Treatment of diabetic eye disease

Abstract

Provided herein are compositions and methods for the treatment of diabetic eye disease. The compositions comprise isoform selective pyrrolo-pyrazole PKC inhibitors.

Description

WSGR Docket No. 40190-716.601TREATMENT OF DIABETIC EYE DISEASECROSS-REFERENCE

[0001] This application claims the benefit of US Provisional Application No. 63 / 703,063, filed October 3, 2024, which is incorporated herein by reference in its entirety.BRIEF SUMMARY OF THE INVENTION

[0002] One embodiment provides a method of increasing visual acuity in a patient previously diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4- ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof. Another embodiment provides the method wherein the increase in visual acuity is > 5 letters as determined with an ETDRS chart evaluation. Another embodiment provides the method wherein the increase in visual acuity is > 4 letters as determined with an ETDRS chart evaluation. Another embodiment provides the method wherein the increase in visual acuity is > 3 letters as determined with an ETDRS chart evaluation.

[0003] One embodiment provides a method of increasing visual acuity in a patient previously diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4- ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a baseline visual acuity of > 79 letters in an ETDRS chart evaluation. Another embodiment provides the method wherein the ETDRS chart evaluation is performed after at least one week of administration to at least 8 weeks of administration of the pharmaceutical composition comprising 5 -{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin- l-yl]carbonyl}-N-(5-fhioro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6-tetrahydropyrrolo[3,4- c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof.

[0004] One embodiment provides a method of increasing visual acuity in a patient previously diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4- ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a baseline visual acuity Snellen equivalent of 20 / 25 or better. Another embodiment provides the method wherein the ETDRS chart evaluation is performed after at leastWSGR Docket No. 40190-716.601 one week of administration to at least 8 weeks of administration of the pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-l- yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6-tetrahydropyrrolo[3,4- c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof.

[0005] One embodiment provides a method of decreasing retinal central subfield thickness (CST) in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H- pyran-4-ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl- l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof. Another embodiment provides the method wherein the patient has a baseline CST on OCT demonstrating presence of diabetic macular edema that is eligible for administering anti-VEGF therapy. Another embodiment provides the method wherein the baseline CST is >250 pm on Zeiss Stratus or the equivalent on spectral domain OCTs based on gender specific cutoffs.

[0006] One embodiment provides a method of decreasing retinal central subfield thickness (CST) in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H- pyran-4-ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl- l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a best corrected visual acuity score of > 79 letters in an ETDRS chart evaluation.

[0007] One embodiment provides a method of decreasing retinal central subfield thickness (CST) in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H- pyran-4-ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl- l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a baseline visual acuity Snellen equivalent of 20 / 25 or better.

[0008] One embodiment provides a method of decreasing retinal central subfield thickness (CST) in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H- pyran-4-ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl- l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a best corrected visual acuity score of < 78 letters in an ETDRS chart evaluation.WSGR Docket No. 40190-716.601

[0009] One embodiment provides a method of decreasing retinal central subfield thickness (CST) in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H- pyran-4-ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-1.4.5.6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a baseline visual acuity Snellen equivalent of 20 / 32 or worse.

[0010] Another embodiment provides the method wherein the decrease in CST is > 50 micrometers. Another embodiment provides the method wherein the decrease in CST is >10% of the baseline value before treatment administration. Another embodiment provides the method wherein the CST is measured after at least one week of administration to at least 4 weeks of administration of the pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4- (tetrahydro-2H-pyran-4-ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6.6-dimethyl-l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG. 1 shows the comparison of PKC activity in the retina following dosing with Compound A.INCORPORATION BY REFERENCE

[0012] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein.DETAILED DESCRIPTION OF THE INVENTIONCertain Terminology

[0013] Unless defined otherwise, all technical and scientific terms used herein have the same meaningas is commonly understood by one of skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. In this application, the use of “or” means “and / or” unless stated otherwise. Furthermore, use of theWSGR Docket No. 40190-716.601 term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting.

[0014] As used herein, ranges and amounts can be expressed as “about” a particular value or range. About also includes the exact amount. Hence “about 5 pg” means “about 5 pg” and also “5 pg.” Generally, the term “about” includes an amount that would be expected to be within experimental error.

[0015] As used herein, the terms “comprising” and “including” are used in their open, non- limiting sense.

[0016] A "solvate" is intended to mean a pharmaceutically acceptable solvate form of a specified compound that retains the biological effectiveness of such compound. Examples of solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, DMSO (dimethylsulfoxide), ethyl acetate, acetic acid, or ethanolamine.

[0017] The phrase "pharmaceutically acceptable salt(s)", as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds described herein. The compounds described herein that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edislyate, estolate, esylate, ethylsuccinate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phospate / diphosphate, poly galacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodode, and valerate salts.

[0018] The term "treating", as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. In some embodiments, the tern “treating” includes slowing or delaying the progression of the disease or disorder to which the term is applied. Additionally, in some embodiments, the term “treating” is applied to one or more of the complications resulting from the disease or disorder to which the term is applied. The term "treatment", as used herein, unless otherwise indicated, refers to the act of treating as "treating" is defined immediately above.WSGR Docket No. 40190-716.601

[0019] The phrase "therapeutically effective amount", as used herein, refers to that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, or medical doctor.

[0020] Certain compounds utilized in the methods disclosed herein may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds utilized in the methods disclosed herein, and mixtures thereof, are considered to be within the scope of the invention. With respect to the compounds utilized in the methods disclosed herein, the invention includes the use of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, or mixtures thereof. The compounds utilized in the methods disclosed herein may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.

[0021] The subject invention also includes isotopically -labelled compounds, which are identical to the compounds utilized in the methods disclosed herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,170,31P,32P,35S,18F, and36C1, respectively. Compounds of the present invention and pharmaceutically acceptable salts or solvates of said compounds which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically -labelled compounds of the present invention, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H, and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e.,2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, maybe preferred in some circumstances. Isotopically labeled compounds utilized in the methods disclosed herein can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples below, by substituting a readily available isotopically labeled reagent for a non -isotopically labeled reagent.

