Tivozanib for treating posterior segment eye diseases

Abstract

Disclosed are methods of treating a human patient with a posterior segment eye disease, the method comprising topically administering a maintenance effective dose of a tivozanib formulation as a maintenance phase dose or a therapeutically effective dose of a tivozanib formulation 1 to 3 times per day to the eye of the human patient. The method may further comprise an induction phase treatment with an anti-VEGF agent.

Description

[0001] TIVOZANIB FOR TREATING POSTERIOR SEGMENT EYE DISEASES

[0002] CROSS-REFERENCE TO RELATED APPLICATION

[0003] This application claims the benefit of priority of United States Provisional Application No. 63 / 665,784, filed June 28, 2024. The foregoing application is incorporated herein by reference in its entirety.

[0004] FIELD OF THE DISCLOSURE

[0005] The present application is concerned with treating posterior segment eye diseases by topically administering tivozanib formulations. The disclosure provides specific methods of administering tivozanib to patients with posterior segment eye diseases, including neovascular macular degeneration, diabetic macular edema, diabetic retinopathy, and retinal vein occlusion.

[0006] BACKGROUND

[0007] Age-related macular degeneration (AMD) is the leading cause of blindness worldwide, as well as in the United States, for individuals aged 60 and older. The incidence of AMD increases with age, and in the age group of 65-74 years, it reaches 11%, while in the population over 74 years, it affects up to 28% of individuals. The number of people living with AMD globally is estimated around 200 million and is expected to reach 288 million by 2040. Neovascular age- related macular degeneration (nAMD) accounts for approximately 10-20% of all AMD cases, but it results in 90% of legal blindness. See Liberski et al., “Aflibercept versus Faricimab in the Treatment of Neovascular Age-Related Macular Degeneration and Diabetic Macular Edema,” 23 INT. J. MOL. 9424 (2022).

[0008] Since 2006, intravitreal therapy (IVT) injections of anti-VEGF agents have served as the standard of care treatment for nAMD. See Flaxel CJ, et al. “Age-Related Macular Degeneration Preferred Practice Pattern®.” Ophthalmology. 2020;127:Pl-65. This includes aflibercept, ranibizumab, off-label use of bevacizumab, brolucizumab, and faricimab. However, patients’ fear of IVT injections, long-term periodic hospital visits and invasive injections, the treatment burden, and the risks of serious adverse events, such as endophthalmitis, bleeding, retinal detachment, and elevated intraocular pressure arising from the IVT injections, render the treatment suboptimal and result in low patient compliance. See Polat O, et al., “Factors Affecting Compliance to Intravitreal Anti-Vascular Endothelial Growth Factor Therapy in Patients with Age-Related Macular Degeneration,” TURK J OPHTHALMOL. 2017;47:205-10; Weiss M, et al., “Compliance and Adherence of Patients with Diabetic Macular Edema to Intravitreal Anti-vascular Endothelial Growth Factor Therapy in Daily Practice,” Retina. 2018;38:2293-300. Therefore, there is a need for a non-invasive treatment for nAMD. An eye drop formulation would provide a beneficial treatment option and an advantage over IVT injections due to its non-invasive (without surgery), potential self-administering, and easy to use characteristics. Moreover, an eye drop formulation would also provide an option for health professionals and patients who cannot operate or undergo surgery for IVT injections of anti-VEGF drugs. However, until now, none of the investigational eye drops for nAMD have been capable of showing clinically meaningful efficacy to obtain approval by any regulatory agencies. Hussain et al., “Vascular Endothelial Growth Factor Antagonists: Promising Players in the Treatment of Neovascular Age-Related Macular Degeneration,” 15 DRUG DESIGN, DEVELOPMENT & THERAPY 2653-65 (2021).

[0009] Diabetic retinopathy (DR) and diabetic macular edema (DME) are posterior segment eye diseases that are caused by diabetes mellitus, a chronic metabolic disease characterized by a prolonged period of hyperglycemia that causes serious damage to many organs, including the eyes. DR, with or without DME, remains a major cause of visual impairment and blindness in workingage adults. World report on vision, Geneva, Switzerland: World Health Organization. 2019 [cited June 10, 2024] (available from: https: / / www.who.int / publications / i / item / 9789241516570). In 2021, 537 million adults (2079 years) were living with diabetes mellitus, one in every ten people worldwide, and this number was predicted to increase to 643 million by 2030 and 783 million by 2045. Despite the advances in optimal control of systemic risk factors for diabetes mellitus, the prevalence of DR remains high in patients with diabetes mellitus (about one third of diabetes mellitus patients suffer from DR). DME remains the main cause of vision impairment in diabetic patients with an increasing prevalence worldwide. The prevalence of DME varies widely, ranging from 4.2% to 14.3% in people with type 1 diabetes mellitus and 1.4% to 5.57% in people with type 2 diabetes mellitus. Zhang et al., “Diabetic Macular Edema: Current Understanding, Molecular Mechanisms and Therapeutic Implications,” 11 CELLS 3362 (2022). Fluid accumulation in the macular area leads to increased central retinal / macular thickness, resulting in DME.

[0010] For DR and DME, treatment with IVT injections of anti-VEGF agents remains the standard of care, similar to nAMD, although DR and DME are neuroretinal diseases (only the retinal layers are involved) whereas nAMD is a chorioretinal (choroid and outer retina) disease. Therefore, similar to nAMD, there is a need for a non-invasive treatment for DR and DME.

[0011] Retinal vein occlusion (RVO) is another posterior segment eye disease that is caused by partial or total blockage in a vein that drains blood from the retina. Macular edema is a leading cause of vision loss in RVO; hence, treatment aimed at resolving macular edema is often utilized. To this end, anti-VEGF IVT injection is the most common first-line treatment for macular edema due to RVO. Hattenbach et al., “BALATON and COMINO: Phase III Randomized Clinical Trials of Faricimab for Retinal Vein Occlusion,” 3 OPHTHALMOLOGY SCIENCE (2023). Indeed, nAMD, DME / DR, and macular edema due to RVO all share common pathological pathways. Protocol GR41986, Version 2, “A Phase III, Multicenter, Randomized, Double-Masked, Active Comparator- Controlled Study to Evaluate the Efficacy and Safety of Faricimab in Patients With Macular Edema Secondary to Central Retinal or Hemiretinal Vein Occlusion,” sponsored by F. Hoffmann-La Roche Ltd., dated Nov. 17, 2020. Accordingly, similar to nAMD, DR and DME, there is a need for an effective non-invasive treatment for RVO.

[0012] A number of investigational eye drops using small molecule kinase inhibitors have been investigated for treatment of posterior segment eye diseases. These investigational eye drops have shown positive signs in animal models, but as it currently stands, all have ultimately failed in clinical studies tested on human patients.

[0013] For example, pazopanib is a multitargeted tyrosine kinase inhibitor of VEGF receptors (VEGFR), VEGFR-1, VEGFR-2, and VEGFR-3 and platelet-derived growth factor receptors (PDGFR), PDGFR-a and PDGFR-p. It is an antiangiogenic agent approved as an oral therapy for the treatment of advanced renal cell carcinoma and soft tissue sarcoma. In a laser-induced choroidal neovascularization (CNV) model using rats, it was confirmed that twice-daily topical dosing completely inhibited the progression of CNV. In addition, it was confirmed that pazopanib is detectable in the retina / choroid of laboratory animals after topical ocular instillation. Moreover, a Phase Ila study showed promising data that one of the tested dosages (5mg / mL TID) resulted in a significant mean best-corrected visual acuity (BCVA) improvement of 4.3 letters after 28 days of administration. However, because no statistically significant reduction in central retinal thickness (CRT) was observed, it was concluded that the observed efficacy of pazopanib is not sufficient for further monotherapy. See Ronald Danis et al., “Pazopanib eye drops: a randomised trial in neovascular age-related macular degeneration,” 98 BR J OPHTHALMOL 172-78 (2014).

[0014] Despite the promising showing in animal models, and at least a promising showing of BCVA improvement in a tested dosage used in a Phase Ila study, pazopanib ultimately failed in another Phase Ila study and a Phase lib study in human nAMD patients, even when it was used in combination with an IVT anti- VEGF agent. Specifically, another Phase Ila study was conducted using pazopanib eye drops in subjects with previously untreated subfoveal CNV secondary to nAMD. It was concluded that pazopanib instilled 4 times daily as a monotherapy for patients with no prior VEGF therapy resulted in no statistically significant change from baseline in CRT or BCVA. See Rishi Singh et al., “Clinical Evaluation of Pazopanib Eye Drops in Healthy Subjects and in Subjects with Neovascular Age-related Macular Degeneration,” 34 THE JOURNAL OF RETINAL AND VITREOUS DISEASES 1787-95 (2014).

[0015] After the Phase Ila studies that confirmed that pazopanib could not be used as a monotherapy, a Phase lib study was conducted to evaluate the use of pazopanib eye drops in maintenance therapy. Specifically, a total of 510 subjects with subfoveal CNV secondary to nAMD after being subjected to IVT treatment using an anti-VEGF agent (ranibizumab) were tested for 52 weeks with a dosage of pazopanib 5 mg / mL, 3 or 4 times a day or 10 mg / mL 2, 3, or 4 times a day. It was concluded that pazopanib eye drops did not decrease as-needed injections of ranibizumab by350%, which was the prespecified minimal success criterion to demonstrate efficacy. Moreover, it was concluded that daily doses of pazopanib eye drops with as-needed ranibizumab injection did not provide any therapeutic benefit beyond that obtained from dosing with ranibizumab alone. See Karl G Csaky et al., “Clinical Evaluation of Pazopanib Eye Drops versus Ranibizumab Intravitreal Injections in Subjects with Neovascular Age-Related Macular Degeneration,” 122 OPHTHALMOLOGY 579-588 (Mar. 2015).

[0016] Regorafenib is another multitargeted tyrosine kinase inhibitor of VEGFR-2, VEGFR-3 and PDGFR-P, in addition to other kinases. As with pazopanib, regorafenib was initially developed as an oral oncology drug for the treatment of solid organ malignancies and was approved for the treatment of metastatic colorectal cancer in 2012 and for locally advanced, unresectable or metastatic gastrointestinal stomal tumors in 2013. And as with pazopanib, preclinical results from rat and monkey laser-induced CNV models had shown that the efficacy of topical regorafenib was similar to that observed with intravitreal anti-VEGF agents. In addition, sufficient concentrations of regorafenib were reached in the back of the eye of the same species, substantiating the observed in vivo efficacy. However, as with pazopanib, regorafenib failed in Phase II studies for showing lack of efficacy. Specifically, patients with CNV secondary to nAMD received regorafenib (25 ml, 30 mg / mL) three times a day for 12 weeks. Primary endpoint was mean change in BCVA from baseline to weeks 4 and 12. The program was terminated after Phase Ila study was concluded because efficacy was lower than with current nAMD treatments. This failure was even so with optimization efforts for drug delivery including formulating as an oily suspension in light liquid paraffin. Joussen et al., “The Developing Regorafenib Eye Drops for neovascular Age-related Macular degeneration (DREAM) study: an open-label phase II trial,” 85 BR J CLIN PHARMACOL 347-55 (2019).

[0017] Acrizanib is another multi targe ted tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a, and PDGFR-P, among others. It was confirmed that topical acrizanib was found to achieve robust exposure in rabbit and rodent retina and choroid, and rat laser-induced CNV model had shown that the efficacy of topical acrizanib was similar to that observed with intravitreal anti-VEGF agents. Despite the favorable preclinical data, as with the failures of pazopanib and regorafenib, acrizanib also failed to demonstrate clinical efficacy in human nAMD patients. Specifically, in a Phase II study, 90 patients with CNV secondary to nAMD were tested using either placebo or topical acrizanib 2% twice a day for 8 weeks and then three times a day for 4 weeks. All patients received an IVT injection of ranibizumab at baseline and were retreated when there was evidence of disease recurrence (rescue). The study resulted in a showing of no clinical efficacy, as 75.8% of the acrizanib treated group required rescue by injecting ranibizumab by day 84 whereas 67.6% of the placebo group required rescue by day 84. This failure was even so with a multiyear program of medicinal chemistry optimization for topical delivery. See Poor et al., “A Randomized, Double-Masked, Multicenter Trial of Topical Acrizanib (LHA510), a Tyrosine Kinase VEGF- Receptor Inhibitor, in Treatment-Experienced Subjects With Neovascular Age-Related Macular Degeneration,” 239 AM J OPHTHALMOL 180-89 (2022).

