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WO2024226533A1 - Méthodes de traitement de troubles oculaires avec une composition d'antagoniste de l'intégrine - Google Patents

Méthodes de traitement de troubles oculaires avec une composition d'antagoniste de l'intégrine Download PDF

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Publication number
WO2024226533A1
WO2024226533A1 PCT/US2024/025876 US2024025876W WO2024226533A1 WO 2024226533 A1 WO2024226533 A1 WO 2024226533A1 US 2024025876 W US2024025876 W US 2024025876W WO 2024226533 A1 WO2024226533 A1 WO 2024226533A1
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Prior art keywords
integrin antagonist
formulation
scs
retina
administration
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PCT/US2024/025876
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English (en)
Inventor
Viral KANSARA
Thomas CIULLA
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Clearside Biomedical, Inc.
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Publication of WO2024226533A1 publication Critical patent/WO2024226533A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions

Definitions

  • Prolonged or severe inflammation in the back of the eye can result in the breakdown of cells at the interface of the retina and choroid, resulting in the leakage and accumulation of fluid in the macular region of the retina.
  • This build-up of fluid can cause abnormal swelling of the macula, or macular edema, which can rapidly result in distortion of vision and eventually blindness.
  • macular edema can rapidly result in distortion of vision and eventually blindness.
  • Diabetic macular edema is caused by diabetic retinopathy, which is the most common diabetic eye disease and the leading cause of vision loss in the United States.
  • Anti- VEGF agents are often used to treat DME.
  • anti-VEGF treatments are associated with complications relating to repeated administration, and insufficient or only modest improvements in visual acuity.
  • This invention is generally related to ophthalmic therapies, and more particularly to methods, devices, and compositions that allow for infusion of a fluid drug formulation into posterior ocular tissues for targeted, localized treatment of posterior ocular disorders.
  • the compositions, devices, and methods provided herein allow for the treatment of diabetic macular edema.
  • the present disclosure provides methods for treating diabetic macular edema in a subject in need thereof, the method comprising non-surgically administering an effective amount of an integrin antagonist drug formulation to the suprachoroidal space (SCS) of the eye of the human subject in need of treatment.
  • the integrin antagonist is MK-0429, SF-0166 (OT-166), JSM-6427, THR-687, AXT-107, SB-267268, JNJ-26076713, cilengitide, lebecetin, or risuteganib.
  • the integrin antagonist is MK-0429.
  • the effective amount of the integrin antagonist is about 2 mg to about 12 mg.
  • the effective amount of the integrin antagonist is about 2 mg, about 4 mg, about 6 mg, or about 8 mg. In some embodiments, the effective amount of the integrin antagonist is 3 mg. In some embodiments, the integrin antagonist formulation comprises carboxymethyl cellulose.
  • the integrin antagonist formulation comprises the integrin antagonist at a concentration of about 20 mg/mL to about 80 mg/mL.
  • the administration provides the mean integrin antagonist concentration of about 500 ng/mL to 1000 ng/mL in the central retina on day 112 following administration.
  • the administration provides the mean integrin antagonist concentration of about 800 ng/mL to 1200 ng/mL in the peripheral retina on day 112 following administration.
  • the mean integrin antagonist concentration is maintained in the central retina or peripheral retina for at least 1 to 6 months following a single administration of the integrin antagonist formulation to the SCS.
  • the mean integrin antagonist concentration is maintained in the central retina or peripheral retina for at least 4 months following a single administration of the integrin antagonist formulation to the SCS.
  • the method results in the resolution of inflammation in the eye.
  • the integrin antagonist formulation is administered to the subject by suprachoroidal injection comprising the use of an SCS microinjector.
  • the SCS microinjector comprises a 30-gauge needle that is about 700 pm, about 900 pm, or about 1100 pm in length.
  • the SCS microinjector comprises a 30-gauge needle that is about 900 pm in length.
  • the posterior ocular disorder is age-related macular degeneration (AMD), macular edema, macular edema associated with uveitis, diabetic retinopathy (DR), or diabetic macular edema (DME).
  • AMD age-related macular degeneration
  • DR diabetic retinopathy
  • DME diabetic macular edema
  • FIG. 1 is an illustration of a microneedle device according to one embodiment.
  • FIG. 2 shows ocular exam scores following 2, 4, 6, and 8 mg/eye administration of the integrin antagonist formulation as described in Example 1.
  • FIG. 3 shows intraocular pressure (mmHg) following 2, 4, 6, and 8 mg/eye administration of the integrin antagonist formulation as described in Example 1.
  • FIG. 4 shows representative histology images of the cornea, iris, ciliary body, pars plana, superior retina, and vitreous humor in rabbits following 0, 4, 6, and 8 mg/eye integrin antagonist formulation administration as described in Example 1.
  • FIG. 5 shows the geometric mean of the integrin antagonist levels in peripheral and central RCS following 2 mg/eye administration as described in Example 1.
  • FIG. 6 shows the geometric mean of the integrin antagonist levels in retina following 4, 6, and 8 mg/eye administration as described in Example 1.