[0022] The term “mmol”, as used herein, unless otherwise indicated, is intended to mean millimole. The term “equiv”, as used herein, unless otherwise indicated, is intended to mean equivalent. The term “mL”, as used herein, unless otherwise indicated, is intended to mean milliliter. The term “mm” as used herein, unless otherwise indicated, is intended to mean millimeter. The term “g”, as used herein, unless otherwise indicated, is intended to mean gram.WSGR Docket No. 40190-716.601The term “kg”, as used herein, unless otherwise indicated, is intended to mean kilogram. The term “h”, as used herein, unless otherwise indicated, is intended to mean hour. The term “min”, as used herein, unless otherwise indicated, is intended to mean minute. The term “pL”, as used herein, unless otherwise indicated, is intended to mean microliter. The term “pM”, as used herein, unless otherwise indicated, is intended to mean micromolar. The term “gm”, as used herein, unless otherwise indicated, is intended to mean micrometer. The term “M”, as used herein, unless otherwise indicated, is intended to mean molar. The term “N”, as used herein, unless otherwise indicated, is intended to mean normal. The term “nm”, as used herein, unless otherwise indicated, is intended to mean nanometer. The term “nM”, as used herein, unless otherwise indicated, is intended to mean nanoMolar. The term “amu”, as used herein, unless otherwise indicated, is intended to mean atomic mass unit. The term “°C”, as used herein, unless otherwise indicated, is intended to mean Celsius. The term “m / z”, as used herein, unless otherwise indicated, is intended to mean, mass / charge ratio. The term “wt / wt”, as used herein, unless otherwise indicated, is intended to mean weight / weight. The term “v / v”, as used herein, unless otherwise indicated, is intended to mean volume / volume. The term “mL / min”, as used herein, unless otherwise indicated, is intended to mean milliliter / minute. The term “UV”, as used herein, unless otherwise indicated, is intended to mean ultraviolet. The term “APCI-MS”, as used herein, unless otherwise indicated, is intended to mean atmospheric pressure chemical ionization mass spectroscopy. The term “HPLC”, as used herein, unless otherwise indicated, is intended to mean high performance liquid chromatograph. The chromatography was performed at a temperature of about 20 °C, unless otherwise indicated. The term “LC”, as used herein, unless otherwise indicated, is intended to mean liquid chromatograph. The term “LCMS”, as used herein, unless otherwise indicated, is intended to mean liquid chromatography mass spectroscopy. The term “TLC”, as used herein, unless otherwise indicated, is intended to mean thin layer chromatography. The term “SFC”, as used herein, unless otherwise indicated, is intended to mean supercritical fluid chromatography. The term “sat” as used herein, unless otherwise indicated, is intended to mean saturated. The term “aq” as used herein, is intended to mean aqueous. The term “ELSD” as used herein, unless otherwise indicated, is intended to mean evaporative light scattering detection. The term “MS”, as used herein, unless otherwise indicated, is intended to mean mass spectroscopy. The term “FIRMS (ESI)”, as used herein, unless otherwise indicated, is intended to mean high -resolution mass spectrometry (electrospray ionization). The term “Anal.”, as used herein, unless otherwise indicated, is intended to mean analytical. The term “Calcd”, as used herein, unless otherwise indicated, is intended to mean calculated. The term “N / A”, as used herein, unless otherwise indicated, is intended to mean not tested. The term “RT”, as used herein, unless otherwiseWSGR Docket No. 40190-716.601 indicated, is intended to mean room temperature. The term “Eg.”, as used herein, unless otherwise indicated, is intended to mean example.

[0023] The term “Ki”, as used herein, unless otherwise indicated, is intended to mean values of enzyme inhibition constant. The term “Ki app”, as used herein, unless otherwise indicated, is intended to mean K; apparent. The term “IC50”, as used herein, unless otherwise indicated, is intended to mean concentrations required for at least 50% enzyme inhibition.

[0024] The term “VA” refers to visual acuity.

[0025] The term “ETDRS” or “ETDRS chart” refers to the early treatment of diabetic retinopathy study eye chart used commonly in ophthalmic clinical trials.

[0026] Other aspects, advantages, and features of the invention will become apparent from the detailed description below.Protein Kinase C

[0027] The superfamily of kinases known as protein kinase C (PKC) are important kinases that are active in and that act as regulators in many cell signaling pathways. (Newton, 2001, Chem. Rev. 101, 2353-2364). Specific isoforms of PKC have been implicated in the response to hyperglycemia (e.g., PKC0 (beta) Das Evcimen and King, 2007, Pharmacol Res,. 55(6): p. 498- 510) and in T and B cell survival and function (e.g., PKC0 (theta): Sun, Z. 2012, Front Immunol 3, 225; PKCp: Leitges, M. et al., 1996, Science 273, 788-791; PKCa (alpha): Gruber, T. et al., 2009, Mol Immunol 46, 2071-2079).

[0028] Both T lymphocytes and B lymphocytes (T cells and B cells) have been shown to contribute to autoimmune disease, often simultaneously (Wahren-Herlenius and Dbrner T. 2013, Lancet. 382:819-31). Recent scientific reports have revealed that specific isoforms of PKC are crucial to the normal function of T and B cells and in their contribution to autoimmune disease.

[0029] Three isoforms, PKC0, PKCa and PKC0, appear to be most important for lymphocyte function. PKC0 is critical to T-cell function (Sun, 2012, Front Immunol 3, 225). Specifically, PKC0 is downstream of the T cell receptor complex and plays a critical role in T cell survival, function and autoimmune stimulation. Mouse models of autoimmune diseases have been used to illustrate PKC9 function in T cell-dependent autoimmunity (Marsland, B.J. and Kopf, M., 2008, Trends Immunol, 29(4) 179-85). PKCa plays a non-redundant role in T cell activation (Gruber, T., et al, 2009, Mol Immunol 46, 2071-2079; Pfeifhofer, C., et al, 2006, J Immunol 176, 6004-6011 ; von Essen, M., et al, 2006, J Immunol 176, 7502-75). And PKC0 plays a key role in B cell survival, function, and the dysfunction seen in autoimmunity (Leitges, M., et al, 1996, Science 273, 788-791; Saijo, K., et al, 2002, J Exp Med 195, 1647-1652; Su, T.T., et al., 2002, Nat Immunol 3, 780-786). Finally, ithas been shown in mice that inhibition ofPKCS (delta) appears toWSGR Docket No. 40190-716.601 have the potential to induce autoimmune disease in B cells. PKC5 knockout mice PKC6'- ) have increased antibody production including auto -antibodies and actually display autoimmune phenotypes. (Mecklenbrauker, I., et al, 2002, Nature 416, 860-865; Miyamoto, A., et al., 2002, Nature 416, 865-869).

[0030] The technical problem to be solved in the use of PKC inhibitors for the treatment of diabetic eye disease is the inhibition of the correct PKC isoform(s) without inhibiting critical PKC isoforms, such as PKC5. Provided herein is a solution to this problem in that the pyrrolo-pyrazole PKC inhibitors described herein are isoform selective PKC inhibitors which lack, in the least,PKC5 activity.Pyrrolo-pyrazole PKC Inhibitors

[0031] The pyrrolo-pyrazole PKC inhibitors employed herein have been previously described in WO 2008 / 096260 and WO 2008 / 125945 and related patents and patent applications, e.g. US 8,183,255, US 8,877,761, US 9,518,060, US 8,114,871, and US 8,999,981 , each of which is incorporated by reference in their entirety. As used herein, the term compound A (or cmpd A) refers to 5-{[(2S,5R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-l-yl]carbonyl}-N- (5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, which was disclosed in WO 2008 / 096260 and has the chemical structure shown below.Diabetic Eye Disease

[0032] Diabetic retinopathy (DR) is a leading cause of blindness in humans and is a complication of diabetes. Diabetic retinopathy occurs when diabetes damages blood vessels inside the retina. Non-proliferative retinopathy is a common, usually mild form that generally does not interfere with vision. Abnormalities are limited to the retina, and vision is impaired only if the macula is involved. If left untreated retinopathy can progress to proliferative retinopathy, the more serious form of diabetic retinopathy. Proliferative retinopathy occurs when new blood vessels proliferate in and around the retina. Consequently, bleeding into the vitreous, swelling of the retina, and / or retinal detachment may occur, leading to blindness.