[0018] TG100801 is a small-molecule multikinase inhibitor prodrug which is cleaved to its active form by hydrolysis in the cornea. Topical TG100801 demonstrated reduction in CNV in a murine model and edema reduction in retinal vein occlusion (RVO). Due to the promising results of TG100801 in the preclinical setting, a Phase II clinical trial (NCT00509548) was conducted to test the drug’s safety and efficacy in treating patients with subfoveal CNV secondary to nAMD. However, it too, failed to show any efficacy for alleviating the condition of nAMD. See Gote et al., “Ocular Drug Delivery: Past, Present, and Future,” 370 J PHARMACOL EXP THER 602-24 (2019).

[0019] Phase I and / or Phase Ila studies have been conducted for PAN-90806, another smallmolecule tyrosine kinase inhibitor, for nAMD patients, and EXN407, a small molecule SRPK1 inhibitor, for patients of mild / moderate non-proliferative diabetic retinopathy (NPDR) and mild DME with Diabetic Retinopathy Severity Scale (DRSS) score less than 43. Both studies investigated biological response for the indicated patient population, but both confirm that Phase lib studies are needed before any conclusions regarding clinical efficacy can be made. Hussain et al., “Vascular Endothelial Growth Factor Antagonists: Promising Players in the Treatment of Neovascular Age-Related Macular Degeneration,” 15 DRUG DESIGN, DEVELOPMENT & THERAPY 2653-65 (2021); Exonate’s press release on Mar. 5, 2024 (https: / / www.exonate.com / updates / exonate-first-class-eye-drop-phase-ibiia-trial-dat / ) (accessed on June 3, 2024).

[0020] Accordingly, despite obtaining promising preclinical data of in vivo efficacy and exposure in the retina and choroid, no small molecule kinase inhibitors have successfully shown clinical efficacy of preventing progression of or eliminating choroidal neovascularization, particularly from Phase II studies and onwards, in treating posterior segment eye diseases. Even optimization efforts to improve drug delivery have failed in obtaining sufficient clinical efficacy in humans. Joussen et al., “The Developing Regorafenib Eye Drops for neovascular Age-related Macular degeneration (DREAM) study: an open-label phase II trial,” 85 BR J CLIN PHARMACOL 347-55 (2019); Poor et al., “A Randomized, Double-Masked, Multicenter Trial of Topical Acrizanib (LHA510), a Tyrosine Kinase VEGF-Receptor Inhibitor, in Treatment-Experienced Subjects With Neovascular Age- Related Macular Degeneration,” 239 AM J OPHTHALMOL 180-89 (2022). In addition, the use of these small molecule kinase inhibitors has failed regardless of whether the use is in induction phase or in maintenance phase of the treatment for these posterior eye segment diseases. There is, therefore, a need for a small molecule kinase inhibitor that could be topically administered with confirmed clinical efficacy in preventing progression of or eliminating choroidal neovascularization in human eyes.

[0021] Tivozanib is a tyrosine kinase inhibitor targeting VEGFRs, among others, with the chemical name of l-{2-chloro-4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-3-(5-methylisoxazol-3-yl)urea. Its chemical structure is the following:

[0022] As disclosed in U.S. Patent No. 10,894,043, which is incorporated by reference in its entirety, the nanoparticle formulation of tivozanib have shown in vivo delivery of the molecule to the posterior segments (choroid and retina) of the eye in rat and rabbit models. Phase I studies have been conducted where the data confirmed safety and non-toxicity of tivozanib formulations in humans, with some basic indication of potential efficacy open for exploration. However, as discussed, it is not believed that tivozanib had previously demonstrated clinical efficacy in humans to treat posterior segment eye diseases, particularly in clinical studies beyond Phase I studies.

[0023] SUMMARY OF THE INVENTION

[0024] Contrary to the failures of other small molecule kinase inhibitors, the inventor discovered, inter alia, a method of treating a human patient with a posterior segment eye disease comprising topically administering a maintenance effective dose of a tivozanib formulation 1 to 3 times per day to the eye of the human patient, wherein the eye of the human patient has been treated with an anti- VEGF agent, wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 0.5 w / v % to about 2 w / v %, and wherein the posterior segment eye disease is neovascular age-related macular degeneration, diabetic macular edema, or retinal vein occlusion.

[0025] The present disclosure further provides a method of treating a human patient with a neovascular age-related macular degeneration comprising: topically administering a maintenance effective dose of a tivozanib formulation 1 to 3 times per day to the eye of the human patient, wherein the eye of the human patient has been treated with an anti-VEGF agent, and wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 0.5 w / v % to about 2 w / v %. By undergoing this method, it was discovered that tivozanib formulation maintains BCVA as measured by ETDRS visual acuity chart at, e.g., 44 weeks and 52 weeks from the initiation of administration of the tivozanib formulation, compared to the day before administration of the tivozanib formulation.

[0026] The present disclosure further provides a method of treating a human patient with a diabetic macular edema comprising: topically administering a maintenance effective dose of a tivozanib formulation 1 to 3 times per day to the eye of the human patient, wherein the eye of the human patient has been treated with an anti-VEGF agent, and wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 0.5 w / v % to about 2 w / v %. By undergoing this method, it was discovered that tivozanib formulation maintains BCVA as measured by ETDRS visual acuity chart at, e.g., 36 and 52 weeks from the initiation of administration of the tivozanib formulation, weeks compared to the day before administration of the tivozanib formulation.

[0027] The present disclosure further provides a method of treating a human patient with a posterior segment eye disease comprising: administering an anti-VEGF agent as an induction phase dose to the human patient in need of said treatment; following the administration of the anti-VEGF agent in the induction phase, topically administering a maintenance effective dose of a tivozanib formulation 1 to 3 times per day to the eye of the human patient as a maintenance phase dose; wherein the posterior segment eye disease is neovascular age-related macular degeneration, diabetic macular edema, or retinal vein occlusion; wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 0.5 w / v % to about 2 w / v %, and wherein the administration of the maintenance phase dose starts after the last administration of the anti-VEGF agent in the induction phase.

[0028] The present disclosure further provides a method of treating a human patient with neovascular-age related macular degeneration comprising: administering an anti-VEGF agent as an induction phase dose to the human patient in need of said treatment; following the administration of the anti-VEGF agent in the induction phase, topically administrating a maintenance effective dose of a tivozanib formulation 1 to 3 times per day to the eye of the human patient as a maintenance phase dose; wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 0.5 w / v % to about 2 w / v %, and wherein the administration of the maintenance phase dose starts after the last administration of the anti-VEGF agent in the induction phase.

[0029] The present disclosure further provides a method of treating a human patient with diabetic macular edema comprising: administering an anti-VEGF agent as an induction phase dose to the human patient in need of said treatment; following the administration of the anti-VEGF agent in the induction phase, topically administrating a maintenance effective dose of a tivozanib formulation 1 to 3 times per day to the eye of the human patient as a maintenance phase dose; wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 0.5 w / v % to about 2 w / v %, and wherein the administration of the maintenance phase dose starts after the last administration of the anti- VEGF agent in the induction phase.

[0030] The present disclosure further provides a method of treating a human patient with neovascular age-related macular degeneration comprising: administering intravitreally to the human patient in need of said treatment an anti-VEGF agent as an induction phase dose; following the administration of the anti-VEGF agent in the induction phase, topically administering a maintenance effective dose of a tivozanib formulation 1 to 3 times per day to the eye of the human patient as a maintenance phase dose; wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 0.5 w / v % to about 2 w / v % in the formulation; wherein the anti-VEGF agent is aflibercept; wherein in the induction phase dose, the anti-VEGF agent is intravitreally administered at day 1, week 4, and week 8; wherein the administration of the maintenance phase dose starts a day after the last intra vitreal administration of the anti-VEGF agent at week 8 in the induction phase dose and is continued for at least 44 weeks; and wherein the maintenance phase dose maintains BCVA as measured by ETDRS visual acuity chart at 44 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of the induction phase.

[0031] The present disclosure further provides a method of treating a human patient with diabetic macular edema comprising: administering intravitreally to the human patient in need of said treatment an anti-VEGF agent as an induction phase dose; following the administration of the anti- VEGF agent in the induction phase, topically administering a maintenance effective dose of a tivozanib formulation 1 to 3 times per day to the eye of the human patient as a maintenance phase dose; wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 0.5 w / v % to about 2 w / v % in the formulation; wherein the anti-VEGF agent is aflibercept; wherein in the induction phase dose, the anti-VEGF agent is intravitreally administered at day 1, week 4, week 8, week 12, and week 16; wherein the administration of the maintenance phase dose starts a day after the last intra vitreal administration of the anti-VEGF agent at week 16 in the induction phase dose and is continued for at least 36 weeks; and wherein the maintenance phase dose maintains BCVA as measured by ETDRS visual acuity chart at 36 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of the induction phase.

[0032] The present disclosure further provides a method of treating a human patient with a posterior segment eye disease comprising: topically administering a therapeutically effective dose of a tivozanib formulation 1 to 3 times per day to the eye of the human patient in need of said treatment, and wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 0.5 w / v % to about 2 w / v %.

[0033] BRIEF DESCRIPTION OF DRAWINGS

[0034] FIG. 1 provides the study scheme for Example 2, Phase 2 clinical trial for nAMD.

[0035] FIG. 2 provides the study scheme for Example 3, Phase 2 clinical trial for DME.

[0036] DETAILED DESCRIPTION

[0037] Definitions

[0038] As used herein and unless otherwise indicated, the terms “a” and “an” are taken to mean “one,” “at least one” or “one or more.” Unless otherwise required by context, singular terms used herein shall include pluralities and plural terms shall include the singular.

[0039] The term “VEGF” refers to vascular endothelial cell growth factor ligands including VEGF-A, VEGF-B, VEGF-C, VEGF-D, PLGF and other ligands binding to VEGF receptors (VEGFR-1, VEGFR-2 and VEGFR-3). VEGF-A is the 165-amino acid vascular endothelial cell growth factor, and related other kinds of amino acid vascular endothelial cell growth factors, together with the naturally occurring allelic and processed forms of those growth factors. Helotera et al., “A Linkage between Angiogenesis and Inflammation in Neovascular Age- Related Macular Degeneration,” 11 CELLS 3453 (2022); Marner et al., “VEGF-A splice variants bind VEGFRs with differential affinities,” SCIENTIFIC REPORTS (2020).

[0040] The term “anti-VEGF agent” refers to an antibody, fusion proteins and other drug modalities that can diminish or inhibit VEGF pathway / activity in vivo and / or in vitro and is used to treat human patients with a need thereof. Preferably, anti-VEGF agents are biologies. Anti- VEGF agents include aflibercept, ranibizumab, bevacizumab, brolucizumab, faricimab, aflibercept HD (high dose), port delivery system of ranibizumab, KSI-301, Sozinibercept (OPT- 302), ABBV-RGX-314, AXPAXLI (axitinib intravitreal implant, OTX-TKI), DURAVYU (vorolanib intravitreal insert, EYP-1901) and biosimilars thereof. Anti-VEGF agents are administered by intravitreal injection or other invasive administration ways (e.g., subre tinal injection, suprachoroidal injection, subconjunctival injection, and ocular implant) to a human patient. Preferably, anti-VEGF agents are administered intravitreally.

[0041] “Subject” or “patient” refers to a human being.

[0042] The term “posterior segment eye disease” refers to an eye disease of the retina, choroid and optic nerve. Posterior segment eye disease includes neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME), diabetic retinopathy (DR) such as proliferative diabetic retinopathy (PDR) and non-proliferative diabetic retinopathy (NPDR), and retinal vein occlusion (RVO) such as central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO).

[0043] “Induction phase” refers to the initial phase of the treatment for posterior segment eye diseases where an anti-VEGF agent is administered, preferably intravitreally. It is generally followed by a “maintenance phase dose” treatment. “Induction phase dose” refers to the dose used during the induction phase where the patient is administered with an anti-VEGF agent.

[0044] “Maintenance phase” refers to the latter phase of the treatment for posterior segment eye diseases where tivozanib formulation is topically administered to the ocular surface. It typically follows the induction phase. The “maintenance phase dose” is administered during the maintenance phase and where the “maintenance effective dose” of tivozanib formulation is topically administered to the eye of the patient.

