Compositions comprising axitinib and methods for treating ocular diseases

Abstract

The present disclosure relates generally to ophthalmic therapies, and more particularly to methods and devices that allow for the infusion of fluid drug formulations into posterior ocular tissue for targeted localized therapy, e.g., for the treatment of wet AMD in human patients. The drug formulation can be injected into the suprachoroidal space (SCS) or subretinal space of the eye. The drug formulation can include a tyrosine kinase inhibitor, such as axitinib.

Description

[0001] This application is a divisional application of the Chinese patent application with application number 202180028112.6 (application date: February 19, 2021, invention name: Compositions containing axitinib and methods for treating eye diseases).

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Application No. 62 / 978,540, filed on February 19, 2020; the entirety of which is incorporated herein by reference. Background Art

[0004] Neovascular age-related macular degeneration (nAMD, also called "wet" AMD) is the leading cause of vision loss in the industrialized world. It is caused by abnormal blood vessel growth in the choriocapillaris, a layer of capillaries just below Bruch's membrane. Choroidal neovascularization results in the infiltration of blood, lipids, and serum into the retinal layers, which can lead to permanent damage to light-sensitive retinal cells and irreversible distortion of central vision.

[0005] Although not fully elucidated, much is known about the pathogenesis of nAMD. The vascular endothelial growth factor (VEGF) signaling pathway has been implicated in 10% to 15% of AMD diagnoses, which are classified as neovascular (nAMD). In this pathway, VEGF signaling ligands bind to different VEGF receptor (VEGFR) isoforms to activate cellular processes that promote the growth of new vasculature. Specifically, VEGF-A, which acts on VEGFR-1 and VEGFR-2, has been shown to promote abnormal blood vessel growth and is therefore an optimal target for treatment. Currently, anti-VEGF-A drugs are the standard of care for nAMD; however, there remains an unmet need to significantly improve and maintain patient vision.

[0006] Choroidal neovascularization (CNV) is the formation of new blood vessels in the choroid layer of the eye. Choroidal neovascularization is a common cause of and / or may be associated with nAMD. CNV can develop rapidly in individuals with defects in Bruch's membrane, the innermost layer of the choroid. It has also been associated with excess VEGF. CNV also often occurs in the rare genetic disease pseudoxanthoma elasticum and rarely in the more common optic disc drusen. CNV has also been associated with extreme myopia or malignant myopic degeneration, in which choroidal neovascularization occurs primarily in the presence of cracks (called lacquer cracks) in the retinal macular tissue. CNV causes a sudden deterioration in central vision that is noticeable within a few weeks. Other symptoms that may occur include color disturbances and metamorphosis (distortion of straight lines to appear wavy). Bleeding from the new vessels can accelerate the onset of CNV symptoms.

[0007] Currently, even the most successful treatments for nAMD and CNV do not exclude recurrence, so multiple treatments are possible. In addition, currently available treatments do not restore vision that has already been lost. Therefore, a therapeutic breakthrough is needed in the field to preserve vision longer without repeated use of lasers. Summary of the invention

[0008] Provided are methods and compositions for treating neovascular age-related macular degeneration (nAMD; also referred to herein as wet AMD), choroidal neovascularization (CNV), nAMD associated with CNV, diabetic retinopathy, diabetic macular edema (DME), and related diseases. The composition comprises one or more tyrosine kinase inhibitors and is delivered to the suprachoroidal space of the eye by a non-surgical method. In some embodiments, the tyrosine kinase inhibitor has activity against vascular endothelial growth factor (VEGF) and / or platelet-derived growth factor (PDGF). In some embodiments, the tyrosine kinase inhibitor is axitinib. In some embodiments, the disclosure provides an axitinib formulation, CLS-AX.

[0009] In some embodiments, the present disclosure provides a method for treating nAMD, choroidal neovascularization (CNV), nAMD associated with CNV and / or DME, the method comprising administering a formulation comprising axitinib to the choroidal space of the eye of a subject in need thereof. In some embodiments, the method comprises administering about 0.01 mg to about 3.0 mg of axitinib to the eye. In some embodiments, the method comprises administering about 0.01 mg to about 0.5 mg of axitinib to the eye. In some embodiments, the method comprises administering about 0.01 mg to about 0.3 mg of axitinib to the eye. In other embodiments, the method comprises administering about 0.03 to about 0.1 mg of axitinib to the eye. In some embodiments, the method comprises administering about 0.01, about 0.02, about 0.03, about 0.04, about 0.05, about 0.06, about 0.07, about 0.08, about 0.09, about 0.10, about 0.2, about 0.3, about 0.4, about 0.5, about 1.0, about 2.0, or about 3.0 mg of axitinib to the eye. In some embodiments, the method comprises administering about 0.03 mg of axitinib to the eye. In some embodiments, the method comprises administering about 0.06 mg of axitinib to the eye. In some embodiments, the method comprises administering about 0.1 mg of axitinib to the eye. In some embodiments, the method comprises administering about 0.3 mg of axitinib to the eye. In some embodiments, axitinib is administered in a volume of about 100 μL. Thus, in some embodiments, the method comprises administering an axitinib formulation at a concentration of about 0.1 mg / mL to about 1 mg / mL, or about 0.1 mg / mL, about 0.3 mg / mL, about 0.6 mg / mL, or about 1.0 mg / mL. In some embodiments, the method comprises administering axitinib to the eye in a non-surgical manner. For example, in embodiments, the method comprises administering axitinib to the eye by non-surgical suprachoroidal injection. In embodiments, non-surgical suprachoroidal injection is achieved by administering axitinib using an injection device comprising a needle, wherein the needle has an effective length of about 500 to about 2000 microns.

[0010] In some embodiments, the method comprises administering axitinib to the eye in at least one dose. In some embodiments, the method comprises administering axitinib to the eye in two doses, wherein the two doses are separated by at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or at least about 12 months.

[0011] In some embodiments, after axitinib is applied to the subject's eyes, the subject does not experience vision loss, as measured by best corrected visual acuity (BCVA). In some embodiments, after axitinib is applied to the subject's eyes, the subject experiences minimal vision loss, as measured by best corrected visual acuity (BCVA). In embodiments, minimal vision loss is a loss of no more than 2 letters. In other embodiments, the subject experiences an improvement in BCVA of ≥10 letters, ≥15 letters, or ≥25 letters compared to the subject's vision before the administration of the axitinib formulation. In embodiments, the subject does not experience vision loss for 2 months, 3 months, 4 months, 5 months, 6 months, or longer after the administration of the axitinib formulation, as measured by BCVA. In embodiments, the subject experiences minimal vision loss for 2 months, 3 months, 4 months, 5 months, 6 months, or longer after the administration of the axitinib formulation, as measured by BCVA. In embodiments, the subject experiences improvement in vision as measured by BCVA 2 months, 3 months, 4 months, 5 months, 6 months or longer following administration of the axitinib formulation.

[0012] In some embodiments, after axitinib is applied to the subject's eye, the subject experiences a decrease in retinal thickness relative to baseline (e.g., retinal thickness before treatment such as central subfield thickness (CST)) at any given time point after administering a drug provided herein, for example, a decrease of at least about 20 μm, or at least about 40 μm, or at least about 50 μm, or at least about 100 μm, or at least about 150 μm, or at least about 200 μm, or about 50-100 μm, and all values ​​therebetween. In another embodiment, the patient experiences a decrease in retinal thickness (e.g., CST) of ≥5%, ≥10%, ≥15%, ≥20%, ≥25% after administering axitinib. In one embodiment, the change in retinal thickness relative to baseline is measured, for example, by spectral domain optical coherence tomography (SD-OCT) as a change in CST. In embodiments, the subject experiences a decrease in retinal thickness at 2 months, 3 months, 4 months, 5 months, 6 months, or longer after administering an axitinib formulation. In embodiments, the subject does not experience an increase in retinal thickness for 2 months, 3 months, 4 months, 5 months, 6 months or longer following administration of the axitinib formulation.

[0013] In some embodiments, axitinib is form IX axitinib. In some embodiments, axitinib is present in the formulation in an amount of about 0.5 mg / mL to about 100 mg / mL, for example, about 1 mg / mL to about 10 mg / mL or about 20 mg / mL to about 80 mg / mL. In embodiments, axitinib is present in the formulation in an amount of about 1 mg / mL or about 40 mg / mL. In some embodiments, the present disclosure provides a formulation comprising axitinib and polysorbate 80. In other embodiments, the present disclosure provides a formulation comprising sodium carboxymethylcellulose, polysorbate 80, sodium chloride, and sodium phosphate. In other embodiments, the formulation comprises polysorbate 80 of about 0.025% to about 0.2% w / v. In some embodiments, polysorbate 80 is present in the formulation in an amount of about 0.05% to about 0.1%. In some embodiments, polysorbate 80 is present in the formulation in an amount of about 0.05% or about 0.1%. In some embodiments, the formulation comprises about 0.04% w / v to about 0.07% w / v sodium phosphate (monobasic sodium phosphate monohydrate). In other embodiments, the formulation comprises about 0.059% w / v sodium phosphate (monobasic sodium phosphate monohydrate). In some embodiments, the formulation comprises about 0.05% w / v to about 0.09% w / v sodium phosphate (anhydrous disodium hydrogen phosphate). In some embodiments, the formulation comprises about 0.079% w / v sodium phosphate (anhydrous disodium hydrogen phosphate). In some embodiments, the formulation comprises about 0.5% w / v to about 1.0% w / v sodium chloride. In other embodiments, the formulation comprises about 0.7% w / v to about 0.9% w / v sodium chloride. In some embodiments, the formulation comprises about 0.79% w / v sodium chloride. In some embodiments, the formulation comprises about 0.25% w / v to about 0.75% w / v sodium carboxymethylcellulose. In other embodiments, the formulation comprises about 0.3% w / v to about 0.7% w / v sodium carboxymethylcellulose. In some embodiments, the formulation comprises about 0.5% w / v sodium carboxymethylcellulose. In some embodiments, the axitinib formulation comprises microparticles comprising axitinib. In some embodiments, for D 90 Distribution, the size of the particles is about 1-20 microns. In some embodiments, for D 50 Distribution, the size of the particles is about 1-10 microns. In some embodiments, for D 10 distribution, the size of the particles is about 1-4 microns. In some embodiments, for D 90 distribution, the size of the microparticles is about 3-5 microns. In some embodiments, for D 90 distribution, the size of the particles is about 3 microns. In some embodiments, for D 90 distribution, the size of the microparticles is about 10 microns. In some embodiments, the clinical formulation of CLS-AX comprises90 Axitinib particles having a size of about 10 microns are distributed. In some embodiments, the clinical formulation of CLS-AX comprises for D 10 Axitinib particles having a size of about 2 microns are distributed. In some embodiments, the clinical formulation of CLS-AX comprises for D 50 Axitinib particles having a size of about 5 microns are distributed. In some embodiments, the clinical formulation of CLS-AX comprises for D 90 Axitinib particles were distributed as approximately 10 microns. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1A and Figure 1B Shown are the mean (±SD) CLS-AX concentrations in the indicated tissues following suprachoroidal injection of CLS-AX into the eyes of male Dutch-band rabbits. Figure 1A Shown are drug residues (mg) in the sclera / choroid / RPE (upper panel) and drug concentrations (nM) in the retina and vitreous (lower panel) at indicated time points up to day 91. Figure 1B Concentrations of axitinib (ng / g or ng / mL) at lower (0.03 mg / eye) or higher (0.1 mg / eye) doses in the vitreous humor, sclera / choroid / RPE, or retina are shown.

[0015] Figure 2A Shown is the fluorescein angiography (FA) grading scale for the laser CNV model in rats. Figure 2B Shown are the percentages of grade IV lesions in control and CLS-AX recipient animals at day 21 *, Fischer's exact p value = 0.0002.

[0016] Figure 3A and Figure 3B Shown are the results of vascular leakage studies in a porcine CNV model. Figure 3A is a bar graph showing the vascular leakage area 7 or 14 days after laser treatment-induced retinal damage. OS = left eye; OD = right eye; BSS = balanced salt solution; SCS = suprachoroidal space. OS-BSS treatment is shown as the left bar at both time points, and OD-CLS-AX treatment is shown as the right bar at both time points. Figure 3B Representative images from BSS-treated eyes and CLS-AX-treated eyes are provided.