[0033] As the disease progresses, the lack of oxygen in the retina stimulates angiogenesis along the retina and in the clear, gel-like vitreous humor that fills the inside of the eye. WithoutWSGR Docket No. 40190-716.601 timely treatment, these new blood vessels can bleed, cloud vision, and destroy the retina. The new blood vessels can also grow into the angle of the anterior chamber of the eye and cause neovascular glaucoma.

[0034] Diabetic macular edema (DME) is the swelling and thickening of the macula. Signs and symptoms of DME include blurry vision, double vision, difficulty seeing colors, dark spots (scotomas), and difficulty seeing in bright light. This is due to fluid leakage from the retinal blood vessels in the macula. The vision becomes blurry because the structure and function of the macular photoreceptor cells becomes disrupted. Risk factors for development of DME include long duration diabetes mellitus (DM), poor control of DM resulting in elevated Elb Ale, hypertension and hyperlipidemia. The occurrence of DME in the DM patient population is significant with about one-third to one-half of type 1 DM patients being diagnosed with DME within 10 years. Current therapy for diabetic macular edema includes treatment with a vascular endothelial growth factor (VEGF) agonist therapeutic, and / or treatment with an anti-inflammatory steroid. Alternatively, laser photocoagulation procedures can be used to seal the blood vessels leaking fluid into the macula. Diagnosis of DME is performed with the technique of optical coherence tomography (OCT), an imaging method used to generate a detailed image of the back of the eye and retina. OCT has proven to provide important quantitative imaging of the retina and has given rise to the classification of DME status into two sub-types based on location: center-involved DME and noncenter involved DME. Center-involved DME describes retinal thickening in the macula that involves the central subfield zone (1 mm in diameter). Non-center involved DME describes retinal thickening that does not involve the central subfield zone (1mm in diameter). Additionally, it has become recognized in the art (Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial. Ophthalmology. 2016; 123(6): 1351-1359) that therapeutic thresholds for the initiation of therapy, based on the sex of the patient, can be established upon imaging the central sub-field thickness (CST). The thresholds are different depending upon the type of instrument used in the determination. Currently, anti-VEGF therapies are the first-line treatment for DME that meets or exceeds the therapeutic threshold. These therapies include intravitreal bevacizumab, ranibizumab, aflibercept, brolucizumab and faricimab.

[0035] As defined herein the term “therapeutic threshold” or “therapeutic threshold for initiation of anti-VEGF therapy” refers to an OCT determination based on the type of instrument employed and the sex of the patient. For example, in some instances, the treatment threshold for a Heidelberg Spectralis OCT instrument is 320 pm for men or 305 pm for women. The treatmentWSGR Docket No. 40190-716.601 threshold for a Zeiss Cirrus OCT instrument is 305 m for men or 290 pm for women. The treatment threshold for a Zeiss Stratus OCT instrument is 250 pm for both men and women.Prior Uses of PKC Inhibitors in the Treatment of Diabetic Eye Disease

[0036] For diabetes, activation of PKC-beta has been demonstrated in tissues of diabetic animals and has been implicated in the development of microvascular abnormalities related to the hyperglycemic state. Genetic polymorphisms have been identified in the 5' -flanking upstream region of the PKC-beta gene in Japanese patients with type II diabetes. This PKC-beta genetic variation was associated with a significant increase in the susceptibility to develop diabetic vascular complications and macrovascular diseases such as coronary heart disease. In a large case-control study at the Joslin Diabetes Center, additional polymorphisms were identified in the PKC-beta promoter region that had an association with type I diabetes mellitus (duration <24 years) and a greater risk for development of diabetic nephropathy.

[0037] There is significant literature from the late 1990s and early 2000s that show the preclinical possibility of PKC-beta inhibition being potentially beneficial in the prevention or treatment of diabetic eye disease. The literature at the time focuses on PKC inhibitors impeding VEGF induced vascular permeability (Aiello, LP Surv Ophthalmol, 2002, Suppl: 47:S263 -9.). A review by Evcimen and King (Das Evcimen, N. et al. Pharmacol Res. 2007, 55(6): p. 498-510) outlines the rationale for using PKC inhibitors in the various diseases with diabetic vascular complications. One of the prominent mechanisms is VEGF inhibition, but it also lists other potential pathways that a PKC inhibitor might impact. Another clear demonstration that inhibition of VEGF was important in the rationale of using PKC inhibitors was the resistance to vascular leakage in an animal model using VEGF knockout animals (Aiello et al, Diabetes 46:1473-80, 1997).

[0038] The compound with greatest experimental data is the inhibitor ruboxistaurin. Administration of PKC-beta inhibitors, such as ruboxistaurin mesylate (LY333531), in diabetic animal models, was shown to prevent or ameliorate the hemodynamic changes and vascular damage associated with diabetic nephropathy, diabetic peripheral neuropathy, and diabetic retinopathy. (Way, K. J. etal, Diabet. Med. 18: 945-959 (2001); Vinik, A., Expert Opin. Investig. Drugs 14: 1547-1559 (2005). This aligns with published data demonstrating PKC-beta is critical for the breakdown of tight junctions induced by hyperglycemia (Murakami, et al, Diabetes, 2012, 61 : 1573 -83). However, these results in animal models were not replicated in the clinic in patients treated long term with ruboxistaurin.WSGR Docket No. 40190-716.601

[0039] Multiple clinical trials with ruboxistaurin were conducted in eye diseases (diabetic retinopathy and diabetic macular edema) and kidney disease (diabetic nephropathy and diabetic neuropathy). The nephropathy and neuropathy studies were not successful.

[0040] The clinical experience of ruboxistaurin, to date the only PKC inhibitor in clinical trial for DR and DME, never showed either improvement of visual acuity or reduction of centrally involved retinal edema after multiple large-scale phase 2 and 3 clinical trials. In constrast, ruboxistaurin only showed minimal clinical benefit in slowing down of moderate visual loss, instead of improvement of visual acuity, after a longer period of 2 years of therapy. (Aiello et al. Retina 2011, (10):2084-94 Aiello et al. Diabetes 54:2188-2197, 2005; Aiello et al. Ophthalmology 2006, 113(12), 2221-2230; Aiello et al. ARCH OPHTHALMOL. 2007, 125, 318-324; Sheetz et al. Investigative Ophthalmology & Visual Science, 2013, 54(3) 1750-1757). An important conclusion of the Sheetz study is that while the compound has an effect in preventing sustained moderate visual loss as measured by visual acuity measurements, it did nothing to reduce central subfield thickness over a 48-month treatment period.