[0045] The term “maintenance effective dose” refers to the dose of tivozanib formulation that maintains the visual acuity of a patient compared to the visual acuity before administration of the tivozanib formulation, for example after completing the induction phase. The visual acuity is considered maintained if there is no reduction of 15 or more letters in BCVA as measured by ETDRS visual acuity chart at, for example, week 4 (day 29), week 8 (day 57), week 12 (day 85), week 16 (day 113), week 20 (day 141), week 24 (day 169), week 28 (day 197), week 32 (day 225), week 36 (day 253), week 40 (day 281), week 44 (day 309), week 48 (day 337), and / or week 52 (day 365) from administering the tivozanib formulation compared to the measured BCVA before administration of the tivozanib formulation, preferably compared to the day before administration of the tivozanib formulation. When there is an induction phase in the treatment, the visual acuity is compared against the last day of the induction phase. The visual acuity is maintained if there is no reduction of 15 or more letters in BCVA as measured by ETDRS visual acuity chart at, for example, week 4 (day 29), week 8 (day 57), week 12 (day 85), week 16 (day 113), week 20 (day 141), week 24 (day 169), week 28 (day 197), week 32 (day 225), week 36 (day 253), week 40 (day 281), week 44 (day 309), week 48 (day 337), week 52 (day 365), week 56 (day 393), week 60 (day 421), week 64 (day 449), and / or week 68 (day 477) from, e.g., the initiation of the induction phase dose or the maintenance phase dose, compared to the last day of the induction phase.

[0046] The term “a therapeutically effective dose” refers to the dose of tivozanib formulation that provides a therapeutic benefit in the treatment or management of the claimed ocular disease.

[0047] The term “tivozanib formulation” refers to an aqueous composition that includes tivozanib as an active ingredient with pharmaceutically acceptable excipients. Preferably, the tivozanib formulation includes nanoparticle tivozanib in a suspension form. Exemplary nanoparticle tivozanib formulations are disclosed in U.S. Patent No. 10,894,043.

[0048] Tivozanib may be in a form of its pharmaceutically acceptable salt or a hydrate or a solvate of tivozanib or its salt. Preferably, tivozanib hydrochloride monohydrate is included in the tivozanib formulation. Tivozanib hydrochloride monohydrate has the following chemical structure:

[0049] The term “about” in the context of the amount of tivozanib in the formulation allows for a 10% margin of error. For example, about 0.5 w / v % would encompass 0.45 w / v % - 0.55 w / v %, and about 2.0 w / v % would encompass 1.8 w / v % - 2.2 w / v %.

[0050] The term “QD” means administering once per day.

[0051] The term “BID” means administering twice per day.

[0052] The term “TID” means administering three times per day.

[0053] The term “QID” means administering four times per day.

[0054] The term “screening” refers to the process or phase where the potential patients for the clinical trial are screened using inclusion and exclusion criteria to determine whether they are eligible to undergo the clinical trial.

[0055] The term “baseline” refers to day 1 of the claimed treatment. When there is an induction phase dose followed by a maintenance phase dose, then “baseline” refers to the first day of treatment with the anti-VEGF agent in the induction phase. When there is no induction phase dose, “baseline” refers to day 1 of treatment with the tivozanib formulation. “Week X” refers to the number of full weeks from Day 1 of the claimed treatment. For example, BCVA measured by ETDRS visual acuity chart at 52 weeks or Week 52 is assessed on Day 365.

[0056] The term “treatment-naive” means patients who have not received any anti-VEGF treatment for the claimed ocular disease. “Treatment experienced” means patients who have previously received treatment with an anti-VEGF agent, including bevacizumab, ranibizumab, aflibercept or their biosimilars, for the claimed ocular disease.

[0057] “Active subfoveal macular neovascularization or juxtafoveal / extrafoveal macular neovascularization secondary to age-related macular degeneration with a subfoveal component related to the macular neovascularization activity” refers to active choroidal neovascularization. Specifically, “juxtafoveal macular neovascularization secondary to age-related macular degeneration” refers to active choroidal neovascularization within a region 1 to 199 pm from the geometrical center of the foveal avascular zone noted on fluorescein angiography. These are conditions of nAMD.

[0058] The term “topical administration,” or the like, to the eye refers to the administration to the eye via an eye drop.

[0059] The “eye,” the “study eye,” or the “treatment eye” refer to the eye subject to the claimed treatment and which has the posterior segment eye disease.

[0060] “Best-corrected visual acuity” or “BCVA” is assessed based on Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart with a starting distance of 4 meters and continues at distance of 1 meter only if the participant reads a total of < 19 letters on the chart at 4 meters. On the Visual Acuity Worksheet, all letters read correctly should be circled. Letters read incorrectly or not read at all should be left unmarked. At the end of each row of letters, the total number of letters read correctly should be written down. Each box / underline should be filled out. If visual acuity was not tested at 1 meter, the 7 lines at the end of the corresponding rows should be crossed out with a single vertical line or a diagonal line, initialed and dated. “ETDRS visual acuity chart” is ETDRS 4-meter Original Series Chart R, 1 or 2 provided by Precision Vision or Good-Lite.

[0061] “Central subfield thickness” or “CST” is measured by Spectral Domain-Optical Coherence Tomography (SD-OCT). Preferably, for nAMD patients, CST is the distance between the surface of the internal limiting membrane (ILM) and the outer border of the retinal pigment epithelium (RPE) at the central fovea (ILM-RPE). Preferably, for DME, CST is the distance between the surface of ILM to Bruch’s Membrane (BM) (ILM-BM).

[0062] “Diabetic Retinopathy Severity Scale score” or “DRSS score” is assessed by Color Fundus Photography. “Hemoglobin Ale” or “hblc” is measured using a hematological laboratory test that shows an average blood sugar level over the past 2 to 3 months.

[0063] The present disclosure provides, inter alia, a method of treating a human patient with a posterior eye disease, specifically nAMD, DME, and RVO (including CRVO and BRVO), comprising topically administering a maintenance effective dose of a tivozanib formulation 1 to 3 times per day to the eye of the human patient, wherein the eye of the human patient has been treated with an anti-VEGF agent, and wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 0.5 w / v % to about 2 w / v %.

[0064] When the posterior segment eye disease is nAMD, administering the tivozanib formulation maintains BCVA as measured by ETDRS visual acuity chart at, for example, week 4 (day 29), week 8 (day 57), week 12 (day 85), week 16 (day 113), week 20 (day 141), week 24 (day 169), week 28 (day 197), week 32 (day 225), week 36 (day 253), week 40 (day 281), week 44 (day 309), week 48 (day 337), and / or week 52 (day 365) compared to the measured BCVA before administration of the tivozanib formulation including, for example, the day before administration of the tivozanib formulation. Consistent with the definition above, BCVA is considered maintained if administering the tivozanib formulation prevents a reduction of 15 or more letters in BCVA as measured by ETDRS visual acuity chart at, for example, 44 weeks or 52 weeks compared to the measured BCVA before administration of the tivozanib formulation, for example, the day before administration of the tivozanib formulation. Preferably, the tivozanib formulation prevents a reduction of 10 or more letters in BCVA as measured by ETDRS visual acuity chart at 44 weeks or 52 weeks compared to the measured BCVA before administration of the tivozanib formulation, including, the day before administration of the tivozanib formulation, or more preferably, the tivozanib formulation prevents a reduction of 5 or more letters in BCVA as measured by ETDRS visual acuity chart at 44 weeks or 52 weeks compared to the measured BCVA before administration of the tivozanib formulation, including, the day before administration of the tivozanib formulation.

[0065] When the posterior segment eye disease is DME, administering the tivozanib formulation maintains BCVA as measured by ETDRS visual acuity chart at, for example, week 4 (day 29), week 8 (day 57), week 12 (day 85), week 16 (day 113), week 20 (day 141), week 24 (day 169), week 28 (day 197), week 32 (day 225), week 36 (day 253), week 40 (day 281), week 44 (day 309), week 48 (day 337), and / or week 52 (day 365) compared to the measured BCVA before administration of the tivozanib formulation including, for example, the day before administration of the tivozanib formulation. Consistent with the definition above, BCVA is considered maintained if administering the tivozanib formulation prevents a reduction of 15 or more letters in BCVA as measured by ETDRS visual acuity chart at, for example, 36 weeks or 52 weeks compared to the measured BCVA before administration of the tivozanib formulation, for example, the day before administration of the tivozanib formulation. Preferably, the tivozanib formulation prevents a reduction of 10 or more letters in BCVA as measured by ETDRS visual acuity chart at 36 weeks or 52 weeks compared to the measured BCVA before administration of the tivozanib formulation, including, the day before administration of the tivozanib formulation, or more preferably, the tivozanib formulation prevents a reduction of 5 or more letters in BCVA as measured by ETDRS visual acuity chart at 36 weeks or 52 weeks compared to the measured BCVA before administration of the tivozanib formulation, for example, the day before administration of the tivozanib formulation.

[0066] In another embodiment, the method of treating a human patient with a posterior segment eye disease, preferably nAMD, DME, and RVO (including CRVO and BRVO), comprises administering an anti-VEGF agent as an induction phase dose to the human patient in need of said treatment; following the administration of the anti-VEGF agent in the induction phase, topically administering a maintenance effective dose of a tivozanib formulation 1 to 3 times per day to the eye of the human patient as a maintenance phase dose; wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 0.5 w / v % to about 2 w / v %, and wherein the administration of the maintenance phase dose starts after, preferably a day after, the last administration of the anti-VEGF agent in the induction phase.

[0067] By following the treatment, administering the tivozanib formulation maintains BCVA as measured by ETDRS visual acuity chart at, for example, week 4 (day 29), week 8 (day 57), week 12 (day 85), week 16 (day 113), week 20 (day 141), week 24 (day 169), week 28 (day 197), week 32 (day 225), week 36 (day 253), week 40 (day 281), week 44 (day 309), week 48 (day 337), and / or week 52 (day 365) from the initiation of the maintenance phase dose compared to the last day of the induction phase. Consistent with the definition above, BCVA is considered maintained if administering the tivozanib formulation prevents a reduction of 15 or more letters in BCVA as measured by ETDRS visual acuity chart at, for example, 36 weeks, 44 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of induction phase. When the posterior segment eye disease is nAMD, preferably, the tivozanib formulation prevents a reduction of 10 or more letters in BCVA as measured by ETDRS visual acuity chart at 44 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of induction phase, or more preferably, the tivozanib formulation prevents a reduction of 5 or more letters in BCVA as measured by ETDRS visual acuity chart at 44 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of induction phase. When the posterior segment eye disease is DME, preferably, the tivozanib formulation prevents a reduction of 10 or more letters in BCVA as measured by ETDRS visual acuity chart at 36 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of induction phase, or more preferably, the tivozanib formulation prevents a reduction of 5 or more letters in BCVA as measured by ETDRS visual acuity chart at 36 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of induction phase. When the posterior segment eye disease is RVO, preferably, the tivozanib formulation prevents a reduction of 10 or more letters in BCVA as measured by ETDRS visual acuity chart at 52 weeks from the initiation of the maintenance phase dose compared to the last day of induction phase, or more preferably, the tivozanib formulation prevents a reduction of 5 or more letters in BCVA as measured by ETDRS visual acuity chart at 52 weeks from the initiation of the maintenance phase dose compared to the last day of induction phase.

[0068] In another embodiment, a method of treating a human patient with nAMD comprises: administering an anti-VEGF agent as an induction phase dose to the human patient in need of said treatment; following the administration of the anti-VEGF agent in the induction phase, topically administering a maintenance effective dose of a tivozanib formulation 1 to 3 times per day to the eye of the human patient as a maintenance phase dose; wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 0.5 w / v % to about 2 w / v %, and wherein the maintenance phase dose starts after, preferably a day after, the last administration of the anti- VEGF agent in the induction phase. At baseline of the treatment (day 1 of induction phase), the human patient preferably has at least one of the following characteristics:

[0069] • active subfoveal macular neovascularization or juxtafoveal / extrafoveal macular neovascularization secondary to age-related macular degeneration with a subfoveal component related to the macular neovascularization activity;

[0070] • BCVA ETDRS letter score of 78 letters to 35 letters in the treatment eye as measured by the ETDRS visual acuity chart; and / or

[0071] • CST of the treatment eye is < 450 pm.

[0072] By following the treatment, the maintenance phase dose maintains BCVA measured by ETDRS visual acuity chart at, for example, week 4 (day 29), week 8 (day 57), week 12 (day 85), week 16 (day 113), week 20 (day 141), week 24 (day 169), week 28 (day 197), week 32 (day 225), week 36 (day 253), week 40 (day 281), week 44 (day 309), week 48 (day 337), and / or week 52 (day 365) from the initiation of the maintenance phase dose compared to the last day of the induction phase. Consistent with the definition above, BCVA is considered maintained if administering the tivozanib formulation prevents a reduction of 15 or more letters in BCVA as measured by ETDRS visual acuity chart at, for example, 44 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of induction phase. Preferably, the tivozanib formulation prevents a reduction of 10 or more letters in BCVA as measured by ETDRS visual acuity chart at 44 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of induction phase, or more preferably, the tivozanib formulation prevents a reduction of 5 or more letters in BCVA as measured by ETDRS visual acuity chart at 44 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of induction phase.