[0017] Figure 4A and Figure 4B Mean values ​​(± SEM) of lectin IB4 on retinal flat mounts are shown. Figure 4A Representative images are provided. Scale bar = 100 μm. Figure 4BMean ± SEM of lectin IB4 signals are shown. The signals in the CLS-AX group were significantly lower than those in the BSS-treated group (p = 0.0297; t-test [OS measured at 27 sites; OD measured at 354 sites]). DETAILED DESCRIPTION

[0018] The present disclosure relates generally to ophthalmic therapies, and more particularly to methods and devices that allow fluid drug formulations to be infused into tissues at the back of the eye for targeted localized treatment, e.g., for treating ocular diseases and conditions associated with neovascularization. For example, these diseases and conditions include neovascular age-related macular degeneration (nAMD; also referred to herein as wet AMD), non-exudative AMD, choroidal neovascularization (CNV), retinal vein occlusion (RVO), nAMD associated with RVO, nAMD associated with CNV, retinopathy, diabetic retinopathy, and diabetic macular edema (DME).

[0019] In some embodiments, the formulation comprises one or more tyrosine kinase inhibitors and is administered to the suprachoroidal space (SCS) of the eye by non-surgical means, such as by hollow microneedles and / or injection devices comprising hollow needles, wherein the needle has an effective length of about 500 to about 2000 microns. The methods and formulations provided herein allow for effective posterior segment drug delivery and generally embody the following features: (1) These methods are non-surgical and therefore minimally invasive and safe; (2) The drug formulations are administered in such a manner that they are well targeted to the posterior segment of the eye and / or the suprachoroidal space (SCS) of the eye and / or the supraciliary space of the eye and / or the supraretinal space of the eye and / or the subretinal space of the eye, while limiting exposure of the drug to the anterior segment or other areas of the eye in front of the eye; (3) These methods and formulations are capable of delivering the drug in a sustained and / or controlled manner; (4) These methods and devices are very user-friendly. The non-surgical SCS delivery methods and drug formulations for SCS delivery described herein achieve these desired properties.

[0020] Axitinib is a tyrosine kinase inhibitor (TKI) that antagonizes the vascular endothelial growth factor receptors VEGFR-1, VEGFR-2, and VEGFR-3, as well as the platelet-derived growth factor receptor (PDGFR) and c-Kit receptors. Axitinib was originally approved as an oral tablet formulation in 2012. The dose is 5 mg twice daily for the treatment of advanced renal cell carcinoma after failure of previous systemic therapy. Provided herein are axitinib formulations suitable for delivery to the eye. In some embodiments, provided herein are axitinib formulations suitable for delivery to the eye are "CLS-AX". Exemplary CLS-AX formulations are provided in Table 1A and Table 1B.

[0021] The term "suprachoroidal space" is used interchangeably with suprachoroid, SCS, suprachoroidal layer, suprachoroidal space herein; and describes a potential space in the eye region between the sclera and the choroid. The region is mainly composed of tightly packed layers of long pigmentation processes from each of the two adjacent tissues; however, due to the accumulation of fluid or other substances in the suprachoroidal space and adjacent tissues, the region may form a space. It will be appreciated by those skilled in the art that the suprachoroidal space is often enlarged due to certain disease states in the eye or due to certain trauma or surgical interventions due to fluid accumulation. However, in the present specification, in some embodiments, fluid accumulation is intentionally generated by infusing a drug preparation into the suprachoroidal layer to produce a suprachoroidal space (which is filled with a drug preparation). Without wishing to be bound by theory, it is believed that the SCS region is used as a path for uveoscleral outflow (i.e., the natural process of the eye moving fluid from one region of the eye to another) and becomes a real space when the choroid is detached from the sclera.

[0022] As used herein, "non-surgical" ocular drug delivery devices and methods refer to methods and devices for drug delivery that do not require general anesthesia and / or retrobulbar anesthesia (also known as retrobulbar block). Alternatively or additionally, the "non-surgical" ocular drug delivery method is performed using an instrument with a needle having an effective length of less than 2000 microns; and / or an instrument with a needle having a diameter of 28 or less. Alternatively or additionally, the "non-surgical" ocular drug delivery method does not require a guiding mechanism that is usually required for ocular drug delivery via a shunt or cannula. The non-surgical ocular drug delivery method provided herein can be used in a clinic or outpatient setting, and does not require a hospital environment. As used herein, "surgical" ocular drug delivery includes inserting a device or administering a drug by surgical means, for example, via an incision to expose and provide access to an area of ​​the eye (including the posterior area), and / or via insertion of a stent, shunt or cannula and / or via a method requiring anesthesia (e.g., general anesthesia or retrobulbar anesthesia).

[0023] Surgical and non-surgical posterior ocular disease treatment methods and devices described herein are particularly useful for locally delivering drugs to the posterior region of the eye, such as retinal choroid tissue, macula, retinal pigment epithelium (RPE) and optic nerve in the posterior segment of the eye. In one embodiment, non-surgical methods provided herein can be used for targeting drug delivery to specific posterior ocular tissue or intraocular or adjacent tissues. In one embodiment, the method described herein delivers drugs specifically to the sclera, choroid, Bruch's membrane, retinal pigment epithelium, subretinal cavity, retina, macula, optic disc, optic nerve, ciliary body, trabecular meshwork, aqueous humor, vitreous humor and / or other ocular tissues or adjacent tissues in the eyes of human subjects for treatment. In one embodiment, the method provided herein can be used for targeting drug delivery to specific posterior ocular tissue or intraocular or adjacent tissues.

[0024] As provided throughout, in one embodiment, the methods described herein are performed using a puncture member, which may include a hollow or solid microneedle, such as a rigid microneedle. As used herein, the term "microneedle" refers to a catheter body having a base, shaft, and tip suitable for insertion into the sclera and other ocular tissues and having a size suitable for minimally invasive insertion and drug formulation infusion as described herein. The "length" and "effective length" of a microneedle include the length of the shaft of the microneedle and the bevel height of the microneedle. In some embodiments, the needles used herein are microneedles because they have an effective length of less than 2000 microns. For example, in some embodiments, the needles used for the methods described herein are microneedles because they have an effective length of about 50 microns to about 2000 microns, or about 500 microns to about 1800 microns, or about 700 microns to about 1500 microns, or about 900 microns to about 1200 microns. In some embodiments, the needles used in the methods described herein are microneedles because they have an effective length of about 800 microns, about 900 microns, about 1000 microns, about 1100 microns, or about 1200 microns. In some embodiments, the device used to implement the methods described herein includes one of the devices disclosed in U.S. Patent No. 9,539,139, issued on January 10, 2017, or International Patent Application Publication No. WO2014 / 179698, entitled "Apparatus and Method for Ocular Injection" filed on May 2, 2014 (Application No. PCT / US2014 / 036590), each of which is incorporated herein by reference in its entirety for all purposes. In some embodiments, the device for practicing the methods described herein includes one of the devices disclosed in International Patent Application Publication No. WO2014 / 036009 (Application No. PCT / US2013 / 056863), entitled "Apparatus and Method for Drug Delivery Using Microneedles," filed on August 27, 2013, which is incorporated herein by reference in its entirety for all purposes. In some embodiments, the microneedle is an SCS microinjector as described herein.

[0025] As used herein, the term "hollow" includes a single straight hole through the center of a microneedle, as well as multiple holes, holes along complex paths through the microneedle, multiple entry and exit points from the hole, and intersections or networks of holes. That is, a hollow microneedle has a structure that includes one or more continuous paths from the base of the microneedle to an exit point (opening) in the shaft and / or tip portion of the microneedle away from the base.

[0026] In one embodiment, the microneedle device includes a fluid reservoir for containing a therapeutic agent (e.g., a drug or cell preparation), for example, as a solution or suspension, and a drug reservoir (which may include any therapeutic agent) operably connected to the hole of the microneedle at a location away from the microneedle tip. The fluid reservoir can be integral with the microneedle, integral with the elongated body, or separate from both the microneedle and the elongated body.

[0027] In some embodiments, features of the devices, formulations, and methods are provided in U.S. Patent No. 9,636,332, U.S. Patent Application Publication No. 2018-0042765, International Patent Application Publication No. WO2014 / 074823 (Application No. PCT / US2013 / 069156), WO2015 / 195842 (Application No. PCT / US2015 / 036299), U.S. Patent Publication No. 2019-0269702, WO2017 / 120600 (Application No. PCT / US2017 / 012755) and / or WO2017 / 120601 (Application No. PCT / US2017 / 012757), each of which is incorporated herein by reference in its entirety for all purposes.

[0028] In one embodiment, a device for performing one of the methods described herein comprises a device described in U.S. Design Patent Application Serial No. 29 / 506,275, filed on October 14, 2014, entitled "Medical Injector for Ocular Injection," the disclosure of which is incorporated herein by reference in its entirety for all purposes. In one embodiment, a device for performing one of the methods described herein comprises a device described in U.S. Patent Publication No. 2015 / 0051581 or U.S. Patent Publication No. 2017 / 0095339, each of which is incorporated herein by reference in its entirety for all purposes. In some embodiments, such a device is an SCS microinjector as described herein.

[0029] As used herein, the terms "about" and "approximately" generally refer to plus or minus 10% of the stated value. For example, about 0.5 would include 0.45 and 0.55, about 10 would include 9 to 11, and about 1000 would include 900 to 1100.

[0030] Further details of possible manufacturing techniques for the microneedles and / or microinjectors provided herein are described in, for example, U.S. Patent Application Publication No. 2006 / 0086689, filed May 2, 2014, U.S. Patent Application Publication No. 2006 / 0084942, U.S. Patent Application Publication No. 2005 / 0209565, U.S. Patent Application Publication No. 2002 / 0082543, U.S. Patent No. 6,334,856, U.S. Patent No. 6,611,707, U.S. Patent No. 6,743,211, and PCT / US2014 / 36590, all of which are incorporated herein by reference in their entirety for all purposes.

[0031] Any method described herein can be performed using any suitable syringe of the type shown and described herein. In some embodiments, according to the methods described herein, the drug dose has a delivery volume of at least about 20 μL, at least about 50 uL, at least about 100 μL, at least about 200 μL, or at least about 500 μL. In one embodiment, the amount of the therapeutic preparation delivered to the suprachoroidal space from the device described herein is about 10 μL to about 200 μL, for example, about 50 μL to about 150 μL. In another embodiment, about 10 μL to about 500 μL, for example, about 50 μL to about 250 μL, is applied to the suprachoroidal space in a non-surgical manner. In some embodiments, about 100 μL of drug preparation is applied to the suprachoroidal space in a non-surgical manner. In some embodiments, the drug preparation comprises 100 μL of axitinib preparation, such as CLS-AX.

[0032] Compared to previously known needle devices, the SCS drug delivery methods provided herein allow for delivery of drug formulations over larger tissue areas and are more difficult to target tissues in a single administration. Without wishing to be bound by theory, it is believed that upon entering the SCS, the drug formulation flows circumferentially from the insertion site to the retinal choroidal tissue, macula, and optic nerve in the posterior segment of the eye, and flows forward to the uvea and ciliary body. In addition, a portion of the infused drug formulation can be retained in the SCS as a reservoir, or in tissue covering the SCS, such as the sclera near the microneedle insertion site, serving as an additional reservoir for drug formulations that can subsequently diffuse into the SCS and other adjacent posterior tissues.

[0033] The term "subject" is used interchangeably with the term "patient" herein. The subject can be any mammal. Preferably, the subject is a human subject. The human subject treated with the methods and devices provided herein can be an adult or a child. In one embodiment, the subject presents a retinal thickness greater than 300 μm (e.g., a central subfield thickness as measured by optical coherence tomography). In another embodiment, the BCVA score of the subject in need of treatment is ≥20 letters per eye (e.g., 20 / 400 Snellen approximation). In yet another embodiment, the BCVA score of the subject in need of treatment is ≥20 letters per eye (e.g., 20 / 400 Snellen approximation), but the eye in need of treatment reads ≤70 letters.

[0034] In one embodiment, the therapeutic response is assessed by visual acuity measurement at one and / or two months after treatment (e.g., by measuring the mean change in best corrected visual acuity (BCVA) relative to baseline (i.e., before treatment). In one embodiment, patients treated by one or more of the methods provided herein experience an improvement in BCVA of at least 2 letters, at least 3 letters, at least 5 letters, at least 8 letters, at least 12 letters, at least 13 letters, at least 15 letters, at least 20 letters, and all values ​​therebetween, relative to baseline, compared to the patient's BCVA before administration of axitinib.