[0041] The multiple tyrosine kinase inhibitor midostaurin has been tested in a small scale phase lb diabetic macular edema study (Campochiaro P et al., Invest Ophthalmol Vis Sci. 2004;45: 922-931). The compound did demonstrate activity at the higher doses tested. While the compound inhibits multiple PKC isoforms to a degree, it is very non-selective inhibiting many kinases including VEGFR, PDGFR, FGFR, C-KIT, and FLT3 (https: / / pubmed.ncbi.nlm.nih.gov / 30069632 / ), and it has been found that its most potent activity is against FLT-3 and kit (Karaman, M., Herrgard, S., Treiber, D. et al. A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol 26, 127-132 (2008); https: / / doi.org / 10.1038 / nbtl358). Midostaurin is approved for the treatment of AML because of its inhibition of FLT3. Therefore, any effect it may or may not have in DME can not be attributed to PKC inhibition.

[0042] To date, no PKC inhibitor has been tested in patients who have previously treated with anti-VEGF based therapies. Thus, there is an urgent need for a therapy that reverses the effect of diabetes on the eye and can restore vision in patients who fail, or do not qualify for, anti-VEGF therapy.Methods of Treatment

[0043] One embodiment provides a method of increasing visual acuity in a patient previously diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4- ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof.WSGR Docket No. 40190-716.601Another embodiment provides the method wherein the increase in visual acuity is > 5 letters as determined with an ETDRS chart evaluation. Another embodiment provides the method wherein the increase in visual acuity is > 4 letters as determined with an ETDRS chart evaluation. Another embodiment provides the method wherein the increase in visual acuity is > 3 letters as determined with an ETDRS chart evaluation.

[0044] Another embodiment provides the method wherein the increase in visual acutity is observed as early as 4 weeks after begining therapy with 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro- 2H-pyran-4-ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl- l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof. Another embodiment provides the method wherein the increase in visual acutity is observed as early as 5 weeks after begining therapy with 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro- 2H-pyran-4-ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl- l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof. Another embodiment provides the method wherein the increase in visual acutity is observed as early as 6 weeks after begining therapy with 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro- 2H-pyran-4-ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl- l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof. Another embodiment provides the method wherein the increase in visual acutity is observed as early as 7 weeks after begining therapy with 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro- 2H-pyran-4-ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl- l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof. Another embodiment provides the method wherein the increase in visual acutity is observed as early as 8 weeks after begining therapy with 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro- 2H-pyran-4-ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl- l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof.

[0045] One embodiment provides a method of increasing visual acuity in a patient previously diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4- ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a baseline visual acuity of > 79 letters in an ETDRS chart evaluation. Another embodiment provides the method wherein the ETDRS chart evaluation is performed after at least one week of administration to at least 8 weeks of administration of the pharmaceuticalWSGR Docket No. 40190-716.601 composition comprising 5 -{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2El-pyran-4-ylmethyl)piperazin- l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6-tetrahydropyrrolo[3,4- c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof.

[0046] One embodiment provides a method of increasing visual acuity in a patient previously diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4- ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a baseline visual acuity Snellen equivalent of 20 / 25 or better. Another embodiment provides the method wherein the ETDRS chart evaluation is performed after at least one week of administration to at least 8 weeks of administration of the pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-l- yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6-tetrahydropyrrolo[3,4- c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof.

[0047] One embodiment provides a method of decreasing retinal central subfield thickness (CST) in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H- pyran-4-ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl- l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof. Another embodiment provides the method wherein the patient has a baseline CST on OCT demonstrating presence of diabetic macular edema that is eligible for administering anti-VEGF therapy. Another embodiment provides the method wherein the baseline CST is >250 pm on Zeiss Stratus or the equivalent on spectral domain OCTs based on gender specific cutoffs.

[0048] One embodiment provides a method of decreasing retinal central subfield thickness (CST) in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H- pyran-4-ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl- l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a best corrected visual acuity score of > 79 letters in an ETDRS chart evaluation.

[0049] One embodiment provides a method of decreasing retinal central subfield thickness (CST) in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H- pyran-4-ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-WSGR Docket No. 40190-716.601 l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a baseline visual acuity Snellen equivalent of 20 / 25 or better.

[0050] One embodiment provides a method of decreasing retinal central subfield thickness (CST) in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H- pyran-4-ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl- l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a best corrected visual acuity score of < 78 letters in an ETDRS chart evaluation.

[0051] One embodiment provides a method of decreasing retinal central subfield thickness (CST) in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H- pyran-4-ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-1.4.5.6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a baseline visual acuity Snellen equivalent of 20 / 32 or worse.

[0052] Another embodiment provides the method wherein the decrease in CST is > 50 micrometers. Another embodiment provides the method wherein the decrease in CST is > 10% of the baseline value before treatment administration. Another embodiment provides the method wherein the CST is measured after at least one week of administration of the pharmaceutical composition comprising 5 -{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin- l-yl]carbonyl}-N-(5-fhioro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6-tetrahydropyrrolo[3,4- c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof. Another embodiment provides the method wherein the CST is measured after at least 4 weeks of administration of the pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4- ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof. Another embodiment provides the method wherein the CST is measured after at least 8 weeks of administration of the pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4- (tetrahydro-2H-pyran-4-ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6.6-dimethyl-l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof.

[0053] Another embodiment provides the method wherein the CST is measured after at least one week of administration to at least 8 weeks of administration of the pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-l-WSGR Docket No. 40190-716.601 yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6-tetrahydropyrrolo[3,4- c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof.

[0054] One embodiment provides a method of preventing loss of visual acuity in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4- ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a best corrected visual acuity of > 79 letters in an ETDRS chart evaluation.

[0055] One embodiment provides a method of preventing loss of visual acuity in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4- ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a best corrected visual acuity Snellen equivalent of 20 / 25 or better.

[0056] One embodiment provides a method of increasing visual acuity in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5 -{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin- l-yl]carbonyl}-N-(5-fhioro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6-tetrahydropyrrolo[3,4- c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a best corrected visual acuity score of < 78 letters in an ETDRS chart evaluation.

[0057] One embodiment provides a method of increasing visual acuity in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5 -{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin- l-yl]carbonyl}-N-(5-fhioro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6-tetrahydropyrrolo[3,4- c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a baseline visual acuity Snellen equivalent of 20 / 32 or worse.

[0058] One embodiment provides a method of preventing loss of visual acuity in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4- ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a best corrected visual acuity score of < 78 letters in an ETDRS chart evaluation.WSGR Docket No. 40190-716.601

[0059] One embodiment provides a method of preventing loss of visual acuity in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4- ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a baseline visual acuity Snellen equivalent of 20 / 32 or worse.