[0073] CST could be also measured by SD-OCT at, for example, week 4 (day 29), week 8 (day 57), week 12 (day 85), week 16 (day 113), week 20 (day 141), week 24 (day 169), week 28 (day 197), week 32 (day 225), week 36 (day 253), week 40 (day 281), week 44 (day 309), week 48 (day 337), and / or week 52 (day 365) from the initiation of the maintenance phase dose and could be compared against the CST from the last day of the induction phase. CST for nAMD is preferably ILM-RPE.

[0074] In another embodiment, a method of treating a human patient with DME comprises: administering an anti-VEGF agent as an induction phase dose to the human patient in need of said treatment; following the administration of the anti-VEGF agent in the induction phase, topically administering a maintenance effective dose of a tivozanib formulation 1 to 3 times per day to the eye of the human patient as a maintenance phase dose; wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 0.5 w / v % to about 2 w / v %, and wherein the maintenance phase dose starts after, preferably a day after, the last administration of the anti- VEGF agent in the induction phase. At baseline of the treatment (day 1 of induction phase), the human patient preferably has at least one of the following characteristics:

[0075] • BCVA ETDRS letter score of 78 letters to 35 letters in the treatment eye as measured by the ETDRS visual acuity chart;

[0076] • CST of the treatment eye is > 325 pm and < 500 pm; and / or

[0077] • Hemoglobin Ale level is < 11%.

[0078] By following the treatment, the maintenance phase dose maintains BCVA measured by ETDRS visual acuity chart at, for example, week 4 (day 29), week 8 (day 57), week 12 (day 85), week 16 (day 113), week 20 (day 141), week 24 (day 169), week 28 (day 197), week 32 (day 225), week 36 (day 253), week 40 (day 281), week 44 (day 309), week 48 (day 337), and / or week 52 (day 365) from the initiation of the maintenance phase dose compared to the last day of the induction phase. Consistent with the definition above, BCVA is considered maintained if administering the tivozanib formulation prevents a reduction of 15 or more letters in BCVA as measured by ETDRS visual acuity chart at, for example, 36 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of induction phase. Preferably, the tivozanib formulation prevents a reduction of 10 or more letters in BCVA as measured by ETDRS visual acuity chart at 36 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of induction phase, or more preferably, the tivozanib formulation prevents a reduction of 5 or more letters in BCVA as measured by ETDRS visual acuity chart at 36 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of induction phase.

[0079] CST could be also measured by SD-OCT at, for example, 36 weeks or 52 weeks from the initiation of the maintenance phase dose and could be compared against the CST from the last day of the induction phase. CST for DME is preferably ILM-BM.

[0080] In another embodiment, a method of treating a human patient with a posterior segment eye disease, which includes nAMD, DME, RVO, and DR, comprises topically administering a therapeutically effective dose of a tivozanib formulation 1 to 3 times per day to the eye of the human patient in need of said treatment, and wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 0.5 w / v % to about 2 w / v %.

[0081] When the posterior segment eye disease is DR, administering the tivozanib formulation maintains and / or improves Diabetic Retinopathy Severity Scale (DRSS) score at, for example, week 4 (day 29), week 8 (day 57), week 12 (day 85), week 16 (day 113), week 20 (day 141), week 24 (day 169), week 28 (day 197), week 32 (day 225), week 36 (day 253), week 40 (day 281), week 44 (day 309), week 48 (day 337), and week 52 (day 365), and preferably at weeks 24 or 52 from administering the tivozanib formulation compared to baseline (day 1 of administration of the tivozanib formulation). DRSS score is considered maintained if there is no worsening of 2 or more steps from baseline in the DRSS score. DRSS score is considered improved if the DRSS score improves by 2 or more steps from baseline in the DRSS score.

[0082] When the posterior segment eye disease is nAMD, DME, or RVO (including CRVO and BRVO), the tivozanib formulation maintains BCVA as measured by ETDRS visual acuity chart at, for example, week 4 (day 29), week 8 (day 57), week 12 (day 85), week 16 (day 113), week 20 (day 141), week 24 (day 169), week 28 (day 197), week 32 (day 225), week 36 (day 253), week 40 (day 281), week 44 (day 309), week 48 (day 337), and week 52 (day 365) from the initiation of administering the tivozanib formulation. BCVA is considered maintained if the tivozanib formulation prevents a reduction of 15 or more letters of BCVA as measured by ETDRS visual acuity chart at, for example, 36 weeks, 44 weeks and / or 52 weeks from the initiation of administering the tivozanib formulation compared to baseline (day 1 of administration of the tivozanib formulation). Preferably, the tivozanib formulation prevents a reduction of 10 or more letters in BCVA as measured by ETDRS visual acuity chart at 36 weeks, 44 weeks and / or 52 weeks compared to baseline, or more preferably, the tivozanib formulation prevents a reduction of 5 or more letters in BCVA as measured by ETDRS visual acuity chart at 36 weeks, 44 weeks and / or 52 weeks from the initiation of administrating the tivozanib formulation compared to baseline.

[0083] In an embodiment, and preferably during administration of a maintenance phase dose of tivozanib formulation, a rescue of an anti-VEGF agent could be administered when a healthcare professional believes that the visual acuity has deteriorated. For example, an anti-VEGF agent could be administered during the maintenance phase as a rescue when the BCVA as measured by ETDRS visual acuity chart is reduced by 10 or more letters compared to baseline when there is an induction phase. A rescue administration of an anti-VEGF agent is generally a one-off administration and, therefore, the maintenance phase dose of the tivozanib formulation is resumed thereafter.

[0084] In an embodiment, a healthcare professional will administer the anti-VEGF agent at an induction phase dose to the human patient by intravitreal injection or other invasive administration ways during the induction phase, and after the induction treatment, the healthcare professional will determine whether to proceed with the maintenance phase dose based on disease condition / activity and outcome of the induction treatment (e.g., change of BCVA, change of retinal thickness, anatomical change in the posterior eye tissues). If the healthcare professional determines that the patient could proceed with the maintenance phase dose, the healthcare professional will instruct the patient to topically apply the tivozanib formulation on a daily basis as a maintenance phase dose. The healthcare professional will periodically e.g., 4- week interval) monitor disease condition / activity and outcome of the maintenance phase dose with the tivozanib formulation and may consider any need of a rescue anti-VEGF agent administration.

[0085] For any of the embodiments, the tivozanib formulations could be administered to treatment naive patients and treatment experienced patients. For example, treatment experienced patients may not undergo induction phase dose with an anti-VEGF agent and directly proceed with the administration of the tivozanib formulation.

[0086] Applicable to any of the embodiments discussed in this disclosure, the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt, and a pharmaceutically acceptable excipient, where preferably, the tivozanib formulation comprises tivozanib hydrochloride monohydrate and a pharmaceutically acceptable excipient. Exemplary tivozanib formulations are disclosed in U.S. Patent No. 10,894,043 and methods of making the same are disclosed therein. The amount of tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt, in the tivozanib formulation is about 0.5 w / v % to about 2.0 w / v %, or about 0.5 w / v %, about 0.6 w / v %, about 0.7 w / v %, about 0.8 w / v %, about 0.9 w / v %, about 1.0 w / v %, about 1.1 w / v %, about 1.2 w / v %, about 1.3 w / v %, about 1.4 w / v %, about 1.5 w / v %, about 1.6 w / v %, about 1.7 w / v %, about 1.8 w / v %, about 1.9 w / v %, or about 2.0 w / v %, and preferably about 0.5 w / v %, about 1.0 w / v %, or 2.0 w / v %. Most preferably, the tivozanib formulation includes tivozanib hydrochloride monohydrate in an amount of 0.5 w / v % (0.45 w / v % in freebase form), 1.0 w / v % (0.89 w / v % in freebase form), or 2.0 w / v % (1.8 w / v % in freebase form).

[0087] One or more eye drops of the tivozanib formulation is administered 1 to 3 times a day to the eye of the human patient, and preferably, one eye drop is administered once or twice a day.

[0088] The most preferred dosages of the tivozanib formulation are: 1) once daily administration of an eye drop of 0.5 w / v % tivozanib hydrochloride monohydrate formulation; 2) once daily administration of one eye drop of 2.0 w / v % tivozanib hydrochloride monohydrate formulation; and 3) twice daily administration of an eye drop of 2.0 w / v % tivozanib hydrochloride monohydrate formulation.

[0089] The dosage, including amount, frequency, and duration, of anti-VEGF agents used in any induction phase treatment could be readily determined by a healthcare professional in the relevant field. For example, an anti-VEGF agent is administered at least three times or more during the induction phase. As an additional example, when aflibercept is used in the induction phase for treatment of nAMD, it would be intravitreally administered on day 1, week 4, and week 8, a total of three times prior to the maintenance phase treatment using the tivozanib formulation. In another example, when aflibercept is used in the induction phase for treatment of DME, it would be intravitreally administered on day 1, week 4, week 8, week 12, week 16, a total of 5 times prior to the maintenance phase treatment using the tivozanib formulation. The “last” administration of an anti-VEGF agent is the final dose, which is preferably via an intravitreal injection, of the anti-VEGF agent in the induction phase prior to administering the tivozanib formulation as the maintenance phase dose in the maintenance phase.

[0090] As an additional embodiment, a treatment agent comprising tivozanib for posterior ocular diseases comprises: topically administering a maintenance effective dose of a tivozanib formulation 1 to 3 times per day to the eye of the human patient, wherein the eye of the human patient has been treated with an anti-VEGF agent, wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 0.5 w / v % to about 2 w / v %, and wherein the posterior segment eye disease is neovascular age-related macular degeneration, diabetic macular edema, or retinal vein occlusion.

[0091] As an additional embodiment, a treatment agent comprising tivozanib for posterior ocular diseases comprises: administering an anti-VEGF agent as an induction phase dose to the human patient in need of said treatment; following the administration of the anti-VEGF agent in the induction phase, topically administering a maintenance effective dose of a tivozanib formulation 1 to 3 times per day to the eye of the human patient as a maintenance phase dose; wherein the posterior segment eye disease is neovascular age-related macular degeneration, diabetic macular edema, or retinal vein occlusion; wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 0.5 w / v % to about 2 w / v %, and wherein the administration of the maintenance phase dose starts after the last administration of the anti-VEGF agent in the induction phase.

[0092] As an additional embodiment, a treatment agent comprising tivozanib for posterior ocular diseases comprises: topically administering a therapeutically effective dose of a tivozanib formulation 1 to 3 times per day to the eye of the human patient in need of said treatment, and wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 0.5 w / v % to about 2 w / v %.

[0093] EXAMPLES

[0094] Certain embodiments of the present invention will be described in greater detail by way of specific examples. Those examples demonstrating the invention are offered for illustrative purposes and are not intended to limit the present invention in any manner. Persons of skill in the art will readily recognize a variety of non-critical parameters that can be changed or modified to yield essentially the same results. Example 1.

[0095] A Phase 1 clinical study of tivozanib formulation was conducted to study safety, tolerability, and pharmacokinetics of single or multiple ocular doses of tivozanib in healthy people and patients with nAMD. Exploratory efficacy, which refers only to the possibility, but not any prediction, of demonstrating clinical efficacy in further clinical studies, was also investigated after multiple ocular doses of tivozanib in patients with nAMD.

[0096] The study had three cohorts (Cohort 1, 2, and 3). Cohort 1 was a single-dose cohort with 5 steps in healthy Japanese men (Steps 1 to 3, and 5) and White healthy men (Step 4). Cohort 2 was a 21 -day multiple-dose cohort with 6 steps in healthy Japanese men (Steps 1 to 4 and 6) and White healthy men (Step 5). Cohort 3 was a 21-day multiple-dose cohort with 3 steps in Japanese patients with nAMD (Steps 1 to 3).

[0097] In Cohort 1 , either the placebo or the tivozanib formulation were administered to one study eye. The doses of tivozanib were 0.15 mg / day (one drop [30 pL] of 0.5 w / v% formulation) in Step 1, 0.3 mg / day (one drop of 1.0 w / v%) in Step 2, 0.6 mg / day (two drops of 1.0 w / v%) in Steps 3 and 4, and 0.6 mg / day (one drop of 2.0 w / v%) in Step 5. Nasolacrimal occlusion or eyelid closure was applied immediately after administration of tivozanib in all steps.