[0035] In one embodiment, the patient's BCVA measurement after the administration of axitinib increases by about 5 letters or more, about 10 letters or more, 15 letters or more, about 20 letters or more, about 25 letters or more, compared to the patient's BCVA measurement before treatment. In another embodiment, the patient's BCVA measurement increases by about 5 to about 30 letters, 10 to about 30 letters, about 15 letters to about 25 letters, or about 15 letters to about 20 letters compared to the patient's BCVA measurement before treatment with axitinib. In one embodiment, the BCVA increase is about 2 weeks, about 1 month, about 2 months, about 3 months, or about 6 months after the administration of axitinib. In another embodiment, BCVA is measured at least about 2 weeks, at least about 1 month, at least about 2 months, at least about 3 months, or at least about 6 months after the administration of axitinib.

[0036] In one embodiment, BCVA is based on the Early Treatment of Diabetic Retinopathy Study (ETDRS) eye chart and is assessed at a starting distance of 4 meters.

[0037] In another embodiment, the patient receiving the treatment method, for example, using one of the devices provided herein, substantially maintains his or her vision after treatment (e.g., a single administration or multiple administrations of axitinib to the suprachoroidal space of the eye), as measured by losing less than 15 letters in the best corrected visual acuity (BCVA) measurement, compared to the BCVA measurement of the patient before treatment. In another embodiment, the patient loses less than 10 letters, less than 8 letters, less than 6 letters, less than 5 letters, or less than 2 letters in the BCVA measurement compared to the BCVA measurement of the patient before treatment. In some embodiments, the patient does not experience further vision loss after treatment with axitinib (e.g., the patient experiences a loss of 0 letters, as measured by BCVA). In some embodiments, the patient experiences an increase in vision after treatment (e.g., a single administration or multiple administrations of axitinib to the suprachoroidal space of the eye). For example, in some embodiments, the patient experiences an increase of at least 2, at least 5, at least 10, at least 15, at least 20 or more letters. In some embodiments, "minimal vision loss" as used herein means a loss of no more than 1 letter, no more than 2 letters, no more than 3 letters, no more than 4 letters, no more than 5 letters, no more than 6 letters, no more than 7 letters, no more than 8 letters, no more than 9 letters, no more than 10 letters, no more than 12 letters, or no more than 15 letters. In some embodiments, the patient experiences minimal vision loss within 2, 6, 12, 18, or 24 months relative to the patient's baseline vision before treatment. In some embodiments, the patient experiences an increase in vision within 2, 6, 12, 18, or 24 months relative to the patient's baseline vision before treatment.

[0038] The reduction of retinal thickness and / or macular thickness is a measure of the therapeutic efficacy of the method provided herein.For example, in one embodiment, the patient with nAMD treated by one of the methods provided herein (for example, applying medicine (for example, axitinib) to the suprachoroidal space of eyes) experiences the reduction of retinal thickness relative to baseline.For example, in one embodiment, the patient experiences the reduction of central subdomain thickness (CST) at any given time point after applying the medicine, for example, reducing at least about 20 μm or at least about 40 μm or at least about 50 μm or at least about 100 μm or at least about 150 μm or at least about 200 μm or about 50 -100 μm, and all values ​​therebetween.In another embodiment, the patient experiences the reduction of retinal thickness (for example CST) of ≥5%, ≥10%, ≥15%, ≥20%, ≥25% after applying the medicine.In some embodiments, relative to the baseline CST of the patient before treatment, the patient experiences CST reduction for at least 2,6,12,18 or 24 months.

[0039] In one embodiment, the patient treated by the methods provided herein experiences a decrease in retinal thickness from baseline (i.e., retinal thickness before treatment) by about 20 μm to about 200 μm, about 40 μm to about 200 μm, about 50 μm to about 200 μm, about 100 μm to about 200 μm, or about 150 μm to about 200 μm at any given time point. In one embodiment, the change in retinal thickness relative to baseline is measured, for example, by spectral domain optical coherence tomography (SD-OCT) as a change in CST.

[0040] In one embodiment, the retinal thickness is reduced at about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, about 18 months, or about 24 months after the drug is administered. In another embodiment, the retinal thickness is reduced at least about 2 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, at least about 12 months, at least about 18 months, or at least about 24 months after the drug is administered. In one embodiment, in the case of multiple dosing courses, the patient maintains a reduction in retinal thickness for at least about 2 weeks, at least about 1 month, at least about 2 months, at least about 3 months, or at least about 6 months after each drug administration.

[0041] A reduction in the frequency and / or severity of ocular injuries within the eye is also a measure of the therapeutic efficacy of the methods provided herein.

[0042] In one embodiment, the suprachoroidal drug dose sufficient to achieve a therapeutic response in a human subject treated with a non-surgical SCS drug delivery method is less than the intravitreal, parenteral, intracameral, topical, or oral drug dose sufficient to elicit the same or substantially the same therapeutic response. In another embodiment, the suprachoroidal drug dose is at least 10% less than the oral, parenteral, or intravitreal dose sufficient to achieve the same or substantially the same therapeutic response. In another embodiment, the suprachoroidal dose is about 10% to about 25% less, or about 10% to about 50% less than the oral, parenteral, intracameral, topical, or intravitreal dose sufficient to achieve the same or substantially the same therapeutic response.

[0043] In some embodiments, non-surgical administration of axitinib according to the methods described herein reduces the number and / or frequency of administration of a VEGF modulator to a subject. Thus, in some embodiments, administration of axitinib increases the effectiveness and / or durability of VEGF modulator treatment. For example, in some embodiments, SCS administration of axitinib results in the need for fewer administrations of a VEGF modulator, and / or results in longer time periods between administrations of a VEGF modulator.

[0044] In some embodiments, the non-surgical administration of axitinib according to the methods described herein results in an improvement in BCVA and / or an improvement in CST of the subject after the initial dose of axitinib for at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 30 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks or longer. In some embodiments, the non-surgical administration of axitinib according to the methods described herein results in an improvement in BCVA and / or an improvement in CST of the subject after the second dose of axitinib for at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 30 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, at least 52 weeks or longer.

[0045] In one embodiment, non-surgical administration of axitinib to the eye according to the methods provided herein results in a reduction in the number of adverse side effects or clinical manifestations in the treated patient compared to the number of adverse side effects or clinical manifestations caused by the same drug dose administered intravitreally, intracamerally, orally, or parenterally; or results in a reduction in the number of adverse side effects or clinical manifestations in the treated patient compared to those caused by administration of a drug previously used to treat the disease.

[0046] Examples of side effects and clinical manifestations that may be alleviated or improved include, but are not limited to, inflammation, gastrointestinal side effects (e.g., diarrhea, nausea, gastroenteritis, vomiting, gastrointestinal bleeding, rectal bleeding and duodenal bleeding, hemorrhagic pancreatitis, black or bloody stools due to perforation of the large intestine, and / or hemoptysis); hematological side effects (e.g., leukopenia, anemia, pancytopenia and agranulocytosis, thrombocytopenia, neutropenia, pure red cell aplasia (PRCA), deep vein thrombosis, easy bruising, and / or abnormal bleeding from the nose, mouth, vagina, or rectum); immune side effects / clinical manifestations (e.g., immunosuppression, immunosuppression leading to sepsis, opportunistic infections (herpes simplex virus, herpes zoster, and invasive candidal infections) and / or increased infections); oncological side effects / clinical manifestations (e.g., lymphoma, lymphoproliferative disorders, and / or non-melanoma skin cancer); renal side effects / clinical manifestations (e.g., dysuria, urgency, urinary tract infections); infection, hematuria, tubular necrosis and / or BK virus-related nephropathy); metabolic side effects / clinical manifestations (e.g., edema, hyperphosphatemia, hypokalemia, hyperglycemia, hyperkalemia, swelling, rapid weight gain and / or thyroid enlargement); respiratory side effects / clinical manifestations (e.g., respiratory tract infection, dyspnea, increased cough, dry cough in primary tuberculosis, wheezing and / or nasal congestion); skin side effects / clinical manifestations (e.g., acne, rash, eczema hyperhidrosis, papulosquamous psoriasiform rash, blisters, oozing, mouth ulcers and / or alopecia); musculoskeletal side effects / clinical manifestations (e.g., myopathy and / or muscle pain), hepatic side effects / clinical manifestations (e.g., hepatotoxicity and / or jaundice), abdominal pain, increased incidence of early pregnancy loss, delayed menstruation, severe headache, confusion, altered mental status, loss of vision, seizure (convulsions), increased sensitivity to light, dry eyes, red eyes, itchy eyes and / or hypertension.

[0047] As provided throughout, in one embodiment, the compositions administered herein, the methods described herein include administering a tyrosine kinase inhibitor. Exemplary tyrosine kinases for use in the methods described herein include, but are not limited to, alectinib Angiokinase inhibitors such as nintedanib Afatinib and motesanib; apatinib; axitinib; cabozantinib Calaticinib; crenolanib; tannicacin; forretinib; fostamatinib; growth factor receptor inhibitor; ibrutinib Icotinib; Imatinib Linitinib; Mubutinib; Radotinib; T790M; V600E; Vatalanib; Vemurafenib AEE788 (TKI, VEGFR-2, EGFR: Novartis); ZD6474 (TKI, VEGFR-1, -2, -3, EGFR: Vandetanib: AstraZeneca); AZD2171 (TKI, VEGFR-1, -2: AstraZeneca); SU 11248 (TKI, VEGFR-1, -2, PDGFR: Sunitinib: Pfizer); AG13925 (TKI, VEGFR-1, -2: Pfizer); AG013736 (TKI, VEGFR-1, -2: Pfizer); CEP-7055 (TKI, VEGFR-1, -2, -3: Cephalon); CP-547,632 (TKI, VEGFR-1, -2: Pfizer); GW7S6024 (TKL, VEGFR-1, -2, -3: GlaxoSmithKline); GW786034 (TKI, VEGFR-1, -2, -3: GlaxoSmithKline); Sorafenib (TKI, Bay 43-9006, VEGFR-1, -2, PDGFR: Bayer / Onyx); SU4312 (TKI, VEGFR-2, PDGFR: Pfizer); AMG706 (TKI, VEGFR-1, -2, -3: Amgen); XL647 (TKI, EGFR, HER2, VEGFR, ErbB4: Exelixis); XL999 (TKI, FGFR, VEGFR, PDGFR, FII-3: Exelixis); PKC412 (TKI, KIT, PDGFR, PKC, FLT3, VEGFR-2: Novartis); AEE788 (TKI, EGFR, VEGFR2, VEGFR-1: Novartis): OSI-030 (TKI, c-kil, VEGFR: OSI Pharmaceuticals); OS1-817 (TKI c-kit, VEGFR: OSI Pharmaceuticals); DMPQ (TKI, ERGF, PDGFR, ErbB2.p56.pkA, pkC); MLN518 (TKI, Flt3, PDGFR, c-KIT (T53518: Millennium Pharmaceuticals); lestaurinib (TKI, FLT3, CEP-701, Cephalon); ZD 1839 (TKI, EGFR: gefitinib, Iressa: AstraZcneca); OSI-774 (TKI, EGFR: erlotinib: Tarceva: OSI Pharmaceuticals); Lapatinib (TKI, ErbB-2, EGFR and GD-2016: Tykerb: GlaxoSmithKline).

[0048] Axitinib is a potent tyrosine kinase inhibitor of the vascular endothelial growth factor receptors VEGFR-1, VEGFR-2, and VEGFR-3. These receptors are involved in pathological angiogenesis, tumor growth, and metastatic progression of cancer. Axitinib has been shown to potently and selectively inhibit VEGF-mediated signaling and endothelial cell proliferation and survival at picomolar concentrations. Axitinib also inhibits other RTKs, including PDGFR-α, PDGFR-β, and c-Kit, at low nanomolar concentrations. The most common metabolites of axitinib, N-glucuronide (M7) and sulfoxide (M12), are ≥-400-fold less potent against VEGFR-2.

[0049] "CLS-AX" is used herein to describe formulations comprising axitinib. Exemplary formulations are provided in Table 1A and Table 1B and throughout the disclosure.