[0060] Another embodiment provides the method wherein the patient has previously received anti-VEGF therapy. Another embodiment provides the method wherein the patient has previously failed anti-VEGF therapy. Another embodiment provides the method wherein the patient has relapsed on anti-VEGF therapy. Another embodiment provides the method wherein the patient did not tolerate anti-VEGF therapy. Another embodiment provides the method wherein the patient did not fully respond to anti-VEGF therapy. Another embodiment provides the method wherein the patient failed to comply with the anti-VEGF therapy schedules as prescribed in product labels or according to the standard of care. Another embodiment provides the method wherein the anti- VEGF therapy comprised intraocular injection of an anti-VEGF antibody. Another embodiment provides the method wherein the anti-VEGF antibody is selected from aflibercept, ranibizumab, bevacizumab, faricimab, brolucizumab, or conbercept.

[0061] Another embodiment provides the method further comprising administration of an anti-VEGF therapy. Another embodiment provides the method wherein the anti-VEGF therapy is an anti-VEGF antibody. Another embodiment provides the method wherein the anti-VEGF antibody is selected from aflibercept, ranibizumab, bevacizumab, faricimab, brolucizumab, or conbercept. Another embodiment provides the method wherein the method results in superior vision improvement. Another embodiment provides the method wherein the method results in CST reductions compared to anti-VEGF monotherapy. Another embodiment provides the method wherein the method results in superior vision improvement and / or CST reductions compared to anti-VEGF monotherapy in DME patients who have been treated with anti-VEGF therapies including those who have failed, replapsed, or do not respond fully to VEGF monotherapies. Another embodiment provides the method wherein the method results in CST reductions compared to anti-VEGF monotherapy in DME patients who have been treated with anti-VEGF therapies including those who have failed, replapsed, or do not respond fully to VEGF monotherapies. Another embodiment provides the method wherein the method results in a reduced frequency of the administration of the anti-VEGF therapy compared to anti-VEGF monotherapy. Another embodiment provides the method wherein the method results in a reduced duration of the administration of the anti-VEGF therapy compared to anti-VEGF monotherapy. AnotherWSGR Docket No. 40190-716.601 embodiment provides the method wherein the method results in a reduced dosage of the administration of the anti-VEGF therapy compared to anti-VEGF monotherapy.

[0062] One embodiment provides a method of decreasing retinal central subfield thickness (CST) in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H- pyran-4-ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl- l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof, wherein the method results in improved vision outcomes such as vision improvements or vision loss prevention. Another embodiment provides a method of decreasing retinal central subfield thickness (CST) in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5 -{[(2S,5R)-2,5- Dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2- methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof, wherein the method results in improved vision outcomes such as vision improvements or vision loss prevention in patients previously treated with anti-VEGF therapy.

[0063] Another embodiment provides a method of preventing loss of visual acuity in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4- ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof, wherein the method results in improved vision outcomes such as vision improvements or vision loss prevention. Another embodiment provides a method of preventing loss of visual acuity in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4- ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof, wherein the method results in improved vision outcomes such as vision improvements or vision loss prevention in patients previously treated with anti-VEGF therapy.

[0064] A method of increasing visual acuity in a patient previously diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-l- yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6-tetrahydropyrrolo[3,4- c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof, wherein the methodWSGR Docket No. 40190-716.601 results in improved vision outcomes such as vision improvements or vision loss prevention. A method of increasing visual acuity in a patient previously diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5 - { [(2 S, 5R)-2,5 -Dimethyl-4-(tetrahy dro-2H-pyran-4-ylmethyl)piperazin- l-yl]carbonyl }-N-(5 -fluoro- 2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof, wherein the method results in improved vision outcomes such as vision improvements or vision loss prevention in patients previously treated with anti-VEGF therapy.

[0065] Another embodiment provides the method wherein the pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-l- yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6-tetrahydropyrrolo[3,4- c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof, is orally administered. Another embodiment provides the method wherein the pharmaceutical composition comprising 5- {[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro- 2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof, is orally administered at a total dose of about 25 mg per day to about 250 mg per day. Another embodiment provides the method wherein the pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4- ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof, is orally administered at a total dose of about 150 mg per day to about 250 mg per day. Another embodiment provides the method wherein the pharmaceutical composition comprising 5 -{ [(2 S, 5R)-2,5 -Dimethyl-4-(tetrahy dro-2H-pyran-4-ylmethyl)piperazin- l-yl]carbonyl }-N-(5 -fluoro- 2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof, is orally administered at a total dose of about 200 mg per day to about 250 mg per day.

[0066] Another embodiment provides the method wherein the pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-l- yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6-tetrahydropyrrolo[3,4- c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof, is orally administered at a dose level resultingin the daily average drug concentrations in peripheral circulation not higher than its EC50 of PKC 0 inhibtion.

[0067] Another embodiment provides the method wherein the pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-l-WSGR Docket No. 40190-716.601 yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6-tetrahydropyrrolo[3,4- c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof is orally administered once per day, two times per day, three times per day or four times per day.Non-limiting Embodiments of the Invention

