, a sustained release, bio-erodible device which comprises the composition.

25. The method of any one of claims 1-3 and 24, wherein the bio-erodible device comprises a poly(lactic-co-glycolic acid) (PLGA) polymer.

26. The method of claims 1-3, 24 or 25, wherein the bio-erodible device contains a total amount of about 200 ptg, about 400 ptg, or about 500 ptg of Edonentan.

27. The method of any one of claims 1-26, wherein the administration comprises administering the composition at a regular interval.

28. The method of claim 27, wherein the regular interval is about three months.

29. The method of claim 27, wherein the regular interval is at least three months.

30. The method of claim 29, wherein the regular interval is about four months.

31. The method of claim 29, wherein the regular interval is about six months.39IPTS / 200315815.1

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