[0050] In one embodiment, a tyrosine kinase inhibitor (e.g., axitinib) can be used in combination with one or more agents listed herein or with other agents known in the art in a single or multiple formulations. In one embodiment, the agent is a VEGF modulator and is administered intravitreally to a patient in need of treatment. In one embodiment, the VEGF modulator is a VEGF antagonist. In one embodiment, the second drug is a VEGF antagonist, including but not limited to a VEGF receptor kinase antagonist, an anti-VEGF antibody or fragment thereof, an anti-VEGF receptor antibody, an anti-VEGF aptamer, a small molecule VEGF antagonist, a thiazolidinedione, a quinoline, or a designed ankyrin repeat protein (DARPin). In one embodiment, VEGF antagonists include but are not limited to aflibercept, ziv-aflibercept, bevacizumab, pinepizumab, VEGF sticky trap (sticky trap), cabozantinib, forretinib, vandetanib, nintedanib, regorafenib, cediranib, ranibizumab, lapatinib, sunitinib, sorafenib, prixin, regorafenib, verteporfin, bucillamine, axitinib, pazopanib, fluocinolone, nintedanib, AL8326, 2C3 antibody, AT001 antibody, XtendVEGF antibody, HuMax-VEGF antibody, R3 antibody, AT001 / r84 antibody, HyBEV, ANG3070, APX0 03 antibody, APX004 antibody, ponatinib, BDM-E, VGX100 antibody, VGX200, VGX300, COSMIX, DLX903 / 1008 antibody, ENMD2076, INDUS815C, R84 antibody, KD019, NM3, MGCD265, MG516, MP0260, NT503, anti-DLL4 / VEGF bispecific antibody, PAN90806, Palomid529, BD0801 antibody, XV615, ruxitinib, motesanib diphosphate, AAV2-sFLT01, soluble Flt1 receptor, AV-951, volasertib, CEP11981, KH903, lenvatinib, lenvatinib mesylate, terameprocol, PF00337210, PRS050, SP01, carboxyaminotriazole orotate, hydroxychloroquine, linifanib, ALG1001, AGN150998, MP0112, AMG 386, Ponatinib, PD173074, AVA101, BMS690514, KH902, Govatinib (E7050), Dovitinib, Dovitinib lactate (TKI258, CHIR258), ORA101, ORA102, Axitinib (Inlyta, AG013736), PTC299, Pegaptanib sodium, Troponin, EG3306, Vatalanib, Bmab100, GSK2136773, Anti-VEGFR Alternase, Avila, CEP7055, CLT009, ES BA903, GW654652, HMPL010, GEM220, HYB676, JNJ17029259, TAK593, Nova21012, Nova21013, CP564959, smart anti-VEGF antibody, AG028262, AG13958, CVX241, SU14813, PRS055, PG501, PG545, PTI101, TG100948, ICS283, XL647, Enzastatin hydrochloride, BC194, COT6 01M06.1, COT604M06.2, MabionVEGF, Apatinib, RAF265 (CHIR-265), Motesanib diphosphate (AMG-706), Lenvatinib (E7080), TSU-68 (SU6668, Orantinib), Brivanib (BMS-540215), MGCD-265, AEE788 (NVP-AEE788), ENMD-2076, OSI-930, CYC116, Ki8751, Telatinib, KRN 633, SAR131675, dovitinib (TKI-258) dilactate, apatinib, BMS-794833, brivanib alanine (BMS-582664), govatinib (E7050), semasanib (SU5416), ZM323881HCl, cabozantinib malate (XL184), ZM 306416, AL3818, AL8326, 2C3 antibody, AT001 antibody, HyBEV, bevacizumab ANG3070, APX003 antibody, APX004 antibody, ponatinib (AP24534), BDM-E, VGX100 antibody (VGX100 CIRCADIAN), VGX200 (c-fos-induced growth factor monoclonal antibody), VGX300, COSMIX, DLX903 / 1008 antibody, ENMD2076, sunitinib malate INDUS815C, R84 antibody, KD019, NM3, allogeneic mesenchymal precursor cells in combination with an anti-VEGF antagonist (e.g., anti-VEGF antibody), MGCD265, MG516, VEGF receptor kinase inhibitors, MP0260, NT503, anti-DLL4 / VEGF bispecific antibody, PAN90806, Palomid 529, BD0801 antibody, XV615, lucitanib (AL3810, E3810), AMG706 (motesanib diphosphate), AAV2-sFLT01, soluble Flt1 receptor, cediranib (Recentin TM ), AV-951, Tivozanib (KRN-951), Regorafenib Vlasitinib (BI6727), CEP11981, KH903, Lenvatinib (E7080), Lenvatinib mesylate, Termeprol (EM1421), Ranibizumab Pazopanib hydrochloride (Votrient TM ), PF00337210, PRS050, SP01 (curcumin), carboxyaminotriazole orotate, hydroxychloroquine, linifanib (ABT869, RG3635), fluocinolone ALG1001, AGN150998, DARPin MP0112, AMG386, ponatinib (AP24534), AVA101, nintedanib (Vargatef TM )、BMS690514、KH902、Govatinib(E7050)、Everolimus Dovitinib lactate (TKI258, CHIR258), ORA101, ORA102, axitinib ( AG013736), plitidepsin PTC299, Aflibercept Pegaptanib sodium (Macugen TM , LI900015), Verteporfin Bucillamine (Rimatil, Lamin, Brimani, Lamit, Boomiq), R3 antibody, AT001 / r84 antibody, Troponin (BLS0597), EG3306, Vatalanib (PTK787), Bmab100, GSK2136773, Anti-VEGFR Alterase, Avila, CEP7055, CLT009, ESBA903, HuMax-VEGF antibody, GW654652, HMPL010, GEM220, HYB676, JNJ17029259, TAK593, XtendVEGF antibody, Nova21012, Nova21013, CP564959, Smart anti-VEGF antibody, AG028262, AG13958, CVX 241, SU14813, PRS055, PG501, PG545, PTI101, TG100948, ICS283, XL647, enzastatin hydrochloride (LY317615), BC194, quinoline, COT601M06.1, COT604M06.2, MabionVEGF, SIR-Spheres conjugated to anti-VEGF or VEGF-R antibodies, apatinib (YN968D1), or AL3818.

[0051] In embodiments, compositions and methods provided herein are used to treat ocular diseases and disorders. Exemplary ocular diseases and disorders include, but are not limited to, wet AMD, non-exudative AMD, CNV, RVO (including central RVO, semi-RVO, branch RVO), retinopathy, diabetic retinopathy, and diabetic macular edema (DME). In embodiments, disease or disorder is macular edema (ME). ME may be associated with and / or caused by central RVO, semi-RVO, branch RVO, inflammation, uveitis, or CNV. In embodiments, disease or disorder is map-like atrophy, such as from AMD, degenerative retinal disorders, or hereditary retinal disorders. In embodiments, disease or disorder is retinal neovascularization. For example, in embodiments, retinal neovascularization may be caused by ischemic causes, such as diabetic retinopathy, central RVO, semi-retinal RVO, branch RVO, central retinal artery occlusion, branch retinal artery occlusion, sickle cell retinopathy, or precocious retinopathy. In embodiments, retinal neovascularization may lead to inflammation and uveitis diseases.

[0052] Specific conditions in which choroidal neovascularization may occur include wet AMD, angioid streaks, anterior ischemic optic neuropathy, bacterial endocarditis, Best disease, shotgun retinopathy elasticum, choroidal angioma, choroidal nevus, choroidal nonperfusion, choroidal osteoma, choroidal rupture, choroidodermopathy, chronic retinal microscopy, retinal coloboma, diabetes, drusen, endogenous candidal endophthalmitis, extrapapillary hematoma of the retinal pigment epithelium, fundus yellow proliferation, idiopathic conditions, macular hole, malignant melanoma, membranous glomerulonephritis (type II), metallic intraocular foreign body, morning-gray disc syndrome, retinitis pigmentosa, retinochoroidal coloboma, urticaria, sarcoidosis, serous or geographic choroiditis, subretinal effusion, tilted disc syndrome, arcuate retinochoroiditis, tuberculosis, Vogt-Koyanagi-Harada syndrome syndrome), idiopathic polyposis vascular stenosis, ocular ischemic syndrome, and vascular stenosis.

[0053] Example

[0054] The present invention is further illustrated by reference to the following examples. However, it should be noted that these examples, like the above-described embodiments, are illustrative and should not be construed as limiting the scope of the present invention in any way.

[0055] Example 1. Axitinib Formulation

[0056] An exemplary axitinib formulation denoted CLS-AX comprises the following components.

[0057] Table 1A. Exemplary Axitinib Formulations

[0058] Element CLS-AX (% w / v or as above) Axitinib 40mg / mL Sodium Carboxymethyl Cellulose (NaCMC) 0.5％ Polysorbate 80 (PS-80) 0.1％ Sodium chloride 0.79％ Sodium dihydrogen phosphate monohydrate 0.059％ Anhydrous disodium hydrogen phosphate 0.079％ Water for injection Moderate Sodium hydroxide / hydrochloric acid Adjust pH to 6.8

[0059] An exemplary axitinib formulation (also denoted as CLS-AX in the table below) is a 1 mg / mL formulation and comprises the following components.

[0060] Table 1B. Exemplary Axitinib Formulations

[0061]

[0062] In exemplary axitinib formulations, axitinib is present at a concentration of 1 mg / mL or 10 mg / mL. In addition, in some exemplary axitinib formulations, polysorbate 80 is present in the formulation at about 0.04% w / v to about 0.05% w / v. In addition, in some exemplary embodiments, sodium chloride is present at a concentration of 0.8%, and / or sodium phosphate (sodium dihydrogen phosphate monohydrate) is present at 0.05% w / v; and / or sodium phosphate (sodium dihydrogen phosphate anhydrous) is present at 0.085% w / v. Thus, the concentration of polysorbate 80 may be in the range of about 0.04% w / v to about 0.1% w / v, the concentration of sodium chloride may be in the range of about 0.7% w / v to about 0.9% w / v, the concentration of sodium phosphate (sodium dihydrogen phosphate monohydrate) may be in the range of about 0.05% to about 0.06% w / v, and the concentration of sodium phosphate (sodium hydrogen phosphate anhydrous) may be in the range of about 0.075% w / v to about 0.085% w / v.

[0063] In some embodiments, NaCMC or a similar compound is included in the formulation as a viscosity modifier. In some embodiments, polysorbate 80 (PS-80) or a similar agent is included in the formulation as a surfactant wetting agent for the active pharmaceutical ingredient axitinib. In some embodiments, sodium chloride is included in the formulation as a tension modifier. In some embodiments, sodium dihydrogen phosphate monohydrate and / or anhydrous disodium hydrogen phosphate are included as pH buffers. In some embodiments, sodium hydroxide / hydrochloric acid is included in the formulation as a pH modifier. In some embodiments, water for injection is the solvent of the formulation.

[0064] In some embodiments, no preservative is present. In some embodiments, the formulation is terminally sterilized by autoclave.

[0065] Further information providing solubility, particle size, viscosity, and other product profile parameters for exemplary CLS-AX compositions (active pharmaceutical ingredients (API) and drug products) is provided in Table 1C.

[0066] Table 1C. Exemplary Product Profiles

[0067]

[0068] Example 2. Ocular distribution of CLS-AX after suprachoroidal administration to pigmented rabbits

[0069] The purpose of the following study was to evaluate the pharmacokinetics and ocular tissue distribution of CLS-AX following a single bilateral suprachoroidal microneedle injection into male pigmented Dutch-belted rabbits. In one study, CLS-AX was administered at a dose of 4 mg / eye (100 μL / injection). In separate studies, CLS-AX was administered at a dose of 0.1 mg / eye or 0.03 mg / eye. The eyes of the animals were examined by a board-certified veterinary ophthalmologist using a slit-lamp biomicroscope and indirect ophthalmoscopy. Examinations occurred on designated study days prior to dosing and prior to sacrifice (if applicable). On designated days, at least two animals / time points were euthanized to collect blood (plasma) and ocular tissues (aqueous humor, vitreous humor, retina, and sclera / choroid-RPE). Plasma and ocular tissue concentrations of CLS-AX were analyzed using liquid chromatography / mass spectrometry.

[0070] For the initial study, animals were acclimated to study conditions for 16 days prior to dosing. At the time of dosing, animals weighed 1721-1941 g and were 5 months old. During the acclimation and testing period, all animals were housed in individually hung stainless steel cages. A certified high-fiber rabbit diet #5325 (PMI) was provided. Fresh water was provided daily for them to drink ad libitum. During the acclimation and testing period, all animals were housed in individually hung stainless steel cages. The environmental control of the animal room was set to maintain a temperature of 16-22°C (bias), a relative humidity of 50±20% (bias) and a 12-hour light / 12-hour dark cycle. When necessary, the 12-hour dark cycle was interrupted to adapt to the study procedures. A temporary identification number was assigned to each animal. At the time of selection, a permanent animal number (bias) was assigned. Prior to animal selection, each animal was uniquely identified using an individually numbered cage card and identified using an implantable microchip identification device when assigned to the study. Immediately prior to dosing, animals were anesthetized by intramuscular (IM) injection of ketamine, dexmedetomidine, and glycopyrrolate. After application of the local anesthetic, the eyes were flushed with iodine solution followed by saline. Animals were not fasted prior to dosing.