[0068] These embodiments are provided for illustrative purposes only and do not limit the scope of the claims provided herein.1 . A method of increasing visual acuity in a patient previously diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4- ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl- l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof.2. The method of embodiment 1, wherein the increase in visual acuity is > 5 letters, or > 4 letters, or > 3 letters as determined with an ETDRS chart evaluation.3. A method of increasing visual acuity in a patient previously diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4- ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl- l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a baseline visual acuity of > 79 letters in an ETDRS chart evaluation.4. A method of increasing visual acuity in a patient previously diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4- ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl- l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a baseline visual acuity Snellen equivalent of 20 / 25 or better.5. The method of embodiment 2 or 3, wherein the ETDRS chart evaluation is performed after at least one week of administration, at least 4 weeks of administration, or at least 8 weeks of administration of the pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4- (tetrahydro-2H-pyran-4-ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin- 4-yl)-6,6-dimethyl-l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof.WSGR Docket No. 40190-716.6016. A method of decreasing retinal central sub field thickness (CST) in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran- 4-ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl- l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof.7. The method of embodiment 6, wherein the patient has a baseline CST on OCT demonstrating presence of diabetic macular edema that is eligible for administering anti- VEGF therapy.8. The method of embodiment 7, wherein the baseline CST is >250 pm on Zeiss Stratus or the equivalent on spectral domain OCTs based on gender specific cutoffs.9. A method of decreasing retinal central sub field thickness (CST) in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran- 4-ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl- l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a best corrected visual acuity score of > 79 letters or Snellen equivalent 20 / 25 or better in an ETDRS chart evaluation.10. A method of decreasing retinal central subfield thickness (CST) in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran- 4-ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl- l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a baseline visual acuity Snellen equivalent of 20 / 25 or better.11. A method of decreasing retinal central subfield thickness (CST) in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran- 4-ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl- l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a best corrected visual acuity score of < 78 letters in an ETDRS chart evaluation.12. A method of decreasing retinal central subfield thickness (CST) in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient aWSGR Docket No. 40190-716.601 pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran- 4-ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl- l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a baseline visual acuity Snellen equivalent of 20 / 32 or worse.13. The method of any one of embodiments 6-12, wherein the decrease in CST is > 50 micrometers or >10% of baseline prior to treatment administration.14. The method of any one of embodiments 6-13, wherein the CST is measured after at least one week of administration to at least 4 weeks of administration of the pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4- ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl- l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof.15. The method of any one of embodiments 6-14, wherein the CST is measured after at least one week of administration to at least 8 weeks of administration of the pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4- ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl- l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof.16. A method of preventing loss of visual acuity in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5 - { [(2 S, 5R)-2, 5 -Dimethy l-4-(tetrahy dro-2H-py ran-4-y Imethy l)piperazin- 1 - yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a best corrected visual acuity of > 79 letters in an ETDRS chart evaluation.17. A method of preventing loss of visual acuity in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5 - { [(2 S, 5R)-2, 5 -Dimethy l-4-(tetrahy dro-2H-py ran-4-y Imethy l)piperazin- 1 - yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a best corrected visual acuity Snellen equivalent of 20 / 25 or better.WSGR Docket No. 40190-716.60118. A method of increasing visual acuity in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5 - { [(2 S, 5R)-2, 5 -Dimethy l-4-(tetrahy dro-2H-py ran-4-y Imethy l)piperazin- 1 - yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a best corrected visual acuity score of < 78 letters in an ETDRS chart evaluation.19. A method of increasing visual acuity in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5 - { [(2 S, 5R)-2, 5 -Dimethy l-4-(tetrahy dro-2H-py ran-4-y Imethy l)piperazin- 1 - yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a baseline visual acuity Snellen equivalent of 20 / 32 or worse.20. A method of preventing loss of visual acuity in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5 - { [(2 S, 5R)-2, 5 -Dimethy l-4-(tetrahy dro-2H-py ran-4-y Imethy l)piperazin- 1 - yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a best corrected visual acuity score of < 78 letters in an ETDRS chart evaluation.21. A method of preventing loss of visual acuity in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5 - { [(2 S, 5R)-2, 5 -Dimethy l-4-(tetrahy dro-2H-py ran-4-y Imethy l)piperazin- 1 - yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a baseline visual acuity Snellen equivalent of 20 / 32 or worse.22. The method of any one of the preceding embodiments, wherein the patient has previously received anti-VEGF therapy.23. The method of embodiment 22, wherein the patient has previously failed anti-VEGF therapy.24. The method of embodiment 22, wherein the patient has relapsed on anti-VEGF therapy.25. The method of embodiment 22, wherein the patient did not tolerate anti-VEGF therapy.WSGR Docket No. 40190-716.60126. The method of embodiment 24, wherein the patient did not respond to anti-VEGF therapy.27. The method of embodiment 22, wherein the patient failed to comply with the anti-VEGF therapy schedules as prescribed in product labels or according to the standard of care.28. The method of any one of embodiments 24-27, wherein the anti-VEGF therapy comprised intraocular injection of an anti-VEGF antibody.29. The method of any one of embodiments 22-28, wherein the anti-VEGF antibody is selected from aflibercept, ranibizumab, bevacizumab, faricimab, brolucizumab, or conbercept.30. The method of any one of embodiments 1-21, further comprising administration of an anti- VEGF therapy.31. The method of embodiment 30, wherein the anti-VEGF therapy is an anti-VEGF antibody.32. The method of embodiment 31, wherein the anti-VEGF antibody selected from aflibercept, ranibizumab, bevacizumab, faricimab, brolucizumab, or conbercept.33. The method of any one of embodiments 30-32, wherein the method results in a reduced frequency of the administration of the anti-VEGF therapy compared to anti-VEGF monotherapy.34. The method of any one of embodiments 30-33, wherein the method results in a reduced duration of the administration of the anti-VEGF therapy compared to anti-VEGF monotherapy.35. The method of any one of embodiments 30-34, wherein the method results in a reduced dosage of the administration of the anti-VEGF therapy compared to anti-VEGF monotherapy.36. The method of any one of embodiments 1-35, wherein the pharmaceutical composition comprising 5 - { [(2 S, 5R)-2, 5 -Dimethy l-4-(tetrahy dro-2H-py ran-4-y Imethy l)piperazin- 1 - yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof, is orally administered.37. The method of any one of embodiments 1-35, wherein the pharmaceutical composition comprising 5 - { [(2 S, 5R)-2, 5 -Dimethy l-4-(tetrahy dro-2H-py ran-4-y Imethy l)piperazin- 1 - yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof, is orally administeredat a total dose of about 25 mg per day to about 250 mg per day.38. The method of any one of embodiments 1 -37, wherein the pharmaceutical composition comprising 5 - { [(2 S, 5R)-2, 5 -Dimethy l-4-(tetrahy dro-2H-py ran-4-y Imethy l)piperazin- 1 -WSGR Docket No. 40190-716.601 yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof, is orally administered at a dose level resulting in the daily average drug concentrations in peripheral circulation not higher than its EC50of PKC 0 inhibtion.39. The method of any one of embodiments 1 -36, wherein the pharmaceutical composition comprising 5 - { [(2 S, 5R)-2, 5 -Dimethy l-4-(tetrahy dro-2H-py ran-4-y Imethy l)piperazin- 1 - yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof is orally administered once per day, two times per day, three times per day or four times per day.EXAMPLES

[0069] These examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.

[0070] Compound A refers to 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4- ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3-amine, which was disclosed in WO 2008 / 096260 and having the chemical structure:Example 1: Compound A is an Isoform Selective PKC Inhibitor

[0071] A summary of PKC inhibition by compound A is provided in Table 1. The methods for these determinations have been described (Grant, et al. 2010, Eur J Pharmacol . 627:16-25). Compound A is a potent, ATP-competitive and reversible inhibitor of conventional PKC enzymes with a Ki = 5.3 nM for recombinant PKC beta and a Ki = 10.4 nM for recombinant PKC alpha. Compound A is a potent inhibitor of the novel isoform PKC theta with an IC50 = 25.6 nM. While Compound A demonstrated some potency for conventional isoform PKC gamma with an IC50= 57.5 nM, Compound A demonstrated a high degree of selectivity against other members of the conventional, novel, and atypical isoforms of PKC as shown by lower potency in Table 1.Inhibition of PKC delta has been shown to lead to B-cell lymphoproliferative conditions and autoimmune disease in both animal studies and humans. Unlike other PKC inhibitors, Compound A does not inhibit PKC delta to any appreciable degree. Conversely, PKC beta inhibition has beenWSGR Docket No. 40190-716.601 shown to block B-cell function and proliferation. Therefore, the isoform selective properties of Compound A suggest a safety and efficacy advantage over non-specific PKC inhibitors.Table 1Example 2: Compound A in Animal Model of Diabetic Eye Disease

[0072] The rationale for use of Compound A for the treatment of DME, was evaluated in an animal model of diabetic eye disease, the streptozotocin (STZ) induced diabetic rat model.Compound A completely inhibited retinal leakage in STZ-treated diabetic rats with three days of treatment. Follow-up pharmacodynamic studies demonstrated that Compound A inhibited 87% of PKC activity in retina after 3 days dosing at 3 mg / kg.