[0098] In Cohort 2, either the placebo or the tivozanib formulation were administered to one study eye. The doses of tivozanib were 0.45 mg / day (one drop of 0.5 w / v%, three times a day) in Step 1, 0.9 mg / day (one drop of 1.0 w / v%, three times a day) in Step 2, 1.8 mg / day (two drops of 1.0 w / v%, three times a day) in Steps 3 to 5, and 1.8 mg / day (one drop of 2.0 w / v%, three times a day) in Step 6. Nasolacrimal occlusion or eyelid closure was applied immediately after each administration of tivozanib formulation in all steps except in Step 4.

[0099] In Cohort 3, tivozanib formulation were administered to one study eye. The doses of tivozanib were 0.45 mg / day (one drop of 0.5 w / v%, three times a day) in Step 1, 0.9 mg / day (one drop of 1.0 w / v%, three times a day) in Step 2, and 1.8 mg / day (two drops of 1.0 w / v%, three times a day) in Step 3. Nasolacrimal occlusion or eyelid closure was applied immediately after each administration in all steps.

[0100] A total of 30 participants in Cohort 1 (6 participants per step), 36 participants in Cohort 2 (6 per step), and 28 participants in Cohort 3 (7 in Step 1, 10 in Step 2, and 11 in Step 3) received at least 1 dose of KHK4951 (tivozanib-containing formulation). All participants completed the scheduled KHK4951 administrations except for 1 patient in Cohort 3 due to the subject proceeding to out-of-study treatment after the first administration.

[0101] Overall, tivozanib formulation was well tolerated both in healthy participants (Japanese and White) and patients with nAMD. No notable differences in safety profile were observed between the two populations (Japanese healthy participants vs White healthy participants), the two formulations (two drops of 1.0 w / v% vs one drop of 2.0 w / v%), or the two administration conditions (with nasolacrimal occlusion or eyelid closure vs without nasolacrimal occlusion and eyelid closure).

[0102] The exploratory efficacy assessments in participants with nAMD in Cohort 3 were generally inconclusive and not encouraging. The mean changes from baseline in CST, as assessed by SD-OCT, showed a decreasing trend in a dose-dependent manner. Additionally, the mean changes from baseline in BCVA, as measured by ETDRS visual acuity chart, showed no clear trends toward improvement. The CST and BCVA results for the tested tivozanib formulations were, at best, only comparable to the obtained results from Phase 2a studies for pazopanib, which ultimately failed to show clinical efficacy in its use as a maintenance therapy to treat nAMD patients. Moreover, the CST and BCVA results for the tested tivozanib formulations were poor compared to efficacy data of anti-VEGF agents including ranibizumab and aflibercept in Phase 3 studies.

[0103] Example 2. Phase 2 study for nAMD

[0104] A phase 2, multicenter, randomized, double-masked, parallel-group study in nAMD patients with nAMD, specifically patients with subfoveal macular neovascularization (MNV) or juxtafoveal / extrafoveal macular neovascularization (MNV) with a subfoveal component related to the macular neovascularization activity is performed. The study consists of an up to 30-day screening period, an 8-week run-in period (induction phase), a 44-week treatment period (maintenance phase) and an up to 4-week safety follow-up period. Participants will receive three IVT injections of aflibercept every 4 weeks as the induction treatment during the 8-week run-in period. From the day after the third IVT injection, patients receive tivozanib eye drops in the study eye with three different dosages (tivozanib eye drop 0.5 w / v% QD, 2.0 w / v% QD, or 2.0 w / v% BID) during the 44-week treatment period. FIG. 1 provides a detailed scheme of the study.

[0105] Number of participants:

[0106] Approximately 180 participants will be enrolled to the 8-week run-in period. (Approximately 117 participants (39 patients for each arm) will be administered with the tivozanib eye drops.) Study Arms and Duration:

[0107] The study duration will be up to 56 weeks. Study details are shown below. Screening period (SCREENING): Up to 30 days from obtaining informed consent Run-in period (RUN-IN): 8 weeks from the first IVT injection of aflibercept Treatment period (TREATMENT): 44 weeks from the first tivozanib formulation administration

[0108] • Tivozanib hydrochloride monohydrate eye drop 0.5 w / v% QD arm

[0109] • Tivozanib hydrochloride monohydrate eye drop 2.0 w / v% QD arm

[0110] • Tivozanib hydrochloride monohydrate eye drop 2.0 w / v% BID arm

[0111] After each instillation of KHK4951 (tivozanib-containing formulation) or placebo, participants will apply digital pressure to the nasolacrimal duct and close the eyelid for approximately 1 minute.

[0112] Follow-up period (FOLLOW-UP): Up to 4 weeks from the end of treatment or early termination examination (whichever occurs earlier) The visit frequency will be every 4 weeks after Day 1.

[0113] Inclusion criteria:

[0114] 1) Patient must be 50 years of age or older at the time of signing the informed consent;

[0115] 2) Patient with active subfoveal MNV (any subtype) or juxtafoveal / extrafoveal MNV secondary to AMD with a subfoveal component related to the macular neovascularization activity in the eye;

[0116] 3) BCVA ETDRS letter score of 78 letters to 35 letters (Snellen equivalent of approximately 20 / 32 to 20 / 200) for the study eye at screening and on Day 1 ;

[0117] 4) CST < 450 pm at screening as assessed by the central reading center; and

[0118] 5) If woman, confirmed to be not pregnant.

[0119] Exclusion criteria: Patients were excluded from the study for various reasons, including any medical conditions, abnormalities, or any therapies (e.g., medicinal or surgical) that might confound the results of the study relevant to the investigated endpoints.

[0120] Response criterion:

[0121] Participants who meet all of the eligibility criteria above will receive IVT injections in the study eye on Day 1 and Week 4. Participants who respond to the first two IVT injections of aflibercept during the run-in period will receive the third IVT injection of aflibercept at Day 57 (Week 8) and proceed to administration of tivozanib formulations during the treatment period (maintenance phase). Participants who do not meet the response criterion will be discontinued from the study at Week 8. A response is defined as an increase of > 5 letters in BCVA compared to the Day 1 score at the measurement before the third IVT injection of aflibercept at Week 8. Primary endpoint: The primary efficacy endpoint is achieved where a patient, from Week 8 to Week 52, does not experience a reduction of 15 or more letters in BCVA as measured by ETDRS visual acuity chart.

[0122] Secondary endpoints:

[0123] 1) Time to first rescue IVT injection or discontinuation due to lack of efficacy from Week 8 for each treatment arm.

[0124] Time to first rescue IVT injection or discontinuation due to lack of efficacy from Week 8 for each treatment arm will be summarized by Kaplan-Meier method. A Kaplan Meier plot will also be provided for each treatment arm. If the participants are evaluated to require rescue IVT injection for the first time, the date at which first rescue IVT injection was required will be used as the date of the event. Relatedly, if the participants used any treatment / therapy not permitted in the protocol in the study eye during the treatment period to treat nAMD without the use of protocol-permitted rescue IVT injection, the data at which this treatment / therapy was used will be the date of the event. For participants who did not have rescue IVT injection and stayed until the end of treatment, the date of assessments for the end of treatment visit (Week 52) will be used as the date of censoring.

[0125] 2) The number of rescue IVT injections during the treatment period.

[0126] Descriptive statistics for the number of rescue IVT injections during the treatment period will be summarized for each treatment arm. The number and percentage of participants will also be summarized by the total number of rescue IVT injections during the treatment period.

[0127] 3) Change from Week 8 in BCVA as Measured by ETDRS Visual Acuity Chart at Each Assessment Time Point.

[0128] Descriptive statistics of actual and change from analysis baseline in BCVA will be presented for each time point in both the run-in period and the treatment period for each treatment arm. The mean (± standard deviation (SD)) BCVA over time will be plotted. The mean (+SD) change from analysis baseline in BCVA over time will be plotted.

[0129] 4) A Reduction of > 15 letters / > 10 letters / > 5 letters from Week 8 in BCVA as measured by ETDRS visual Acuity Chart at Each Assessment Time Point after initiating administration of tivozanib formulation.

[0130] The number and percentage of participants having 15, 10, or 5 letters or more reduction in BCVA from analysis baseline at each time point in the treatment period will be presented for each treatment arm.

[0131] 5) Change from Week 8 in CST as measured by SD-OCT at each assessment time point after initiating administration of tivozanib formulation Descriptive statistics of actual and change from analysis baseline in CST will be presented for the analysis baseline and each time point in both the run-in period and the treatment period for each treatment arm. The mean (+SD) CST over time will be plotted. The mean (+SD) change from analysis baseline in CST over time will be plotted.

[0132] 6) Change from Week 8 in Subretinal Hyperreflective Material (SHRM) and Retinal Morphology (Intraretinal Fluid (IRF), Subretinal Fluid (SRF), Sub-Retinal Pigment Epithelial Fluid (Sub-RPEF), Dry Macula) as Measured by SD-OCT at Each Assessment Time Point after initiating administration of tivozanib formulation

[0133] The number and percentage of participants having SHRM and retinal morphology changes at the analysis baseline and each time point in the treatment period will be presented for each treatment arm. In addition, the morphology at analysis baseline and each time point in the treatment period after the analysis baseline will be summarized in a shift table for each treatment arm.

[0134] 7) Change from Week 8 in MNV Lesion Area and Total MNV Leakage Area at Each Assessment Time Point after initiating administration of tivozanib formulation Descriptive statistics of actual and change from analysis baseline in MNV lesion area and total MNV leakage area will be presented for the analysis baseline and each time point in the treatment period for each treatment arm.

[0135] The mean (+SD) MNV lesion area and total MNV leakage area over time will be plotted. The mean (+SD) change from analysis baseline in MNV lesion area and total MNV leakage area over time will be plotted.

[0136] 8) Change from Week 8 in National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25) at Each Assessment Time Point after initiating administration of tivozanib formulation

[0137] Descriptive statistics of actual and change from analysis baseline in NEI VFQ-25 total and subscale scores will be presented for the analysis baseline and each time point in the treatment period for each treatment arm. The mean (+SD) NEI VFQ-25 total and subscale scores over time will be plotted. The mean (+SD) change from analysis baseline in NEI VFQ-25 total and subscale scores over time will be plotted.

[0138] Rescue criteria during administration of tivozanib eye drop:

[0139] If a participant meets the following criterion on examinations at the time of study visits (every 4 weeks) during the treatment period (maintenance phase), aflibercept 2 mg will be intravitreally administered:

[0140] • Decrease of 10 or more letters compared to the Day 1 score (from baseline, or from the initiation of the induction phase) in BCVA as measured by ETDRS visual acuity chart. Assessment at each study visit:

[0141] Assessments at each study visit include BCVA as measured by ETDRS visual acuity chart and CST as measured by SD-OCT.

[0142] Results:

[0143] The study assesses whether the patients have maintained in BCVA as measured by ETDRS visual acuity chart at Week 52 (i.e., Week 44 from the initiation of the treatment with tivozanib formulation) compared to Week 8.

[0144] Blinded aggregate data:

[0145] Based on the ongoing Phase 2 study, blinded aggregate data indicate that several nAMD patients receiving one of the dose levels of KHK4951 continue without receiving any IVT injections during the maintenance phase, and even beyond the Week 20 mark, i.e., over 8 weeks after the last IVT injection of the induction phase. As the recommended dose of aflibercept IVT injections during maintenance phase is once every 8 weeks (two months) for nAMD patients, these blinded aggregate data support that the tivozanib eye drops used in accordance with the invention could lessen the need for or reduce the number of the invasive aflibercept IVT injections in the maintenance phase, all of which substantiates the effectiveness of the invention. See EYLEA® (aflibercept 2 mg) package insert, Oct. 2024 revision.

[0146] Example 3. Phase 2 study for DME

[0147] A phase 2, multicenter, randomized, double-masked, parallel-group study in DME patients is performed. The study consists of an up to 30-day screening period (SCREENING), an 16-week run-in period (RUN-IN), a 36-week treatment period (TREATMENT) and an up to 4- week safety follow-up period (FOLLOW-UP). During the 16-week run-in period (induction phase), participants will receive aflibercept in the study eye every 4 weeks up to Week 16 (5 injections) to confirm response to aflibercept. Participants who do not meet the response criteria at Week 16 will be withdrawn from the study. During the 36-week treatment period (maintenance phase), eligible participants will receive tivozanib eye drops in the study eye with three different dosages (tivozanib eye drop 0.5 w / v% QD, 2.0 w / v% QD, or 2.0 w / v% BID) from the next day of the fifth IVT injection. FIG. 2 provides a detailed scheme of the study.