[0071] The dosing formulation was drawn into a 1-mL Luer lock syringe using a standard 21-gauge 1-inch needle; any air bubbles were squeezed out and a 30-gauge microneedle with a length of 700 μm was used in place of the standard needle. A single suprachoroidal injection of 100 μL was given to each eye (3-4 mm from the limbus, in the superior temporal quadrant) over approximately 5-10 seconds by an OSOD representative according to study-specific procedures. After injection, the needle was kept in the eye for approximately 20 seconds and then removed. After the microneedle was removed, a cotton-tipped applicator (CTA, dose wipe) was placed over the injection site for approximately 10 seconds; the dose wipe was discarded. The eye was examined by an OSOD representative to confirm the accuracy of the injection. The right eye was dosed first; all post-dose times were based on the dosing time of the second (left) eye. Any dosing observations were recorded.

[0072] Animals were given an intramuscular (IM) injection of flunixin (2 mg / kg) prior to sedation and approximately 24 hours after the first flunixin administration (0.08 mL per animal), if applicable. Buprenorphine extended release (SR, 0.2 mg / kg) was administered subcutaneously (SQ) and a mild ophthalmic ointment was applied to each eye upon recovery. Topical ocular neo-bac ointment and atropine ointment were administered to both eyes of the animals once after dosing on Study Day 1 and twice daily on Study Days 2 and 3.

[0073] Twice daily (morning and afternoon), animals were observed for mortality and signs of pain and distress. Cages were observed once daily for general health and appearance, paying particular attention to the eyes.

[0074] Body weight measurements were performed on the day of arrival, at animal selection, on the day of dosing administration, and weekly throughout the remainder of the study, as applicable.

[0075] Ophthalmic examinations were performed by a board-certified veterinary ophthalmologist prior to dosing and on study days 4, 15, 28, and 91. At each time point, an external examination was performed using a slit-lamp biomicroscope to examine the adnexa and anterior aspect of each eye. In addition, the eyes were dilated with mydriatics, and the fundus of each eye was examined with an indirect ophthalmoscope.

[0076] The following samples were collected for analysis.

[0077] Blood and plasma: At 24, 72 and 168 hours after dosing and on study days 15, 29, 61 and 91, two animals / time point were euthanized with an overdose of sodium pentobarbital and blood (approximately 5 mL) was collected by cardiac puncture into tubes containing K2EDTA. The samples were kept on wet ice until centrifugation to obtain plasma. All plasma samples were placed on dry ice and then stored at approximately -70°C until analysis. The cell fraction was discarded. Additional blood was collected and discarded to facilitate the collection of ocular tissue.

[0078] Ocular tissue: At the time of sacrifice, both eyes were immediately removed. Aqueous humor was collected and each eye was snap frozen in liquid nitrogen for 15-20 seconds and then placed on dry ice for at least 2 hours (bias). Within approximately one day, aqueous humor, retina, sclera / choroid (including retinal pigment epithelium), and vitreous humor tissue were collected. Ocular tissue was rinsed with saline and blotted appropriately, weighed, and placed on dry ice until stored at approximately -70°C until analysis. Remaining carcasses and remaining ocular tissue were discarded.

[0079] Plasma and ocular tissue CLS-AX concentrations were analyzed using liquid chromatography / mass spectrometry.

[0080] The values ​​from instruments such as balances are reported as generated (or recorded) by each instrument. Unless otherwise stated, the calculated values ​​of the mean and standard deviation are reported as three significant figures. Statistical analysis is limited to descriptive statistics, such as mean and standard deviation. Since the data are generated by a computer and are appropriately rounded to be included in the report, in some cases, using the reported values ​​to calculate subsequent parameters will produce slight differences from the parameters listed in the table. The dose table is edited with the values ​​calculated using Excel version 14.0 (Microsoft Corporation). If applicable, for each animal, the maximum concentration (C max ) and the time to reach maximum concentration (T max The pharmacokinetic parameters calculated include half-life (t 1 / 2 ), the area under the concentration-time curve from time 0 to the last measurable time point (AUC 0-t ) and the area under the concentration-time curve from 0 to infinity (AUC 0-∞ Pharmacokinetic parameters were calculated using Phoenix Winnonlin version 6.2.1 (Pharsight Corporation).

[0081] All animals appeared clinically healthy throughout the acclimation process and were released from acclimation and approved for research. Suprachoroidal administration of CLS-AX had no deleterious effects on body weight during the study period.

[0082] Sporadic instances of low food consumption were observed throughout the study. The infrequency of these observations is considered normal for species in laboratory settings.

[0083] Results. All animals had no ophthalmic findings before the test article was administered. CLS-AX was well tolerated when administered suprachoroidally at 4 mg / eye (100 μL / injection) on the 91st day of the study. Once the initial conjunctival reaction to the injection subsided, subconjunctival white patches that may represent the test article were usually observed at subsequent time intervals. The observed white patches were consistent with the above-mentioned administration observations, indicating that the patches may enter the subconjunctival space from a small reflux of CLS-AX after administration. On the 15th day of the study and thereafter, clear subconjunctival channels filled with clear fluid were also observed in some eyes near the injection site. Although the exact nature of these channels is unclear, they may represent congested water veins or lymphoid vessels. On the 91st day of the dosing phase, RPE pigment spots were observed in one eye, indicating that the tissue was disturbed by injection or the test article.

[0084] White deposits were observed during tissue collection. White deposits were observed on the outside of the eye for up to 61 days after dosing and could be removed with the bulbar conjunctiva. However, on day 91 of the study, once the conjunctiva was removed, attempts were made to remove white deposits adhering to the sclera. These attempts were unsuccessful, indicating that the deposits were located under the sclera. The appearance of the deposits may be more obvious because the white test article is located between the translucent sclera and the darkly pigmented choroid. These white deposits were not seen when examining the fundus, indicating that the deposits are most likely CLS-AX located in the suprachoroidal space, which can be observed during external examination of the eye.

[0085] After multiple injections, a small amount of test material may have remained in the subconjunctiva or sclera when the needle was withdrawn. The regurgitated material may have appeared to the examiner as a subconjunctival white patch. Consistent with post-dose observations and examination results, white deposits were observed during tissue collection. White deposits were observed on the outside of the eye up to 61 days after dosing and could be removed with the bulbar conjunctiva until study day 91, indicating that the deposit was located on part of the choroid.

[0086] Figure 1A The results of the 4 mg / eye study are presented graphically. The results of the pharmacokinetic analysis are shown in Table 2. Figure 1B Results from studies at 0.1 mg / eye or 0.03 mg / eye are presented graphically.

[0087] Following a single bilateral suprachoroidal administration of CLS-AX (4 mg / eye), no quantifiable levels of the analyte were observed in either plasma or aqueous humor samples. Following administration of 4 mg / eye, CLS-AX was quantifiable at all time points in the vitreous humor, retina, and sclera / choroid-RPE (SCR). A concentration gradient of CLS-AX existed in the tissues, with the highest dose reservoir (SCR), followed by the retina, and finally the lowest concentration in the vitreous humor ( Figure 1A The extrapolated initial concentration (C0) of the dose reservoir (SCR) was 17.2 mg / g. The mean concentration of CLS-AX in the SCR increased slightly on study day 4, most likely due to inter-animal variability. The dose reservoir (SCR) concentration of CLS-AX was highest early in the study and then began to decline from study day 8 to study day 91 ( Figure 1A , upper panel). The remaining high levels of CLS-AX are consistent with the observation of subscleral white patches, suggesting that these patches are a reservoir of residual dose. The elimination half-life (t 1 / 2 ) was 102 days; more than 60% of CLS-AX remained in the SCR at 3 months after injection ( Figure 1A, top). The level of CLS-AX in the retina is 100,000-fold higher than the IC50 of axitinib for its receptors (VEGFr and PDGFr) ( Figure 1A , lower panel). Observed exposure of the dose reservoir (AUC 0-t ) value is 1260μg*day / g.

[0088] Although CLS-AX was administered as a suspension with limited solubility in aqueous solvents, CLS-AX was present in the retina and vitreous humor immediately 24 hours after administration, indicating that the test article was released suddenly into the tissue after administration. CLS-AX levels in the retina and vitreous humor increased over time, reaching maximum mean concentrations of 325 μg / g and 0.857 μg / mL, respectively (C max On the fourth day of the study (T max ), reaching C in the vitreous humor max Levels then decreased, although with some variability. Mean concentrations in the retina were similar from study day 2 until study day 15, then increased approximately 3-fold by study day 29. On study day 91, retinal concentrations of CLS-AX were similar to those of CLS-AX. max The CLS-AX (AUC 0-t ) exposure was consistent with a concentration gradient between the two tissues. Retinal concentrations of CLS-AX remained above 44 μg / g throughout the study.

[0089] The individual concentrations of CLS-AX in plasma, aqueous humor, retina, sclera / choroid-RPE (SCR), and vitreous humor are presented in Table 2. The concentration of CLS-AX was determined using a liquid chromatography coupled with tandem mass spectrometry (LC-MS / MS) method. Sample analysis was performed using a validated method. Software (version 1.6.2) captured LC-MS / MS data and integrated peak areas. Watson LIMS software (version 7.4.1) was used for data storage, management and reporting.

[0090] As mentioned above, the concentrations of CLS-AX in all plasma samples and aqueous humor samples were below the limit of quantification (BLQ). In retinal samples, the concentrations of CLS-AX ranged from 2750 ng / mL to 60,100 ng / mL homogenate and from 44,500 ng / g to 1,220,000 ng / g tissue. In SCR, the concentrations of CLS-AX ranged from 1,870,000 ng / mL to 3,360,000 ng / mL homogenate and from 9,790,000 ng / g to 24,400,000 ng / g tissue. In vitreous humor, the concentrations of CLS-AX ranged from 60 ng / mL to 6,030 ng / mL.

[0091] In summary, following suprachoroidal administration of CLS-AX (4 mg / eye), no quantifiable levels of the analyte (LOQ = 1 ng / mL) were observed in either plasma or aqueous humor samples throughout the study period. However, CLS-AX was quantifiable at all time points in the vitreous humor, retina, and sclera / choroid-RPE (SCR).

[0092] In the second study, both doses of CLS-AX were detectable in the retina and choroid-RPE / sclera at levels well above the IC50 ( Figure 1B The concentrations detected in the vitreous were significantly lower than those detected in the posterior tissues, and CLS-AX was no longer detected in the vitreous by day 14 ( Figure 1B ).

[0093] Additional data from the second study are provided below and in Table 1C. For both doses, mean axitinib concentrations in the SCR, retina, and vitreous humor reached maximum values ​​on Day 1. Elimination t values ​​of 257 and 379 hours were calculated for the 0.03 and 0.1 mg / eye SCR drug depots, respectively. 1 / 2 The average C value of 0.1 mg / eye max and AUC 0-∞ The values ​​were approximately 6 and 7 times higher than the parameter of 0.03 mg / eye, respectively.

[0094] After bilateral suprachoroidal administration, mean axitinib retinal concentrations were significantly higher on study day 2 (t max = 24 hours after administration) reached 4480 and 6260 ng / g C max After study day 2, the mean retinal concentration in the lower dose group dropped dramatically and was essentially below the limit of quantification (16.7 ng / g) by day 15, with only 1 of 4 eyes having quantifiable levels of axitinib on days 31 and 61. The mean retinal concentration in the higher dose group also dropped dramatically after 24 hours post-dose, and only 1 of 4 eyes had quantifiable levels on days 45 to 66. The higher dose mean C max and AUC 0-t The values ​​were 1.4- and 1.6-fold higher than the lower dose parameters, respectively. These concentrations and exposures were less than dose proportional.

[0095] After day 2, mean vitreous humor concentrations were quantifiable in only a few eyes in each group on day 8. The mean vitreous humor C max The values ​​were very similar, indicating that CLS-AX does not readily partition into the vitreous humor, independent of dose level.