[0073] Retinal leakage in the STZ diabetic rat model was assessed in the Long Evans (LE) rats. LE rats became diabetic and hyperglycemia (plasma glucose >300 mg / dl) on day 1 post-STZ injection and remained elevated for the duration of study. Treatment began 2 weeks following STZ injection. After treatment, retinal leakage was measured using an Evan’s Blue albumin leakage model (Figure 1). Overall, there was an approximate 2-fold increase in retinal leakage in STZ- diabetic rats compared to that observed in non-STZ rats, which is consistent with previous reports.

[0074] In experiments where multiple doses of Compound A were given to diabetic STZ treated rats for 3 days (QD oral dosing), there was a correlation between the inhibition of PKCWSGR Docket No. 40190-716.601 activity in the retina and inhibition of leakage. Data from STZ treated animals dosed with 1 or 10 mg / kg Compound A for 3 days indicated that when PKC activity in the retina of diabetic animals was reduced to a level equal to, or below, the level observed in normal animals, the amount of vascular leakage in the retina is reduced to a level comparable to that observed in normal animals (FIG. 1). FIG. 1 illustrates percent inhibition of PKC activity in retinal lysate that was determined relative to STZ + vehicle controls (0% inhibition) and samples of retinal lysates pre-treated with 5 pM Compound A (which gave essentially zero counts = 100% inhibition). Percent inhibition of retinal leakage was calculated using level of leakage in STZ + vehicle group as 0% inhibition and level of retinal leakage in normal + vehicle group as 100% inhibition.Example 3: Compound A in a Clinical Trial of Diabetic Eye Disease

[0075] Compound A was studied in human patients with diabetic eye disease whose disease has progressed on anti-VEGF therapy.

[0076] In this example, an eight-week dose escalation study was tested to evaluate the safety and initial efficacy of oral Compound A in patients with DME. A total of 45 patients with DME were enrolled and treated across three dosing cohorts: Cohort 1 (150 mg Compound A, twice a day) and Cohort 2 (200 mg Compound A, once a day) enrolled treatment-naive patients, while Cohort 3 (125 mg Compound A, twice a day) enrolled patients with prior ant-VEGF therapy.

[0077] The treatment included administrating Compound A orally according to the cohortspecific dose schedules. Evaluations were conducted at day 56, the end of the treatment period, with safety as the primary endpoint and changes in CST and BCVA as secondary endpoints. Safety was monitored through adverse event reporting, with no dose-limiting toxicities or drug-related grade 3 or serious adverse evets reported. The most common adverse events were nausea (20%) and dizziness (15.6%).

[0078] In terms of efficacy, the mean reduction in CST from baseline to Day 56 was -83.1 pm in Cohort 1, -69.7 pm in Cohort 2, and -80.7 pm in Cohort 3. Additionally, 46.7% of patients in Cohort 1, 53.3% of patients in Cohort 2, and 33.3% of patients in Cohort 3 experienced a > 5-letter gain in BCVA. These findings showed that oral Compound A had a favorable safety profile and demonstrated preliminary efficacy in reducing CST and improving BCVA in DME patients, regardless of prior anti-VEGF therapy.

[0079] Table 2 provides a summary of data from the human clinical trial and demonstrates that Compound A displays efficacy in patients who have failed prior anti-VEGF therapy.WSGR Docket No. 40190-716.601Table 2

[0080] Conclusion: Clinical data demonstrates efficacy at oral doses after only one weekof treatment in patients with DME, including improvement in VA as measured by number of letters read on an ETDRS chart with many patients experienced >5 letters improvement which is considered clinically significant. Also observed was an improvement in CST as measured by a decreased thickness of the retina (decreased edema) with many patients seeing greater than 50 pM decrease which is considered clinically significant. The onset of efficacy is rapid with many patients seeing significant improvement in as little as 4-weeks during an 8-week course of therapy. At the highest dose tested (125 mg BID), patients who had received prior VEGF therapy were enrolled. In this patient group, a response rate of 50% was observed. Taken together these results are supring and unexpected for an oral therapy.Example 4: Compound A in a Clinical Trial of DME Patients with Prior History of anti- VEGF Antibody Treatment

[0081] In a phase lb study of Compound A in DME patients, a cohort of eight patients with prior history of VEGF therapy were treated with Compound A for eight weeks. Some of these patients were confirmed as refractory to VEGF therapy by the investigators.WSGR Docket No. 40190-716.601CST: Central Subfield Thickness of Retina; BCVA: Best Corrected Visual Acuity

[0082] After eight weeks of therapy with Compound A, none of the patients had significant visual loss with 50% of the patients exhibiting significant visual acuity improvement of 5 to 17 letters. Seven out of the eight patients had significant reductions of macula edema with a mean of 134 pM and up to 441 pM.

[0083] Conclusion: These data demonstrated clinical success of Compound A in DME patients who have been treated with anti-VEGF therapies including VEGF antibody refractory patients.

Claims

WSGR Docket No. 40190-716.601CLAIMSWE CLAIM:1 . A method of increasing visual acuity in a patient previously diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4- ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl- l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof.

2. The method of claim 1, wherein the increase in visual acuity is > 5 letters as determined with an ETDRS chart evaluation.

3. The method of claim 1, wherein the increase in visual acuity is > 4 letters as determined with an ETDRS chart evaluation.

4. The method of claim 1, wherein the increase in visual acuity is > 3 letters as determined with an ETDRS chart evaluation.

5. A method of increasing visual acuity in a patient previously diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4- ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl- l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a baseline visual acuity of > 79 letters in an ETDRS chart evaluation.

6. A method of increasing visual acuity in a patient previously diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4- ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl- l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a baseline visual acuity Snellen equivalent of 20 / 25 or better.WSGR Docket No. 40190-716.6017. The method of any one of claims 2-6, wherein the ETDRS chart evaluation is performed after at least one week of administration, at least 4 weeks of administration, or at least 8 weeks of administration of the pharmaceutical composition comprising 5-{[(2S,5R)-2,5- Dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2- methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof.

8. A method of decreasing retinal central sub field thickness (CST) in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran- 4-ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl- l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof.

9. The method of claim 8, wherein the patient has a baseline CST on OCT demonstrating presence of diabetic macular edema that is eligible for administering anti-VEGF therapy.