[0148] Number of participants:

[0149] Approximately 150 participants will be enrolled to a 16-week run-in period. (Approximately 117 participants (39 patients for each arm) will be administered with the tivozanib eye drops.)

[0150] Study Arms and Duration:

[0151] The study duration will be up to 56 weeks. Study details are shown below. Screening period (SCREENING): Up to 30 days from obtaining informed consent Run-in period (RUN-IN): 16 weeks from the first IVT injection of aflibercept

[0152] Treatment period (TREATMENT): 36 weeks from the first tivozanib formulation administration

[0153] • Tivozanib hydrochloride monohydrate eye drop 0.5 w / v% QD arm

[0154] • Tivozanib hydrochloride monohydrate eye drop 2.0 w / v% QD arm

[0155] • Tivozanib hydrochloride monohydrate eye drop 2.0 w / v% BID arm

[0156] After each instillation of KHK4951 or placebo, participants will apply digital pressure to the nasolacrimal duct and close the eyelid for approximately 1 minute.

[0157] Follow-up period (FOLLOW-UP): Up to 4 weeks from the end of treatment or early termination examination (whichever occurs earlier)

[0158] The visit frequency will be every 4 weeks after Day 1.

[0159] Inclusion criteria:

[0160] 1) Patient must be 18 years of age or older diagnosed with type-1 or 2 diabetes mellitus at the time of signing the informed consent;

[0161] 2) Macular thickening SD-OCT secondary to DME involving the center of the macula: 500 pm > CST > 325 pm with Spectralis (Heidelberg) at screening. CST > 325 pm on Day 1 (where Spectralis is not available, the following devices and CST thresholds are acceptable: CST > 315 pm for Cirrus, CST > 315 pm for Topcon, CST > 295 pm for Optovue);

[0162] 3) BCVA ETDRS letter score of 78 letters to 35 letters (Snellen equivalent of approximately 20 / 32 to 20 / 200) for the study eye at screening and on Day 1 ;

[0163] 4) Patients with glycosylated hemoglobin HbAlc < 11% at screening; and

[0164] 5) If woman, confirmed to be not pregnant.

[0165] Exclusion criteria:

[0166] Patients were excluded from the study for various reasons, including any medical conditions, abnormalities, or any therapies (e.g., medicinal or surgical) that might confound the results of the study relevant to the investigated endpoints.

[0167] Response criterion:

[0168] Participants who meet all of the eligibility criteria above will receive IVT injections in the study eye on Day 1, Week 4, 8, and 12. Participants who respond to the first four IVT injections of aflibercept during the run-in period will receive the fifth IVT injection of aflibercept at Day 113 (Week 16) and proceed to administration of tivozanib formulations during the treatment period. Participants who do not meet the response criterion will be discontinued from the study at Week 16. A response is defined as an increase of >5 letters in BCVA compared to the Day 1 score at the measurement before the fifth IVT injection of aflibercept at Week 16.

[0169] Primary endpoint:

[0170] The primary efficacy endpoint is achieved where a patient, from Week 16 to Week 52, does not experience a reduction of 15 or more letters in BCVA as measured by ETDRS visual acuity chart.

[0171] Secondary endpoints:

[0172] 1) Time to first rescue IVT injection or discontinuation due to lack of efficacy from Week 16 for each treatment arm.

[0173] Time to first rescue IVT injection or discontinuation due to lack of efficacy from Week 16 for each treatment arm will be summarized by Kaplan-Meier method. A Kaplan Meier plot will also be provided for each treatment arm. If the participants are evaluated to require rescue IVT injection for the first time, the date at which first rescue IVT injection was required will be used as the date of the event. Relatedly, if the participants used any treatment / therapy not permitted in the protocol in the study eye during the treatment period to treat DME without the use of protocol-permitted rescue IVT injection, the data at which this treatment / therapy was used will be the date of the event. For participants who did not have rescue IVT injection and stayed until the end of treatment, the date of assessments for the end of treatment visit (Week 52) will be used as the date of censoring.

[0174] 2) The number of rescue IVT injections during the treatment period.

[0175] Descriptive statistics for the number of rescue IVT injections during the treatment period will be summarized for each treatment arm. The number and percentage of participants will also be summarized by the total number of rescue IVT injections during the treatment period.

[0176] 3) Change from Week 16 in BCVA as Measured by ETDRS Visual Acuity Chart at Each Assessment Time Point.

[0177] Descriptive statistics of actual and change from analysis baseline in BCVA will be presented for each time point in both the run-in period and the treatment period for each treatment arm. The mean (± standard deviation (SD)) BCVA over time will be plotted. The mean (+SD) change from analysis baseline in BCVA over time will be plotted.

[0178] 4) A Reduction of > 15 letters / > 10 letters / > 5 letters from Week 16 in BCVA as measured by ETDRS visual Acuity Chart at Each Assessment Time Point after initiating administration of tivozanib formulation The number and percentage of participants having 15, 10, or 5 letters or more reduction in BCVA from analysis baseline at each time point in the treatment period will be presented for each treatment arm.

[0179] 5) Change from Week 16 in CST as measured by SD-OCT at each assessment time point after initiating administration of tivozanib formulation

[0180] Descriptive statistics of actual and change from analysis baseline in CST will be presented for the analysis baseline and each time point in both the run-in period and the treatment period for each treatment arm. The mean (+SD) CST over time will be plotted. The mean (+SD) change from analysis baseline in CST over time will be plotted.

[0181] 6) Change from Week 16 in SHRM and Retinal Morphology (IRF, SRF, and Dry Macula) as Measured by SD-OCT at Each Assessment Time Point After initiating administration of tivozanib formulation

[0182] The number and percentage of participants having SHRM and retinal morphology changes at the analysis baseline and each time point in the treatment period will be presented for each treatment arm. In addition, the morphology at analysis baseline and each time point in the treatment period after the analysis baseline will be summarized in a shift table for each treatment arm.

[0183] 7) Change from Week 16 in Leakage as Measured by Fluorescein Angiography at Each Assessment Time Point after initiating administration of tivozanib formulation

[0184] Descriptive statistics of actual and change from analysis baseline in leakage will be presented for each time point in the treatment period for each treatment arm. The mean (+SD) leakage over time will be plotted. The mean (+SD) change from analysis baseline in leakage over time will be plotted.

[0185] 8) Change from Week 16 in NEI VFQ-25 at Each Assessment Time Point after initiating administration of tivozanib formulation

[0186] Descriptive statistics of actual and change from analysis baseline in NEI VFQ-25 total and subscale scores will be presented for the analysis baseline and each time point in the treatment period for each treatment arm.

[0187] The mean (+SD) NEI VFQ-25 total and subscale scores over time will be plotted. The mean (+SD) change from analysis baseline in NEI VFQ-25 total and subscale scores over time will be plotted.

[0188] Rescue criteria during administration of tivozanib eye drop: If a participant meets the following criterion on examinations at the time of study visits (every 4 weeks) during the treatment period (maintenance phase), aflibercept 2 mg will be intravitreally administered:

[0189] • Decrease of 10 or more letters compared to the Day 1 score (from baseline or from the initiation of induction phase) in BCVA as measured by ETDRS visual acuity chart.

[0190] Assessment at each study visit:

[0191] Assessments at each study visit include BCVA as measured by ETDRS visual acuity chart and CST as measured by SD-OCT.

[0192] Results:

[0193] The study assesses whether patients have maintained in BCVA as measured by ETDRS visual acuity chart at Week 52 (i.e., Week 36 from the initiation of the treatment with tivozanib formulation) compared to Week 16.

[0194] Blinded aggregate data :

[0195] Based on the ongoing Phase 2 study, blinded aggregate data indicate that several DME patients receiving one of the dose levels of KHK4951 continue without receiving any IVT injections during the maintenance phase, and even beyond the Week 28 mark, i.e., over 8 weeks after the last IVT injection of the induction phase. As the recommended dose of aflibercept IVT injections during maintenance phase is once every 8 weeks (two months) for DME patients, these blinded aggregate data support that the tivozanib eye drops used in accordance with the invention could lessen the need for or reduce the number of the invasive aflibercept IVT injections in the maintenance phase, all of which substantiates the effectiveness of the invention. See EYLEA® (aflibercept 2 mg) package insert, Oct. 2024 revision.

[0196] Example 4

[0197] Treatment naive and / or treatment experienced patients with diabetic retinopathy will be administered for at least 52 weeks with the following tivozanib formulations and dosages.

[0198] • Tivozanib hydrochloride monohydrate eye drop 0.5 w / v% QD

[0199] • Tivozanib hydrochloride monohydrate eye drop 2.0 w / v% QD

[0200] • Tivozanib hydrochloride monohydrate eye drop 2.0 w / v% BID

[0201] The study assesses whether the subjects / patients have maintained or improved on Diabetic Retinopathy Severity Scale (DRSS) score at 52 weeks compared to day 1 of treatment (baseline).

[0202] Example 5 Treatment naive and / or treatment experienced patients with retinal vein occlusion will be administered for at least 52 weeks with the following tivozanib formulations and dosages.

[0203] • Tivozanib hydrochloride monohydrate eye drop 0.5 w / v% QD

[0204] • Tivozanib hydrochloride monohydrate eye drop 2.0 w / v% QD • Tivozanib hydrochloride monohydrate eye drop 2.0 w / v% BID

[0205] The study assesses whether the subjects / patients have maintained or improved on BCVA as measured by ETDRS visual acuity chart at 52 weeks compared to day 1 of treatment (baseline).

[0206] Various modifications of the contents of the present disclosure, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims.

Claims

CLAIMSWhat is claimed is:

1. A method of treating a human patient with a posterior segment eye disease comprising: topically administering a maintenance effective dose of a tivozanib formulation 1 to 3 times per day to the eye of the human patient, wherein the eye of the human patient has been treated with an anti-VEGF agent, wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 0.5 w / v % to about 2 w / v %, and wherein the posterior segment eye disease is neovascular age-related macular degeneration, diabetic macular edema, or retinal vein occlusion.

2. The method of claim 1, wherein an eye drop of the tivozanib formulation is topically administered once a day to the eye of the human patient, and wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 0.5 w / v % in the formulation.

3. The method of claim 1, wherein an eye drop of the tivozanib formulation is topically administered once a day to the eye of the human patient, and wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 2.0 w / v % in the formulation.

4. The method of claim 1 , wherein an eye drop of the tivozanib formulation is topically administered twice a day to the eye of the human patient, and wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 2.0 w / v % in the formulation.

5. The method of any of claims 1-4, wherein the posterior segment eye disease is neovascular age-related macular degeneration.

6. The method of any of claims 1-4, wherein the posterior segment eye disease is diabetic macular edema.

7. The method of any of claims 1-4, wherein the posterior segment eye disease is retinal vein occlusion.

8. The method of any of claims 1-7, wherein the anti-VEGF agent is aflibercept, ranibizumab, or bevacizumab.

9. The method of claim 8, wherein the anti-VEGF agent is aflibercept.

10. A method of treating a human patient with a neovascular age-related macular degeneration comprising: topically administering a maintenance effective dose of a tivozanib formulation 1 to 3 times per day to the eye of the human patient, wherein the eye of the human patient has been treated with an anti-VEGF agent, and wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 0.5 w / v % to about 2 w / v %.

11. The method of claim 10, wherein an eye drop of the tivozanib formulation is topically administered once a day to the eye of the human patient, and wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 0.5 w / v % in the formulation.

12. The method of claim 10, wherein an eye drop of the tivozanib formulation is administered once a day to the eye of the human patient, and wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 2.0 w / v % in the formulation.

13. The method of claim 10, wherein an eye drop of the tivozanib formulation is administered twice a day to the eye of the human patient, and wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 2.0 w / v % in the formulation.

14. The method of any of claims 10-13, wherein the anti-VEGF agent is aflibercept, ranibizumab, or bevacizumab.

15. The method of claim 14,wherein the anti-VEGF agent is aflibercept.

16. The method of any of claims 10-15, wherein administering the tivozanib formulation maintains Best Corrected Visual Acuity (BCVA) as measured by ETDRS visual acuity chart at 44 weeks or 52 weeks from the initiation of administration of the tivozanib formulation compared to the measured BCVA before administration of the tivozanib formulation.

17. The method of claim 16, wherein administering the tivozanib formulation maintains BCVA as measured by ETDRS visual acuity chart at 44 weeks or 52 weeks from the initiation of administration of the tivozanib formulation compared to the day before administration of the tivozanib formulation.