[0096] Table 1D. Pharmacokinetic parameters of axitinib in rabbits, administered by SCS injection, with CLS-AX doses of 0.03 mg / eye or 0.1 mg / eye

[0097]

[0098]

[0099] In summary, the results of the study showed that a single bilateral administration of CLS-AX suspension to the suprachoroidal space was well tolerated at all doses tested (4 mg / eye, 0.1 mg / eye, 0.03 mg / eye), and exhibited good ocular distribution and pharmacokinetics for long-lasting treatment of posterior ocular diseases. Minimal or no systemic exposure, minimal anterior segment exposure, high absorption in the posterior segment, and a much longer half-life than expected were achieved. The longer half-life reduces or eliminates the need for repeated injections of axitinib. The problem of effective drug administration to the posterior segment of the eye without the harmful side effects of repeated injections or side effects associated with systemic exposure has always been a difficult problem for those skilled in the art to solve. An unexpected improvement in the method of treating posterior ocular diseases is provided by the SCS delivery of axitinib drug formulations for treating posterior ocular diseases disclosed in the present application and stated in the claims.

[0100] Table 2: Mean pharmacokinetic parameters of retina, sclera / choroid-RPE and vitreous humor in male Dutch-band rabbits treated with axitinib (4 mg / eye) via suprachoroidal injection

[0101]

[0102] NC Not calculated.

[0103] RPE Retinal pigment epithelium.

[0104] aThe calculated half-life value should be interpreted with caution as it is calculated for less than two half-lives.

[0105] Example 3. Rat laser-induced choroidal neovascularization model

[0106] The aim of this study was to determine the potential efficacy of suprachoroidal injection of CLS-AX using a modified microneedle / SCS microinjector in a laser-induced choroidal neovascularization model in brown Norway rats.

[0107] On day 1, mydriatic drops were applied to both eyes before choroidal neovascularization, and the animals were anesthetized before starting the following surgery. A 4-point pattern was formed between the major retinal vessels around the optic disc of each eye. Laser parameters were adjusted as needed to ensure rupture of Bruch's membrane. Thereafter, under anesthesia, a 100 μL Hamilton syringe equipped with a modified Clearside microneedle (No. 33, <400 μm) was used to apply control articles (sodium chloride for injection, United States Pharmacopeia [USP]) or CLS-AX (lot number 50311-1, 40 mg / mL) to both eyes of the male rat group (10 / group) by freehand bilateral suprachoroidal injection. The drug was administered at a dose of 0 or 0.4 mg / eye / dose (0.2 mg / eye was administered per administration) on days 1 and 8, respectively. The target dose volume for each animal was 5 μL / eye / injection.

[0108] Parameters assessed during the study included mortality, clinical signs, body weight, food consumption, ophthalmology (indirect ophthalmoscopy and slit-lamp biomicroscopy) before the study and on day 1 after dosing; and fluorescein angiography (FA) before the study and on days 7 (pre-dose), 14, and 21. Fluorescein angiography is a technique used to assess vascular leakage in ocular neovascular lesions. Leakage at each laser spot on static images was semiquantitatively assessed by 2 independent readers on a scale of 0 to IV, and a consensus score was subsequently determined. The scale is as follows: Figure 2A Animals were sacrificed on day 22, and eyes and optic nerves were collected and preserved in Davidson's fixative.

[0109] The study design is shown in Table 3.

[0110] Table 3: Study design of laser-induced choroidal neovascularization in rats

[0111]

[0112]

[0113] Abbreviations: USP = United States Pharmacopeia; a Group 1 was dosed on days 1 and 8. b Group 2 was administered with 0.2 mg / eye each time on day 1 and day 8.

[0114] There were no deaths and no treatment-related clinical signs or effects on body weight, weight gain, or food consumption. Mild iatrogenic trauma to the retina was caused by the forces applied during the injections, but no clinically important ocular complications were observed immediately after the first injection.

[0115] Administration of CLS-AX using microneedles resulted in successful suprachoroidal and / or subretinal injections of CLS-AX in the majority of animals, although assessment of post-injection results in the control group was complicated by the transparency of the control article. On ophthalmic examination, CLS-AX appeared white, and in Group 2, a total of 11 / 20 eyes had white test article in the SCS and 9 / 20 eyes had subretinal test article as documented by indirect ophthalmoscopy. In 4 eyes, CLS-AX was observed in both the subretinal and suprachoroidal spaces. In 5 / 20 eyes, the test article could be observed near the needle tip and appeared to have been injected subscleratally or suprachoroidally, but in these eyes, funduscopy was likely negative for the test article. The exact localization of CLS-AX in these eyes remains uncertain but is unlikely to be subconjunctival because the conjunctiva was not elevated during injection.

[0116] Reflux was minimal in most eyes and was similar in the reference and CLS-AX groups. Significant reflux was observed in six eyes in the reference group and 10 eyes in the CLS-AX group. The higher incidence in the CLS-AX group may be due to easier visualization of CLS-AX due to its white color. The reflux observed in this study may be due to the difficulty of freehand injection in rats and is not expected to occur when CLS-AX is administered to humans using a microinjector.

[0117] Control animals showed no overall decrease in leakage from day 7 to day 21, except for 2 eyes out of 20, from 2 different animals. This ratio is typical for the laser-induced choroidal neovascularization model in rats, indicating that the model is performing as expected. A reduction in the incidence of clinically important lesions assessed using FA (score of 3 or 4) was observed in rats administered CLS-AX, with 8 of 20 eyes showing improvement (score of 0 to 2). Comparison of the mean scores of the control group to the treated eyes indicated that CLS-AX-treated animals had statistically significantly lower scores at day 21, supporting the activity of CLS-AX in the model. In addition, the percentage of grade IV lesions on day 21 was significantly lower in the CLS-AX group compared to the control group (63.8% and 88.8%, respectively; Figure 2B ). Medication-induced reflux does not appear to be associated with a reduction in benefit from CLS-AX treatment.

[0118] This study demonstrated that CLS-AX administered once weekly by suprachoroidal injection at 0.4 mg / eye / dose for 2 weeks was well tolerated in rats and resulted in a significant reduction in clinically important lesions at day 21 compared to control rats treated with saline.

[0119] Example 4. Pig laser-induced choroidal neovascularization model

[0120] The aim of this study was to evaluate the effect of a single SC injection of CLS-AX on choroidal neovascularization in a porcine laser-induced choroidal neovascularization model, which is a model of human posterior segment neovascular diseases such as nAMD that occur in the choroid.

[0121] The potential efficacy of a single SC injection of CLS-AX was evaluated in eight male weaned piglets. Mydriatic drops were applied to both eyes on day 1, and the animals were anesthetized before choroidal neovascular surgery. Diode laser energy was delivered via a laser indirect headset to create six uniform white laser lesions around the optic nerve in each eye. Immediately after laser treatment, a control article (balanced salt solution [BSS]) was administered to the left eye at a dose volume of 100 μL / eye by freehand SC injection using a syringe equipped with a microneedle (30 gauge, <400 μm), and CLS-AX was administered to the right eye at a dose of 4 mg (concentration 40 mg / mL).

[0122] Parameters assessed over the life of the study included fundus photography and FA immediately after treatment and at 1 and 2 weeks after treatment. Pigs were euthanized 2 weeks after treatment, eyes were removed and retinal flat mounts were processed. Isolectin IB4 staining (a technique used to assess neovascularization) was performed to quantify newly formed blood vessels in retinal flat mounts.

[0123] The experimental design is provided in Table 4.

[0124] Table 4: Study design of porcine laser-induced choroidal neovascularization

[0125]

[0126] Abbreviations: BSS = balanced salt solution; OD = right eye; OS = left eye; OU = both eyes

[0127] Laser-induced retinopathy was readily observed by fundus photography and FA. All lesions became less white and more distinct over time, but there were no significant differences between eyes that received BSS (OS [left eye]) or CLS-AX (OD [right eye]) immediately after laser treatment and at 1 and 2 weeks after laser treatment. On FA, at 1 and 2 weeks after laser treatment, the fluorescent area in eyes treated with CLS-AX was reduced by a mean of 10.5% (P = 0.009) and 16.0% (P = 0.0015), respectively, compared with control eyes given BSS ( Figure 3A ), indicating that treatment with CLS-AX significantly reduced vascular leakage and new blood vessel growth at the site of retinal laser injury. Figure 3B Representative images of BSS-treated eyes and CLS-AX-treated eyes are provided.

[0128] Quantification of newly formed blood vessels (measured by lectin IB4 signal, a marker of newly formed vasculature) performed on retinal flat mounts showed an 18% reduction in lectin IB4 signal area in eyes treated with CLS-AX relative to eyes treated with BSS (representative sample; Figure 4A ; Quantification of average IB4 signal, Figure 4B ). These data indicate that CLS-AX treatment significantly inhibited neovascularization relative to control eyes administered BSS (P=0.0297).

[0129] Thus, a single SCS injection of CLS-AX at a dose of 4 mg / eye significantly reduced vascular leakage (as evidenced by a reduction in fluorescein signal) and new vessel growth (as assessed by a reduction in lectin IB4 signal) at the site of laser injury in the porcine retina compared to control treatment with BSS.

[0130] In summary, the pharmacokinetic and pharmacodynamic data provided herein show that CLS-AX is generally well tolerated in rats, rabbits and pigs after SCS administration, with no obvious signs of toxicity. Throughout the PK study, sustained and high exposure of axitinib was observed in ocular tissues, with the highest levels in the sclera / choroid / RPE, followed by the retina and then the vitreous. No quantifiable axitinib was detected in either plasma or aqueous humor. In rats, CLS-AX reduced the incidence of clinically important neovascular lesions (scores of 3 or 4) compared with the control group, with 8 / 20 eyes (40%) showing overall improvement and reduced clinically important lesions on day 21. In pigs, CLS-AX significantly reduced fluorescein leakage (105% and 16% at week 1) and the growth of new blood vessels (18%) at retinal laser injury sites compared with saline treatment. Therefore, it is an effective anti-angiogenesis / anti-neovascularization treatment for nAMD and is very effective when non-surgically applied to the SCS of the eye. CLS-AX has the potential as a treatment for nAMD, eg, a two-year treatment, due to its pan-VEGF inhibition through receptor blockade as well as pharmacodynamic effects, extended duration, ability to directly target affected tissue layers, and high potency as revealed in the studies provided herein.

[0131] Example 5. Clinical study

[0132] A Phase 1 / 2a clinical study will be conducted to evaluate the safety and efficacy of non-surgical administration of axitinib to the suprachoroidal space of the eye of patients with nAMD. In part, the dose to be tested is consistent with the data obtained in the pharmacodynamic study disclosed herein.

[0133] Neovascular age-related macular degeneration (nAMD) is the leading cause of irreversible central blindness in developed countries (Santarelli, 2015). Although the pathogenesis of AMD is complex and still not fully understood, many of the mechanisms involved are partially known and, particularly for the 10%-15% of AMD classified as wet (nAMD), include the vascular endothelial growth factor (VEGF) signaling pathway. In nAMD, abnormal blood vessel growth, choroidal neovascularization (CNV) in the choroidal vascular layer just below the Bruch's membrane of the retina and macula causes blood, lipids, and serum to leak into the retinal layers and causes the macula to bulge or bulge from its normal position, distorting or destroying central vision. In nAMD, VEGF-A, which acts on VEGF receptors 1 and 2 (VEGFR-1, VEGFR-2), has been shown to promote abnormal blood vessel growth and is therefore the best target for treatment. Currently, anti-VEGF drugs are the standard of care for this disease; however, there is still a significant unmet need to significantly improve and maintain vision in most patients (Martin, 2012). Furthermore, the current treatment paradigm of frequent intravitreal injections is cumbersome; for example, a recent “real-world” retrospective study of nearly 50,000 eyes with wet AMD demonstrated that patients were undertreated with an average of only 7.3 injections, resulting in only a 1-letter gain at 1 year (Ciulla, 2019).

[0134] Primary endpoint: To evaluate the safety and tolerability of CLS-AX in subjects with neovascular age-related macular degeneration who demonstrated stable visual acuity (no loss) after ≥3 injections of intravitreal anti-VEGF therapy in the past 5 months.

[0135] Secondary endpoints: To evaluate and compare the effects of the 3 CLS-AX treatment regimens on visual function and anatomy within 3 months and the need for additional intravitreal aflibercept treatment.