10. The method of claim 8 or 9, wherein the baseline CST is >250 pm on Zeiss Stratus or the equivalent on spectral domain OCTs based on gender specific cutoffs.

11. A method of decreasing retinal central subfield thickness (CST) in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran- 4-ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl- l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a best corrected visual acuity score of > 79 letters in an ETDRS chart evaluation.

12. A method of decreasing retinal central subfield thickness (CST) in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran- 4-ylmethyl)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl- l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt orWSGR Docket No. 40190-716.601 solvate thereof, wherein the patient has a baseline visual acuity Snellen equivalent of 20 / 25 or better.

13. A method of decreasing retinal central subfield thickness (CST) in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran- 4-y Imethy l)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl- l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a best corrected visual acuity score of < 78 letters in an ETDRS chart evaluation.

14. A method of decreasing retinal central subfield thickness (CST) in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran- 4-y Imethy l)piperazin-l-yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl- l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a baseline visual acuity Snellen equivalent of 20 / 32 or worse.

15. The method of any one of claims 8-14, wherein the decrease in CST is > 50 micrometers.

16. The method of any one of claims 8-15, wherein the decrease in CST is >10% of baseline CST prior to treatment administration17. The method of any one of claims 6-16, wherein the CST is measured after at least one week of administration to at least 4 weeks of administration of the pharmaceutical composition comprising 5 - { [(2 S, 5R)-2, 5 -Dimethy l-4-(tetrahy dro-2H-py ran-4-y Imethy l)piperazin- 1 - yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof.

18. The method of any one of claims 6-16, wherein the CST is measured after at least one week of administration to at least 8 weeks of administration of the pharmaceutical composition comprising 5 - { [(2 S, 5R)-2, 5 -Dimethy l-4-(tetrahy dro-2H-py ran-4-y Imethy l)piperazin- 1 -WSGR Docket No. 40190-716.601 yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof.

19. A method of preventing loss of visual acuity in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5 - { [(2 S, 5R)-2, 5 -Dimethy l-4-(tetrahy dro-2H-py ran-4-y Imethy l)piperazin- 1 - yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a best corrected visual acuity of > 79 letters in an ETDRS chart evaluation.

20. A method of preventing loss of visual acuity in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5 - { [(2 S, 5R)-2, 5 -Dimethy l-4-(tetrahy dro-2H-py ran-4-y Imethy l)piperazin- 1 - yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a best corrected visual acuity Snellen equivalent of 20 / 25 or better.

21. A method of increasing visual acuity in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5 - { [(2 S, 5R)-2, 5 -Dimethy l-4-(tetrahy dro-2H-py ran-4-y Imethy l)piperazin- 1 - yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a best corrected visual acuity score of < 78 letters in an ETDRS chart evaluation.

22. A method of increasing visual acuity in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5 - { [(2 S, 5R)-2, 5 -Dimethy l-4-(tetrahy dro-2H-py ran-4-y Imethy l)piperazin- 1 - yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvateWSGR Docket No. 40190-716.601 thereof, wherein the patient has a baseline visual acuity Snellen equivalent of 20 / 32 or worse.

23. A method of preventing loss of visual acuity in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5 - { [(2 S, 5R)-2, 5 -Dimethy l-4-(tetrahy dro-2H-py ran-4-y Imethy l)piperazin- 1 - yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a best corrected visual acuity score of < 78 letters in an ETDRS chart evaluation.

24. A method of preventing loss of visual acuity in a patient diagnosed with diabetic macular edema, the method comprising administering to the patient a pharmaceutical composition comprising 5 - { [(2 S, 5R)-2, 5 -Dimethy l-4-(tetrahy dro-2H-py ran-4-y Imethy l)piperazin- 1 - yl]carbonyl}-N-(5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6- tetrahydropyrrolo[3,4-c]pyrazol-3 -amine, or pharmaceutically acceptable salt or solvate thereof, wherein the patient has a baseline visual acuity Snellen equivalent of 20 / 32 or worse.

25. The method of any one of the preceding claims, wherein the patient has previously received anti-VEGF therapy.

26. The method of claim 25, wherein the patient has previously failed anti-VEGF therapy.

27. The method of claim 25, wherein the patient has relapsed on anti-VEGF therapy.

28. The method of claim 25, wherein the patient did not tolerate anti-VEGF therapy.

29. The method of claim 27, wherein the patient did not respond to anti-VEGF therapy.

30. The method of claim 22, wherein the patient failed to comply with the anti-VEGF therapy schedules as prescribed in product labels or according to the standard of care.WSGR Docket No. 40190-716.60131. The method of any one of claims 25-30, wherein the anti-VEGF therapy comprised intraocular injection of an anti-VEGF antibody.

32. The method of any one of claims 25-31, wherein the anti-VEGF antibody is selected from aflibercept, ranibizumab, bevacizumab, faricimab, brolucizumab, or conbercept.

33. The method of any one of claims 1-24, further comprising administration of an anti-VEGF therapy.

34. The method of claim 33, wherein the anti-VEGF therapy is an anti-VEGF antibody.

35. The method of claim 34, wherein the anti-VEGF antibody selected from aflibercept, ranibizumab, bevacizumab, faricimab, brolucizumab, or conbercept.

36. The method of any one of claims 33-35, wherein the method results in a reduced frequency of the administration of the anti-VEGF therapy compared to anti-VEGF monotherapy.

37. The method of any one of claims 33-36, wherein the method results in a reduced duration of the administration of the anti-VEGF therapy compared to anti-VEGF monotherapy.

38. The method of any one of claims 33-37, wherein the method results in a reduced dosage of the administration of the anti-VEGF therapy compared to anti-VEGF monotherapy.

39. The method of any one of claims 1-38, wherein the pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-l-yl]carbonyl}-N- (5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3- amine, or pharmaceutically acceptable salt or solvate thereof, is orally administered.

40. The method of any one of claims 1-39, wherein the pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-l-yl]carbonyl}-N- (5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3- amine, or pharmaceutically acceptable salt or solvate thereof, is orally administered at a total dose of about 25 mg per day to about 250 mg per day.WSGR Docket No. 40190-716.60141. The method of any one of claims 1-40, wherein the pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-l-yl]carbonyl}-N- (5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3- amine, or pharmaceutically acceptable salt or solvate thereof, is orally administered at a dose level resulting in the daily average drug concentrations in peripheral circulation not higher than its EC50 of PKC 0 inhibtion.

42. The method of any one of claims 1 -41, wherein the pharmaceutical composition comprising 5-{[(2S,5R)-2,5-Dimethyl-4-(tetrahydro-2H-pyran-4-ylmethyl)piperazin-l-yl]carbonyl}-N- (5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3- amine, or pharmaceutically acceptable salt or solvate thereof is orally administered once per day, two times per day, three times per day or four times per day.

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