18. The method of any of claims 10-15, wherein administering the tivozanib formulation prevents a reduction of 5 or more letters in BCVA as measured by ETDRS visual acuity chart at 44 weeks or 52 weeks from the initiation of administration of the tivozanib formulation compared to the measured BCVA before administration of the tivozanib formulation.

19. The method of claim 18, wherein administering the tivozanib formulation prevents a reduction of 5 or more letters in BCVA as measured by ETDRS visual acuity chart at 44 weeks or 52 weeks from the initiation of administration of the tivozanib formulation compared to the day before administration of the tivozanib formulation.

20. The method of any of claims 10-15, wherein administering the tivozanib formulation prevents a reduction of 10 or more letters in BCVA as measured by ETDRS visual acuity chart at 44 weeks or 52 weeks from the initiation of administration of the tivozanib formulation compared to the measured BCVA before administration of the tivozanib formulation.

21. The method of claim 20, wherein administering the tivozanib formulation prevents a reduction of 10 or more letters in BCVA as measured by ETDRS visual acuity chart at 44 weeks or 52 weeks from the initiation of administration of the tivozanib formulation compared to the day before administration of the tivozanib formulation.

22. The method of any of claims 10-15, wherein administering the tivozanib formulation prevents a reduction of 15 or more letters in BCVA as measured by ETDRS visual acuity chart at 44 weeks or 52 weeks from the initiation of administration of the tivozanib formulation compared to the measured BCVA before administration of the tivozanib formulation.

23. The method of any of claims 22, wherein administering the tivozanib formulation prevents a reduction of 15 or more letters in BCVA as measured by ETDRS visual acuity chart at 44 weeks or 52 weeks from the initiation of administration of the tivozanib formulation compared to the day before administration of the tivozanib formulation.

24. A method of treating a human patient with a diabetic macular edema comprising: topically administering a maintenance effective dose of a tivozanib formulation 1 to 3 times per day to the eye of the human patient, wherein the eye of the human patient has been treated with an anti-VEGF agent, and wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 0.5 w / v % to about 2 w / v %.

25. The method of claim 24, wherein an eye drop of the tivozanib formulation is topically administered once a day to the eye of the human patient, and wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 0.5 w / v % in the formulation.

26. The method of claim 24, wherein an eye drop of the tivozanib formulation is administered once a day to the eye of the human patient, and wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 2.0 w / v % in the formulation.

27. The method of claim 24, wherein an eye drop of the tivozanib formulation is administered twice a day to the eye of the human patient, and wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 2.0 w / v % in the formulation.

28. The method of any of claims 24-27, wherein the anti-VEGF agent is aflibercept, ranibizumab, or bevacizumab.

29. The method of claim 28, wherein the anti-VEGF agent is aflibercept.

30. The method of any of claims 24-29,wherein administering the tivozanib formulation maintains Best Corrected Visual Acuity (BCVA) as measured by ETDRS visual acuity chart at 36 weeks or 52 weeks from the initiation of administration of the tivozanib formulation compared to the measured BCVA before administration of the tivozanib formulation.

31. The method of claim 30, wherein administering the tivozanib formulation maintains BCVA as measured by ETDRS visual acuity chart at 36 weeks or 52 weeks from the initiation of administration of the tivozanib formulation compared to the day before administration of the tivozanib formulation.

32. The method of any of claims 24-29, wherein administering the tivozanib formulation prevents a reduction of 5 or more letters in BCVA as measured by ETDRS visual acuity chart at 36 weeks or 52 weeks from the initiation of administration of the tivozanib formulation compared to the measured BCVA before administration of the tivozanib formulation.

33. The method of claim 32, wherein administering the tivozanib formulation prevents a reduction of 5 or more letters in BCVA as measured by ETDRS visual acuity chart at 36 weeks or 52 weeks from the initiation of administration of the tivozanib formulation compared to the day before administration of the tivozanib formulation.

34. The method of any of claims 24-29, wherein administering the tivozanib formulation prevents a reduction of 10 or more letters in BCVA as measured by ETDRS visual acuity chart at 36 weeks or 52 weeks from the initiation of administration of the tivozanib formulation compared to the measured BCVA before administration of the tivozanib formulation.

35. The method of claim 34, wherein administering the tivozanib formulation prevents a reduction of 10 or more letters in BCVA as measured by ETDRS visual acuity chart at 36 weeks or 52 weeks from the initiation of administration of the tivozanib formulation compared to the day before administration of the tivozanib formulation.

36. The method of any of claims 24-29, wherein administering the tivozanib formulation prevents a reduction of 15 or more letters in BCVA as measured by ETDRS visual acuity chart at 36 weeks or 52 weeks from the initiation of administration of the tivozanib formulation compared to the measured BCVA before administration of the tivozanib formulation.

37. The method of any of claims 36,wherein administering the tivozanib formulation prevents a reduction of 15 or more letters in BCVA as measured by ETDRS visual acuity chart at 36 weeks or 52 weeks from the initiation of administration of the tivozanib formulation compared to the day before administration of the tivozanib formulation.

38. A method of treating a human patient with a posterior segment eye disease comprising: administering an anti-VEGF agent as an induction phase dose to the human patient in need of said treatment; following the administration of the anti-VEGF agent in the induction phase, topically administering a maintenance effective dose of a tivozanib formulation 1 to 3 times per day to the eye of the human patient as a maintenance phase dose; wherein the posterior segment eye disease is neovascular age-related macular degeneration, diabetic macular edema, or retinal vein occlusion; wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 0.5 w / v % to about 2 w / v %, and wherein the administration of the maintenance phase dose starts after the last administration of the anti-VEGF agent in the induction phase.

39. The method of claim 38, wherein an eye drop of the tivozanib formulation is administered once a day to the eye of the human patient, and wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 0.5 w / v % in the formulation.

40. The method of claim 38, wherein an eye drop of the tivozanib formulation is administered once a day to the eye of the human patient, and wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 2.0 w / v % in the formulation.

41. The method of claim 38, wherein an eye drop of the tivozanib formulation is administered twice a day to the eye of the human patient, andwherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 2.0 w / v % in the formulation.

42. The method of any of claims 38-41, wherein the anti-VEGF agent used in the induction phase is aflibercept, ranibizumab, or bevacizumab.

43. The method of claim 42, wherein the anti-VEGF agent used in the induction phase is aflibercept.

44. The method of any of claims 38-43, wherein the administration of the maintenance phase dose starts a day after the last administration of the anti-VEGF agent in the induction phase.

45. The method of any of claims 38-44, wherein the posterior segment eye disease is neovascular age-related macular degeneration.

46. The method of any of claims 38-44, wherein the posterior segment eye disease is diabetic macular edema.

47. The method of any of claims 38-44, wherein the posterior segment eye disease is retinal vein occlusion.

48. The method of claim 45, wherein the maintenance phase dose maintains Best Corrected Visual Acuity (BCVA) as measured by ETDRS visual acuity chart at 44 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of the induction phase.

49. The method of claim 45, wherein the maintenance phase dose prevents a reduction of 5 or more letters in BCVA as measured by ETDRS visual acuity chart at 44 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of the induction phase.

50. The method of claim 45, wherein the maintenance phase dose prevents a reduction of 10 or more letters in BCVA as measured by ETDRS visual acuity chart at 44 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of the induction phase.

51. The method of claim 45, wherein the maintenance phase dose prevents a reduction of 15 or more letters in BCVA as measured by ETDRS visual acuity chart at 44 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of the induction phase.

52. The method of claim 46,wherein the maintenance phase dose maintains Best Corrected Visual Acuity (BCVA) as measured by ETDRS visual acuity chart at 36 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of the induction phase.

53. The method of claim 46, wherein the maintenance phase dose prevents a reduction of 5 or more letters in BCVA as measured by ETDRS visual acuity chart at 36 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of the induction phase.

54. The method of claim 46, wherein the maintenance phase dose prevents a reduction of 10 or more letters in BCVA as measured by ETDRS visual acuity chart at 36 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of the induction phase.

55. The method of claim 46, wherein the maintenance phase dose prevents a reduction of 15 or more letters in BCVA as measured by ETDRS visual acuity chart at 36 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of the induction phase.

56. The method of claim 47, wherein the maintenance phase dose maintains Best Corrected Visual Acuity (BCVA) as measured by ETDRS visual acuity chart at 52 weeks from the initiation of the maintenance phase dose compared to the last day of the induction phase.

57. The method of claim 47, wherein the maintenance phase dose prevents a reduction of 5 or more letters in BCVA as measured by ETDRS visual acuity chart at 52 weeks from the initiation of the maintenance phase dose compared to the last day of the induction phase.

58. The method of claim 47, wherein the maintenance phase dose prevents a reduction of 10 or more letters in BCVA as measured by ETDRS visual acuity chart at 52 weeks from the initiation of the maintenance phase dose compared to the last day of the induction phase.

59. The method of claim 47, wherein the maintenance phase dose prevents a reduction of 15 or more letters in BCVA as measured by ETDRS visual acuity chart at 52 weeks from the initiation of the maintenance phase dose compared to the last day of the induction phase.

60. The method of any of claims 38-59, further comprising administering the anti-VEGF agent during the maintenance phase when the BCVA as measured by ETDRS visual acuity chart is reduced by 10 or more letters compared to baseline.

61. A method of treating a human patient with neovascular age-related macular degeneration comprising: administering an anti-VEGF agent as an induction phase dose to the human patient in need of said treatment; following the administration of the anti-VEGF agent in the induction phase, topically administering a maintenance effective dose of a tivozanib formulation 1 to 3 times per day to the eye of the human patient as a maintenance phase dose; wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 0.5 w / v % to about 2 w / v %, and wherein the administration of the maintenance phase dose starts after the last administration of the anti-VEGF agent in the induction phase.

62. The method of claim 61, wherein an eye drop of the tivozanib formulation is administered once a day to the eye of the human patient, and wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 0.5 w / v % in the formulation.

63. The method of claim 61, wherein an eye drop of the tivozanib formulation is administered once a day to the eye of the human patient, and wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 2.0 w / v % in the formulation.

64. The method of claim 61, wherein an eye drop of the tivozanib formulation is administered twice a day to the eye of the human patient, and wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 2.0 w / v % in the formulation.

65. The method of any of claims 61-64, wherein the administration of the maintenance phase dose starts a day after the last administration of the anti-VEGF agent in the induction phase.

66. The method of any of claims 61-65,wherein the anti-VEGF agent used in the induction phase is aflibercept, ranibizumab, or bevacizumab.

67. The method of claim 66, wherein the anti-VEGF agent used in the induction phase is aflibercept.

68. The method of claim 67 wherein in the induction phase dose, aflibercept is intravitreally administered at day 1 , week 4, and week 8.

69. The method of claim 61-65, wherein in the induction phase dose, the anti-VEGF agent is administered at least three times.

70. The method of any of claims 61-69, wherein the maintenance phase is continued for at least 44 weeks.

71. The method of claim 70, wherein the maintenance phase is continued for 44 weeks or 52 weeks.

72. The method of any of claims 61-71, wherein at baseline, the human patient has active subfoveal macular neovascularization or juxtafoveal / extrafoveal macular neovascularization secondary to age-related macular degeneration with a subfoveal component related to the macular neovascularization activity.

73. The method of any of claims 61-72, wherein the human patient has BCVA ETDRS letter score of 78 letters to 35 letters as measured by the ETDRS visual acuity chart at baseline.

74. The method of any of claims 61-73, wherein the central subfoveal thickness (CST) of the human patient’s eye at baseline is < 450 pm.

75. The method of any of claims 61-71, wherein the eye of the human patient at baseline has:(a) active subfoveal macular neovascularization or juxtafoveal / extrafoveal macular neovascularization secondary to age-related macular degeneration with a subfoveal component related to the macular neovascularization activity;(b) BCVA ETDRS letter score of 78 letters to 35 letters as measured by the ETDRS visual acuity chart; and(c) CST is < 450 pm.

76. The method of any of claims 61-75,wherein the maintenance phase dose maintains BCVA as measured by ETDRS visual acuity chart at 44 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of the induction phase.

77. The method of any of claims 61-75, wherein the maintenance phase dose prevents a reduction of 5 or more letters in BCVA as measured by ETDRS visual acuity chart at 44 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of the induction phase.

78. The method of any of claims 61-75, wherein the maintenance phase dose prevents a reduction of 10 or more letters in BCVA as measured by ETDRS visual acuity chart at 44 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of the induction phase.

79. The method of any of claims 61-75, wherein the maintenance phase dose prevents a reduction of 15 or more letters in BCVA as measured by ETDRS visual acuity chart at 44 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of the induction phase.