[0136] Study Design: This is a Phase 1 / 2a open-label, dose-escalation study to evaluate the safety and tolerability of a single dose of CLS-AX administered suprachoroidally in subjects with nAMD after at least 3 prior treatments with intravitreal (IVT) anti-VEGF agents (the last to be administered at the Screening Visit). The study design includes 3 dose groups with 5 subjects in each group. Subject eligibility will be determined at Screening Visit 1 (Day -28±3). Eligible subjects will receive an IVT injection of aflibercept, 2 mg (0.05 mL) at Screening Visit 1 (Day -28±3), followed by a suprachoroidal injection of CLS-AX at Baseline Visit 2 (Day 0). Subjects will return for safety and tolerability assessments, visual function and ocular anatomy assessments, and the need for additional treatment at Visits 3, 4, and 5 (Weeks 4, 8, and 12) (Follow-up Period). In addition, additional treatment will be administered at Visits 3 and 4 (Weeks 4 and 8) based on PRN criteria and will consist of aflibercept (2 mg (0.05 mL)) administered by IVT injection unless additional treatment is medically necessary. All subjects will be followed until Visit 5 (Week 12, study exit) regardless of whether additional treatment is administered. The 3 dose groups will include the following:

[0137] Group 1 (lowest dose group): suprachoroidal injection of 0.03 mg of CLS-AX

[0138] Group 2 (medium-dose group): suprachoroidal injection of 0.06 mg of CLS-AX

[0139] ● Group 3 (high-dose group): suprachoroidal injection of 0.10 mg of CLS-AX

[0140] All groups will be evaluated for safety and tolerability as well as effects on visual function and anatomy as described in the timing and event schedule.

[0141] Number of subjects (planned): Approximately 15.

[0142] Inclusion Criteria: Subjects were eligible to participate in this study if they met all of the following criteria at the Screening Visit (Visit 1) and Baseline Visit (Visit 2):

[0143] 1. To study the diagnosis of neovascular age-related macular degeneration in the eye

[0144] 2. Active subfoveal choroidal neovascularization (CNV) secondary to any lesion type in the study eye, as shown by photographs and / or fluorescein angiography (FA) and / or spectral domain optical coherence tomography (SD-OCD): a. Total lesion area (including blood, neovascularization, and scarring / atrophy) ≤ 30 mm 2, b. The area of ​​the CNV component is ≥ 50% of the total lesion area, and c. The CNV must not be associated with subfoveal hemorrhage, subfoveal fibrosis, or subfoveal atrophy.

[0145] 3. At Screening, based on the Investigator's opinion, two or more anti-VEGF therapies (aflibercept, ranibizumab, bevacizumab, brucelluzumab) within 4 months prior to Screening (Visit 1), with the last treatment administered at least 4 weeks prior to Screening (Visit 1), to obtain neovascular AMD in the study eye with a meaningful response, such as improvement in visual acuity and / or exudates.

[0146] 4. Early Treatment Diabetic Retinopathy Study (ETDRS) best corrected visual acuity (BCVA) score of ≥20 letters reading (20 / 400 Snellen equivalent) and ≤75 letters reading (20 / 32 Snellen equivalent) in the study eye, with a BCVA change of less than 5 letters between Visit 1 and Visit 2 (screening and baseline)

[0147] 5. Understand the language of the informed consent form; be willing and able to provide written informed consent prior to any study procedures; be willing to follow instructions and attend all scheduled study visits

[0148] 6. At least 50 years old

[0149] Ophthalmological Exclusion Criteria: If a subject meets any of the following criteria, she / he is not eligible to participate in this study:

[0150] 1. Any atrophy or fibrosis in the fovea of ​​the study eye assessed by spectral domain optical coherence tomography

[0151] 2. There is significant media opacity in the studied eye, making it impossible to evaluate the retina and vitreous

[0152] 3. Macular edema or CNV in the study eye with etiology other than AMD; any active ocular disease or infection in the study eye other than AMD; CNV in the study eye, any of the following on photographs and / or FA and / or SD-OCT: a. Total lesion area (including CNV, hemorrhage, fibrosis, atrophy) > 30 mm2, b. CNV component area < 50% of the total lesion area, c. Subfoveal hemorrhage, subfoveal fibrosis or subfoveal atrophy, d. Retinal pigment epithelial tear, retinal angiomatous proliferation (RAP)

[0153] 4. Previous treatment for CNV in the study eye other than IVT injection of aflibercept, ranibizumab, bevacizumab, or brucelluzumab.

[0154] 5. Intraocular pressure ≥25 mmHg in the study eye or uncontrolled glaucoma (open angle or closed angle) at visit 1; subjects are not excluded if intraocular pressure (IOP) in the study eye is <25 mmHg and not on more than 1 IOP-lowering medication; or cup-to-disc ratio >0.8

[0155] 6. Any history of vitreoretinal surgery (examples include but are not limited to scleral buckling, pars plana vitrectomy, removal of a detached nuclear or intraocular lens) or panretinal or macular laser photocoagulation in the study eye; intravitreal injections are acceptable; previous cataract extraction, yttrium aluminum garnet laser capsulotomy are allowed but not within 3 months of screening (Visit 1)

[0156] 7. Ciliary body destructive surgery or filtering surgery in the study eye within 3 months before Visit 1

[0157] 8. High myopia in the study eye is defined as spherical equivalent > -6 diopters or axial length ≥ 26 mm. If there is a history of high myopia, if it is pseudophakia

[0158] 9. Photocoagulation or cryotherapy has been performed in the study eye within 6 months before the first visit

[0159] 10. Any topical ocular corticosteroids within 10 days prior to treatment at Visit 2 (Day 0) in the study eye; any intraocular or periocular corticosteroid injection

[0160] 11. Concomitant treatment with any drug that may be toxic to the lens, retina, or optic nerve

[0161] 12. Currently receiving anti-VEGF therapy in the fellow eye at screening, or expected to receive anti-VEGF therapy in the fellow eye during the study.

[0162] General Exclusion Criteria: If a subject meets any of the following criteria, she / he is not eligible to participate in this study:

[0163] 12. Female subjects who are pregnant, breastfeeding, or planning to become pregnant. Females of childbearing potential must agree to undergo a pregnancy test at screening and agree to use an acceptable method of contraception during participation in this study. Acceptable methods of contraception include double-barrier methods (condoms with spermicide or diaphragms with spermicide), hormonal methods (oral contraceptives, implantable contraceptives, transdermal contraceptives, or injectable contraceptives), or intrauterine contraceptive devices with a documented annual failure rate of less than 1%. Abstinence may be considered an acceptable method of contraception at the discretion of the investigator, but if the subject becomes sexually active, she must agree to use one of the acceptable methods of contraception.

[0164] 13. Any uncontrolled systemic illness (e.g., unstable medical condition, including uncontrolled elevated blood pressure, cardiovascular disease, and glycemic control) that the investigator believes may preclude participation in the study or place the subject at risk due to study treatment or procedures

[0165] 14. Taking systemic corticosteroids at a dose greater than 20 mg / day for oral prednisone (or equivalent for other corticosteroids) within 2 weeks prior to Visit 2; subjects taking 20 mg or less per day may be enrolled if the dose is not expected to increase during the study

[0166] 15. May require hospitalization or surgery during the study period, including planned elective surgery or hospitalization that cannot be postponed

[0167] 16. Hypersensitivity to any component of CLS-AX, fluorescein, or local anesthetics

[0168] 17. Currently participating in a study of a study drug or device, or using a study drug or device within 30 days after the first visit

[0169] Investigational Product, Dose, and Administration: CLS-AX, axitinib injectable suspension, administered into the suprachoroidal space at doses of 0.03 mg, 0.06 mg, and 0.10 mg in 100 μL with an SCS microinjector

[0170] Evaluation criteria included the incidence of treatment-emergent adverse events (TEAEs) and serious adverse events grouped by organ system, relevance to study treatment, and severity (primary); and the incidence / descriptive statistics of changes in ocular safety parameters, number of additional aflibercept treatments after CLS-AX administration, mean change from baseline in central subdomain thickness, mean change from baseline in ETDRS BCVA letter score, and systemic and ocular outcomes (secondary).

[0171] All subjects will receive a 2 mg (0.05 mL) IVT injection of aflibercept at Screening (Visit 1), followed by a single suprachoroidal dose of CLS-AX at Baseline (Visit 2). Safety assessments will be reviewed at Week 4 Visit (Visit 3), Week 8 Visit (Visit 4), and Week 12 Visit (Visit 5) following SC injection of CLS-AX. Subjects will be evaluated for additional treatment at Visits 3, 4, and 5 (Weeks 4, 8, and 12). Additional treatments will be administered at Visits 3 and 4 (Weeks 4 and 8), including IVT injections of 2 mg (0.05 mL) of aflibercept based on the "Additional Criteria of Treatment" provided below (unless other treatment is medically indicated).

[0172] The following procedures must be performed prior to SC CLS-AX injection (on the day of injection): assessment of adverse events, review of changes in concomitant medications, resting heart rate and blood pressure measurements, collection of blood for PK analysis, collection of urine for pregnancy testing in females of childbearing age, and ophthalmologic evaluation of the study eye. Ophthalmologic evaluation includes ETDRS BCVA, slit-lamp biomicroscopy (including dilated lens grading), intraocular pressure (IOP) measurement in both eyes, dilated indirect ophthalmoscopy, SD-OCT, and OCT-A. The following photographic evaluations will be performed: fluorescein angiography and fundus photography.

[0173] Eligible subjects will receive a suprachoroidal injection of 100 μL of CLS-AX. The following assessments will be performed after suprachoroidal injection: assessment of adverse events, review of changes in concomitant medications, resting heart rate (5 minutes at rest) and blood pressure measurements at least 30 minutes after injection, 12-lead electrocardiogram at least 30 minutes after injection, blood collection approximately 60 minutes after injection for pharmacokinetic analysis, and ophthalmologic evaluation. Ophthalmologic evaluation will include: indirect ophthalmoscopy, slit-lamp biomicroscopy immediately after injection, and assessment of IOP 10 to 30 minutes after injection. If IOP remains elevated, subjects must remain at the study center until IOP is controlled according to the best medical judgment of the investigator. Subjects may leave the clinic if IOP is <30 mmHg. On non-dosing visit days, the investigator will contact the subject and assess adverse events and review changes in concomitant medications.

[0174] At Visits 3 (Week 4) and 4 (Week 8), and 5 (Week 12), the following procedures will be performed: assessment of adverse events, review of changes in concomitant medications, resting heart rate and blood pressure measurements, 12-lead electrocardiogram, blood collection for PK analysis, blood and urine samples for central laboratory testing prior to fluorescein angiography, and ophthalmologic evaluation of the study eye. Ophthalmologic evaluation will include ETDRS BCVA, slit-lamp biomicroscopy (including dilated lens grading), intraocular pressure (IOP) measurement in both eyes, dilated indirect ophthalmoscopy, SD-OCT, and OCT-A. The following photographic evaluations will be performed: fluorescein angiography and fundus photography. Subjects will be assessed for the need for additional treatment with aflibercept.

[0175] IVT aflibercept will be administered if the following predefined criteria are met (“Additional Treatment Criteria”). Following administration, the following assessments will be performed: assessment of adverse events, review of changes in concomitant medications, and ophthalmologic evaluation of the study eye. Ophthalmologic evaluation will include: evaluation of the study eye by indirect ophthalmoscopy immediately after injection, slit lamp biomicroscopy, and assessment of IOP 10 to 30 minutes after injection. If IOP remains elevated, the subject must remain at the study center until the IOP is controlled according to the best medical judgment of the investigator. If IOP is <30 mmHg, the subject may leave the clinic.

[0176] Study Drug Description: Treatment for each group consists of a single unilateral injection of IVT aflibercept in the study eye at Visit 1 (screening; Days -14 to -1) and a single unilateral suprachoroidal injection of 100 μL (dosing levels of 0.03 mg, 0.06 mg, or 0.10 mg) of CLS-AX at Visit 2 (Day 0). Subjects will be evaluated for additional treatment at Visits 3, 4, and 5 (Weeks 4, 8, and 12). Additional treatment will be administered according to the PRN criteria below ("Additional Treatment Criteria") and will consist of 2 mg IVT aflibercept unless other treatment is medically indicated.

[0177] Enrollment in the next higher dose group will be based on the SMC's recommendation after review of safety data. Five subjects will be enrolled in each group.

[0178] Additional Treatment Criteria: At Visits 3, 4, and 5 (Weeks 4, 8, and 12), subjects will be evaluated for the need for additional treatment for neovascular AMD based on the following criteria. IVT aflibercept (2 mg (0.05 mL)) will be administered if any of the following criteria are met in the study eye at Visits 3 (Week 4) and 4 (Week 8):

[0179] ●A loss of 10 or more letters in BCVA compared to the best prior study-assessed BCVA in the study eye due to intraretinal or subretinal fluid observed by the investigator, or

[0180] ●Increase in central subfield retinal thickness greater than 75 microns compared with baseline (Visit 2) in the study eye, or

[0181] The presence of sight-threatening hemorrhages due to AMD in the study eye.

[0182] Additional treatment was IVT aflibercept 2 mg unless other treatment was medically necessary; even if additional treatment was given, subjects would be followed until the end of the study.

[0183] Axitinib systemic blood concentrations will be collected by venipuncture from consenting subjects by qualified investigators and used to estimate standard population PK parameters. One blood sample will be obtained from each subject at the following time points: Visit 2 before dosing (Day 0), Visit 2 approximately 60 minutes after dosing (Day 0), and Visits 3 and 5 (Weeks 4 and 12).

[0184] Best corrected visual acuity (BCVA) will be assessed by ETDRS using standardized lighting and standardized channels. Results should be reported as the number of letters read. Vision testing should precede any examination requiring contact with the eye. In order to provide standardized and well-controlled assessments of BCVA during the study, all BCVA assessments must be performed by trained personnel certified in study procedures using certified VA equipment / channels.

[0185] Retinal thickness and disease characteristics will be assessed by spectral domain optical coherence tomography (SD-OCT). SD-OCT instruments and technicians must be certified prior to screening any subject. Technicians are encouraged to use the same certified equipment throughout a subject's study participation. All images should be taken by the same technician on each subject at each study center whenever possible. Images will be sent to a central reading center for analysis and interpretation.

[0186] Choroidal neovascular membranes will be classified and subsequent structural changes after suprachoroidal injections will be assessed by optical coherence tomography angiography (OCT-A). The OCT-A instrument and technician must be certified prior to screening any subject. Technicians are encouraged to use the same certified equipment throughout a subject's study participation. All images should be taken by the same technician on each subject at each study center whenever possible.

[0187] Intraocular pressure (IOP) will be measured by applanation tonometer and the results will be recorded in mmHg. A Goldmann applanation tonometer should be used at all visits if possible. Tonopens can be used for post-injection pressure checks and in cases where a Goldmann is not available. Technicians are encouraged to use the same tonometric method throughout the subject's study participation. At baseline, when suprachoroidal CLS-AX is administered, IOP will be measured 2 times: before suprachoroidal CLS-AX injection and after suprachoroidal CLS-AX injection. During the study, the accuracy of the tonometer must be calibrated according to the manufacturer's instructions before the first subject screening at that site and until the last subject withdraws from the study at that site.

[0188] Slit-lamp biomicroscopy (including magnification) will be performed according to standard clinical practice. This procedure should be performed in the same manner for all subjects and will include an assessment of the normal or abnormal appearance of the following: eyelids, sclera and conjunctiva, cornea, anterior chamber, iris, and lens. All abnormal findings will be described. Slit-lamp examination of the iris is performed to exclude neovascularization of the iris (NVI).

[0189] Cataract lens grading: If an abnormal cataract is found during slit lamp examination, the cataract should be graded for nuclear opacity, cortical opacities, and posterior subcapsular opacities. The grader must verify training on the grading procedure. Cataract classification will be based on the Lens Opacity Classification System III (LOCS III) grading scale (Chylack, 1993).

[0190] Indirect ophthalmoscopy should be performed according to the investigator's standard procedure. This procedure should be the same for all subjects seen at the investigator's center. The fundus should be thoroughly examined and the following variables assessed as normal or abnormal (including but not limited to): vitreous, retina, choroid and optic nerve / disk, vascular appearance and absence of neovascularization.

[0191] Fluorescein angiography will be performed for anatomical assessment and will include areas of fluorescein leakage, areas of capillary nonperfusion, presence of retinal vascular and optic nerve head staining, and retinal pigment epithelial abnormalities. The digital device will be registered and the photographer certified for imaging procedures. De-identified images will be uploaded to a central reading center.

[0192] Color fundus photographs will be obtained. It is recommended that fundus photographs be taken prior to fluorescein angiography. All photographs should be taken by the same photographer on all subjects at each study center whenever possible. The digital device will be registered and the photographer certified for the imaging procedure. De-identified images will be uploaded to a central reading center.

[0193] Statistical methods: This is an open-label, phase 1 study. Observations and changes from baseline for each group will be summarized descriptively. Categorical variables are summarized by counts and percentages, and continuous variables are summarized by descriptive statistics (n, mean, standard deviation, standard error, median, minimum, and maximum). Baseline was defined as the last assessment before administration of CLS-AX.

[0194] Dose escalation criteria: All subjects will receive IVT aflibercept at screening (Visit 1) followed by suprachoroidal administration of CLS-AX at baseline (Visit 2). Safety data will be assessed at 4, 8, and 12 weeks after CLS-AX injection. Dose escalation will not proceed to the next highest dose if:

[0195] ●Serious adverse events related to treatment were reported

[0196] ● ≥2 subjects experienced non-serious treatment-related adverse events of grade 3 or higher based on the CTCAE severity grading scale

[0197] ● ≥3 subjects in the same dose group experienced a Grade 2 or higher non-serious treatment-related adverse event in the same MedDRA system organ class

[0198] ● ≥4 subjects in the same dose group experienced non-serious treatment-related adverse events of Grade 2 or higher in any MedDRA system organ class

[0199] ● BCVA decreased by 30 letters compared to pre-injection visual activity

[0200] Prolonged (>15 minutes) loss of light perception due to elevated IOP

[0201] An increase or decrease in IOP of 20 mmHg that does not return to pre-injection levels within seven days of the event

[0202] *******

[0203] References

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[0221] The full text of the publication, patent and patent application cited herein is specifically incorporated by reference. Although described invention has been described with reference to specific embodiments, it will be appreciated by those skilled in the art that, without departing from the true spirit and scope of the present invention, various changes can be made and equivalents can be replaced. In addition, in the objective spirit and scope of the present invention described, many modifications can be made to adopt specific circumstances, materials, material composition, processes, one or more process steps. All such modifications are intended to be within the scope of the attached items.

[0222] In summary, the present invention includes but is not limited to the following items:

[0223] 1. A method of treating neovascular age-related macular degeneration (nAMD), choroidal neovascularization (CNV), or nAMD associated with CNV in a human subject in need thereof, the method comprising:

[0224] An effective amount of a formulation comprising axitinib is non-surgically administered to the suprachoroidal space (SCS) of an eye of said human subject in need of treatment, wherein said effective amount comprises between about 0.01 and about 0.3 mg of axitinib.

[0225] 2. The method of claim 1, wherein the effective amount comprises between about 0.03 mg and about 0.1 mg of axitinib.

[0226] 3. The method of claim 1, wherein the effective amount comprises about 0.03 mg of axitinib.

[0227] 4. The method of claim 1, wherein the effective amount comprises about 0.06 mg of axitinib.

[0228] 5. The method of claim 1, wherein the effective amount comprises about 0.1 mg of axitinib.

[0229] 6. The method of claim 1, wherein the effective amount comprises about 0.3 mg of axitinib.

[0230] 7. A method as described in any of items 1-6, wherein the method comprises administering the axitinib to the subject at a first dose and a second dose, wherein the second dose is administered at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after the first dose.

[0231] 8. A method as described in any one of items 1-7, wherein the method further comprises administering a VEGF antagonist to the subject.

[0232] 9. The method of claim 8, wherein the VEGF antagonist is administered by intravitreal injection.

[0233] 10. The method of claim 8, wherein the VEGF antagonist is selected from the group consisting of aflibercept, bevacizumab, ranibizumab and pegaptanib sodium.

[0234] 11. A method as described in any of items 1-10, wherein the method results in a reduction in retinal thickness in the treated eye compared to the retinal thickness of the eye of the patient in need of treatment before administration of the formulation, as measured by spectral domain optical coherence tomography (SD-OCT).

[0235] 12. The method of claim 11, wherein the retinal thickness is reduced by ≥25 μm, ≥50 μm, ≥75 μm or ≥100.

[0236] 13. The method of claim 12, wherein the retinal thickness is reduced by ≥5%, ≥10% or ≥25%.

[0237] 14. The method of any one of items 1-10, wherein the method results in a reduction in retinal thickness of the eye compared to the retinal thickness of the eye of a subject not administered the formulation comprising axitinib, as measured by SD-OCT.

[0238] 15. The method of any one of items 1-10, wherein the patient does not exhibit an increase in retinal thickness in the eye within 12 weeks after administration of the formulation comprising axitinib.

[0239] 16. The method of claim 15, wherein the patient does not exhibit an increase in retinal thickness in the eye within 2, 3, 4, 5 or 6 months after administration of the formulation comprising axitinib.

[0240] 17. A method as described in any of items 1-10, wherein the patient experiences minimal vision loss compared to the patient's best corrected visual acuity (BCVA) measurement before administration of the formulation, as measured by BCVA measurement, wherein minimal vision loss is a loss of no more than 2 letters.

[0241] 18. A method as described in any of items 1-10, wherein the patient experiences minimal vision loss compared to the patient's best corrected visual acuity (BCVA) measurement before administration of the formulation, as measured by BCVA measurement, wherein minimal vision loss is a loss of no more than 5 letters.

[0242] 19. The method of any one of items 1-10, wherein the patient does not experience vision loss as measured by BCVA compared to the patient's BCVA measurement prior to administration of the formulation.

[0243] 20. The method of any one of items 1-10, wherein the patient experiences an improvement in vision as measured by an increase of ≥5 letters, ≥10 letters, or ≥15 letters in a BCVA measurement compared to the patient's BCVA prior to administration of the formulation.

[0244] 21. The method of claim 20, wherein the patient experiences an improvement in BCVA for at least 2, 3, 4, 5, or 6 months after administration of the formulation comprising axitinib.

[0245] 22. The method of any one of items 1-10, wherein the patient experiences minimal vision loss for 2, 3, 4, 5, or 6 months after administration of the formulation comprising axitinib, wherein the minimal vision loss is a loss of no more than 2 letters as measured by BCVA.

[0246] 23. The method of any one of items 1-10, wherein the patient experiences minimal vision loss for 2, 3, 4, 5 or 6 months after administration of the formulation comprising axitinib, wherein the minimal vision loss is a loss of no more than 5 letters as measured by BCVA.

[0247] 24. The method of any one of items 1-10, wherein the patient does not experience vision loss within 2, 3, 4, 5, or 6 months after administration of the formulation comprising axitinib, wherein the vision is measured by BCVA.

[0248] 25. The method of any one of items 1-24, wherein the axitinib formulation comprises about 1 mg / mL of axitinib.

[0249] 26. A method as described in any of items 1-25, wherein the axitinib formulation comprises about 0.05% polysorbate 80, about 0.5% sodium carboxymethylcellulose, about 0.79% sodium chloride, about 0.06% sodium dihydrogen phosphate and about 0.08% sodium dihydrogen phosphate.

Claims

1. A method of treating neovascular age-related macular degeneration (nAMD), choroidal neovascularization (CNV), or nAMD associated with CNV in a human subject in need thereof, the method comprising: An effective amount of a formulation comprising axitinib is non-surgically administered to the suprachoroidal space (SCS) of an eye of said human subject in need of treatment, wherein said effective amount comprises between about 0.01 and about 0.3 mg of axitinib.

2. The method of claim 1, wherein the effective amount comprises between about 0.03 mg and about 0.1 mg of axitinib.

3. The method of claim 1, wherein the effective amount comprises about 0.03 mg of axitinib.

4. The method of claim 1, wherein the effective amount comprises about 0.06 mg of axitinib.

5. The method of claim 1, wherein the effective amount comprises about 0.1 mg of axitinib.

6. The method of claim 1, wherein the effective amount comprises about 0.3 mg of axitinib.

7. The method of any one of claims 1-6, wherein the method comprises administering the axitinib to the subject at a first dose and a second dose, wherein the second dose is administered at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after the first dose.

8. The method of any one of claims 1-7, wherein the method further comprises administering a VEGF antagonist to the subject.

9. The method of claim 8, wherein the VEGF antagonist is administered by intravitreal injection.

10. The method of claim 8, wherein the VEGF antagonist is selected from the group consisting of aflibercept, bevacizumab, ranibizumab, and pegaptanib sodium.

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