80. The method of any of claims 61-79, further comprising administering the anti-VEGF agent during the maintenance phase when the BCVA as measured by ETDRS visual acuity chart is reduced by 10 or more letters compared to baseline.

81. A method of treating a human patient with diabetic macular edema comprising: administering an anti-VEGF agent as an induction phase dose to the human patient in need of said treatment; following the administration of the anti-VEGF agent in the induction phase, topically administering a maintenance effective dose of tivozanib formulation 1 to 3 times per day to the eye of the human patient as a maintenance phase dose; wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 0.5 w / v % to about 2 w / v %, and wherein the administration of the maintenance phase dose starts after the last administration of the anti-VEGF agent in the induction phase .

82. The method of claim 81, wherein an eye drop of the tivozanib formulation is administered once a day to the eye of the human patient, andwherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 0.5 w / v % in the formulation.

83. The method of claim 81, wherein an eye drop of the tivozanib formulation is administered once a day to the eye of the human patient, and wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 2.0 w / v % in the formulation.

84. The method of claim 81 , wherein an eye drop of the tivozanib formulation is administered twice a day to the eye of the human patient, and wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 2.0 w / v % in the formulation.

85. The method of any of claims 81-84, wherein the administration of the maintenance phase dose starts a day after the last administration of the anti-VEGF agent in the induction phase.

86. The method of any of claims 81-85, wherein the anti-VEGF agent used in the induction phase is aflibercept, ranibizumab, or bevacizumab.

87. The method of claim 86, wherein the anti-VEGF agent used in the induction phase is aflibercept.

88. The method of claims 87, wherein in the induction phase dose, aflibercept is administered at day 1, week 4, week 8, week 12, and week 16.

89. The method of any of claims 81-86, wherein in the induction phase dose, the anti-VEGF agent is administered at least three times.

90. The method of any of claims 81-89, wherein the maintenance phase is continued for at least 36 weeks.

91. The method of claim 90, wherein the maintenance phase is continued for 36 weeks or 52 weeks.

92. The method of any of claims 81-91,wherein the human patient has BCVA ETDRS letter score of 78 letters to 35 letters as measured by the ETDRS visual acuity chart at baseline.

93. The method of any of claims 81-92, wherein the CST of the eye of the human patient at baseline is > 325 pm and < 500 pm.

94. The method of any of claims 81-93, wherein Hemoglobin Ale level of the human patient is < 11% at baseline.

95. The method of any of claims 81-91, wherein the human patient at baseline has:(a) BCVA ETDRS letter score of 78 letters to 35 letters as measured by the ETDRS visual acuity chart;(b) CST of the eye of the human patient is > 325 pm and < 500 pm; and(c) Hemoglobin Ale level is < 11%.

96. The method of any of claims 81-95 wherein the maintenance phase dose maintains Best Corrected Visual Acuity (BCVA) as measured by ETDRS visual acuity chart at 36 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of the induction phase.

97. The method of any of claims 81-95, wherein the maintenance phase dose prevents a reduction of 5 or more letters in BCVA as measured by ETDRS visual acuity chart at 36 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of the induction phase.

98. The method of any of claims 81-95, wherein the maintenance phase dose prevents a reduction of 10 or more letters in BCVA as measured by ETDRS visual acuity chart at 36 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of the induction phase.

99. The method of any of claims 81-95, wherein the maintenance phase dose prevents a reduction of 15 or more letters in BCVA as measured by ETDRS visual acuity chart at 36 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of the induction phase.

100. The method of any of claims 81-99, further comprising administering the anti-VEGF agent during the maintenance phase when the BCVA as measured by ETDRS visual acuity chart is reduced by 10 or more letters compared to baseline.

101. A method of treating a human patient with neovascular age-related macular degeneration comprising:administering intravitreally to the human patient in need of said treatment an anti-VEGF agent as an induction phase dose; following the administration of the anti-VEGF agent in the induction phase, topically administering a maintenance effective dose of a tivozanib formulation 1 to 3 times per day to the eye of the human patient as a maintenance phase dose; wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 0.5 w / v % to about 2 w / v % in the formulation; wherein the anti-VEGF agent is aflibercept; wherein in the induction phase dose, the anti-VEGF agent is intravitreally administered at day 1, week 4, and week 8; wherein the administration of the maintenance phase dose starts a day after the last intra vitreal administration of the anti-VEGF agent at week 8 in the induction phase dose and is continued for at least 44 weeks; wherein the maintenance phase dose maintains BCVA as measured by ETDRS visual acuity chart at 44 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of the induction phase.

102. The method of claim 101, wherein an eye drop of the tivozanib formulation is administered once a day to the eye of the human patient, and wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 0.5 w / v % in the formulation.

103. The method of claim 101, wherein an eye drop of the tivozanib formulation is administered once a day to the eye of the human patient, and wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 2.0 w / v % in the formulation.

104. The method of claim 101, wherein an eye drop of the tivozanib formulation is administered twice a day to the eye of the human patient, and wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 2.0 w / v % in the formulation.

105. The method of any of claims 101-104, wherein the maintenance phase is continued for 44 weeks or 52 weeks.

106. The method of any of claims 101-105, wherein the human patient has BCVA ETDRS letter score of 78 letters to 35 letters as measured by the ETDRS visual acuity chart at baseline.

107. The method of any of claims 101-106, wherein the central subfoveal thickness (CST) of the human patient’s eye at baseline is < 450 pm.

108. The method of any of claims 101-105, wherein the eye of the human patient at baseline has:(a) active subfoveal macular neovascularization or juxtafoveal / extrafoveal macular neovascularization secondary to age-related macular degeneration with a subfoveal component related to the macular neovascularization activity;(b) BCVA ETDRS letter score of 78 letters to 35 letters as measured by the ETDRS visual acuity chart; and(c) CST is < 450 pm.

109. The method of any of claims 101-108, wherein the maintenance phase dose prevents a reduction of 5 or more letters in BCVA as measured by ETDRS visual acuity chart at 44 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of the induction phase.

110. The method of any of claims 101-108, wherein the maintenance phase dose prevents a reduction of 10 or more letters in BCVA as measured by ETDRS visual acuity chart at 44 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of the induction phase.

111. The method of any of claims 101-108, wherein the maintenance phase dose prevents a reduction of 15 or more letters in BCVA as measured by ETDRS visual acuity chart at 44 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of the induction phase.

112. The method of any of claims 101-111, further comprising intravitreally administering the anti-VEGF agent during the maintenance phase when the BCVA as measured by ETDRS visual acuity chart is reduced by 10 or more letters compared to baseline.

113. A method of treating a human patient with diabetic macular edema comprising: administering intravitreally to the human patient in need of said treatment an anti-VEGF agent as an induction phase dose;following the administration of the anti-VEGF agent in the induction phase, topically administering a maintenance effective dose of a tivozanib formulation 1 to 3 times per day to the eye of the human patient as a maintenance phase dose; wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 0.5 w / v % to about 2 w / v % in the formulation; wherein the anti-VEGF agent is aflibercept; wherein in the induction phase dose, the anti-VEGF agent is intravitreally administered at day 1, week 4, week 8, week 12, and week 16; wherein the administration of the maintenance phase dose starts a day after the last intra vitreal administration of the anti-VEGF agent at week 16 in the induction phase dose and is continued for at least 36 weeks; wherein the maintenance phase dose maintains BCVA as measured by ETDRS visual acuity chart at 36 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of the induction phase.

114. The method of claim 113, wherein an eye drop of the tivozanib formulation is administered once a day to the eye of the human patient, and wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 0.5 w / v % in the formulation.

115. The method of claim 113, wherein an eye drop of the tivozanib formulation is administered once a day to the eye of the human patient, and wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 2.0 w / v % in the formulation.

116. The method of claim 113, wherein an eye drop of the tivozanib formulation is administered twice a day to the eye of the human patient, and wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 2.0 w / v % in the formulation.

117. The method of any of claims 113-116, wherein the maintenance phase is continued for 36 weeks or 52 weeks.

118. The method of any of claims 113-117, wherein the human patient has BCVA ETDRS letter score of 78 letters to 35 letters as measured by the ETDRS visual acuity chart at baseline.

119. The method of any of claims 113-118, wherein the central subfoveal thickness (CST) of the human patient’s eye at baseline is > 325 pm and < 500 pm.

120. The method of any of claims 113-119, wherein the Hemoglobin Ale level is < 11%.

121. The method of any of claims 113-117, wherein the eye of the human patient at baseline has:(a) BCVA ETDRS letter score of 78 letters to 35 letters as measured by the ETDRS visual acuity chart;(b) CST of the eye of the human patient is > 325 pm and < 500 pm; and(c) Hemoglobin Ale level is < 11%.

122. The method of any of claims 113-121, wherein the maintenance phase dose prevents a reduction of 5 or more letters in BCVA as measured by ETDRS visual acuity chart at 36 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of the induction phase.

123. The method of any of claims 113-121, wherein the maintenance phase dose prevents a reduction of 10 or more letters in BCVA as measured by ETDRS visual acuity chart at 36 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of the induction phase.

124. The method of any of claims 113-121, wherein the maintenance phase dose prevents a reduction of 15 or more letters in BCVA as measured by ETDRS visual acuity chart at 36 weeks or 52 weeks from the initiation of the maintenance phase dose compared to the last day of the induction phase.

125. The method of any of claims 113-124, further comprising intravitreally administering the anti-VEGF agent during the maintenance phase when the BCVA as measured by ETDRS visual acuity chart is reduced by 10 or more letters compared to baseline.

126. A method of treating a human patient with a posterior segment eye disease comprising: topically administering a therapeutically effective dose of a tivozanib formulation 1 to 3 times per day to the eye of the human patient in need of said treatment, andwherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 0.5 w / v % to about 2 w / v %.

127. The method of claim 126, wherein an eye drop of the tivozanib formulation is administered once a day to the eye of the human patient, and wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 0.5 w / v % in the formulation.

128. The method of claim 126, wherein an eye drop of the tivozanib formulation is administered once a day to the eye of the human patient, and wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 2.0 w / v % in the formulation.

129. The method of claim 126, wherein an eye drop of the tivozanib formulation is administered twice a day to the eye of the human patient, and wherein the tivozanib formulation comprises tivozanib, a pharmaceutically acceptable salt thereof, or a hydrate or a solvate of tivozanib or its salt in the amount of about 2.0 w / v % in the formulation.

130. The method of any of claims 126-129, wherein the eye of the human patient has been treated with an anti-VEGF agent.

131. The method of claim 130, wherein the anti-VEGF agent is aflibercept, ranibizumab, or bevacizumab.

132. The method of claim 131, wherein the anti-VEGF agent is aflibercept.

133. The method of any of claims 126-132, wherein the posterior segment eye disease is neovascular age-related macular degeneration, diabetic macular edema, diabetic retinopathy, or retinal vein occlusion.

134. The method of any of claims 133, wherein the posterior segment eye disease is neovascular age-related macular degeneration.

135. The method of any of claims 133, wherein the posterior segment eye disease is diabetic macular edema.

136. The method of any of claims 133, wherein the posterior segment eye disease is retinal vein occlusion.

137. The method of any of claims 133, wherein the posterior segment eye disease is diabetic retinopathy.

138. The method of any of claims 134-136, wherein administering the tivozanib formulation maintains Best Corrected Visual Acuity (BCVA) as measured by ETDRS visual acuity chart at 36 weeks from administering the tivozanib formulation compared to baseline.

139. The method of any of claims 134-136, wherein administering the tivozanib formulation maintains Best Corrected Visual Acuity (BCVA) as measured by ETDRS visual acuity chart at 44 weeks from administering the tivozanib formulation compared to baseline.

140. The method of any of claims 134-136, wherein administering the tivozanib formulation maintains Best Corrected Visual Acuity (BCVA) as measured by ETDRS visual acuity chart at 52 weeks from administering the tivozanib formulation compared to baseline.

141. The method of claim 137, wherein administering the tivozanib formulation maintains Diabetic Retinopathy Severity Scale (DRSS) score at 24 weeks from administering the tivozanib formulation compared to baseline.

142. The method of claim 137, wherein administering the tivozanib formulation improves DRSS score at 24 weeks from administering the tivozanib formulation compared to baseline.

143. The method of claim 137, wherein administering the tivozanib formulation maintains DRSS score at 52 weeks from administering the tivozanib formulation compared to baseline.

144. The method of claim 137, wherein administering the tivozanib formulation improves DRSS score at 52 weeks from administering the tivozanib formulation compared to baseline.

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