  • DME diabetic macular edema
  • the terms “about” and “approximately” generally mean plus or minus 10% of the value stated. 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.
  • 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 referred to as a retrobulbar block). Alternatively or additionally, a “non- surgical” ocular drug delivery method is performed with an instrument having a diameter of 28 gauge or smaller. Alternatively or additionally, “non-surgical” ocular drug delivery methods do not require a guidance mechanism that is typically required for ocular drug delivery via a shunt or cannula.
  • surgical ocular drug delivery includes insertion of devices or administration of drugs by surgical means, for example, via incision to expose and provide access to regions of the eye including the posterior region, and/or via insertion of a stent, shunt, or cannula.
  • the term “suprachoroidal space,” is used interchangeably with suprachoroidal, SCS, suprachoroid, and suprachoroidia, and describes the potential space in the region of the eye disposed between the sclera and choroid. This region primarily is composed of closely packed layers of long pigmented processes derived from each of the two adjacent tissues; however, a space can develop in this region as a result of fluid or other material buildup in the suprachoroidal space and the adjacent tissues.
  • the “supraciliary space,” as used herein, is encompassed by the SCS and refers to the most anterior portion of the SCS adjacent to the ciliary body, trabecular meshwork, and limbus.
  • the suprachoroidal space frequently is expanded by fluid buildup because of some disease state in the eye or as a result of some trauma or surgical intervention.
  • the fluid buildup is intentionally created by the infusion of a drug formulation into the suprachoroid to create the suprachoroidal space (which is filled with drug formulation).
  • the SCS region serves as a pathway for uveoscleral outflow (i.e., a natural process of the eye moving fluid from one region of the eye to the other through) and becomes a real space in instances of choroidal detachment from the sclera.
  • ocular tissue” and “eye” include both the anterior segment of the eye (i.e., the portion of the eye in front of the lens) and the posterior segment of the eye (i.e., the portion of the eye behind the lens).
  • the terms “subject” and “patient” are used interchangeably herein.
  • the human subject treated with the methods and devices provided herein may be an adult or a child.
  • the human subject treated with the methods and devices provided herein may be an adult or a child.
  • the subject is at least 40 years old, 45 years old, 50 years old, 55 years old, 60 years old, 65 years old, or 70 years old, including any values or ranges therebetween.
  • the patient in some embodiments has macular edema (ME). In some embodiments, the patient has diabetic macular edema (DME).
  • DME diabetic macular edema
  • the patient in one embodiment has macular edema (ME) that involves the fovea.
  • the ME in a method for treating ME associated with uveitis, the ME is due to the uveitis and not due to any other cause.
  • the ME in an embodiment for treating ME following retinal vein occlusion (RVO), the ME is due to RVO and not due to any other cause of ME.
  • the RVO is branch retinal vein occlusion (BRVO), hemiretinal vein occlusion (HRVO) or central retinal vein occlusion (CRVO).
  • the patient in need of treatment experiences a decrease in visual acuity due to the ME.
  • the patient presents with a retinal thickness of greater than 300 pm (e.g., central retinal thickness or central subfield thickness as measured by optical coherence tomography).
  • the patient in need of treatment has a BCVA score of > 20 letters read in each eye (e.g., 20/400 Snellen approximate). In yet another embodiment, the patient in need of treatment has a BCVA score of > 20 letters read in each eye (e.g., 20/400 Snellen approximate), but ⁇ 70 letters read in the eye in need of treatment.
  • the methods comprise administering to a subject need thereof a dose of about 2 mg to about 12 mg (for example, about 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, or 12 mg, including any values or ranges therebetween) of an integrin antagonist to the suprachoroidal space (SCS) of the eye of the subject.
  • a dose of about 2 mg to about 12 mg for example, about 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, or 12 mg, including any values or ranges therebetween
  • SCS suprachoroidal space
  • the methods comprise administering an integrin antagonist to the suprachoroidal space (SCS) of the eye of a subject in need thereof at a dose of about 1 mg to about 20 mg, for example, about 1 mg, about 1.2 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.8 mg, about 2 mg, about 2.2 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.8 mg, about 3 mg, about 3.2 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.8 mg, about 4 mg, about 4.2 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.8 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg,
  • the methods comprise administering integrin antagonist to a subject need thereof at a dose ranging from about 1 mg to about 10 mg, about 1 mg to about 8 mg, about 1 mg to about 6 mg, about 1 mg to about 5 mg, about 1 mg to about 4 mg, about 1 mg to about 3 mg, about 2 mg to about 5 mg, about 2 mg to about 4 mg, about 2 mg to about 6 mg, about 3 mg to about 6 mg, or any values or ranges therebetween.
  • the methods comprise administering about 3 mg of integrin antagonist to the subject need thereof.
  • the methods comprise administering to the subject a single bilateral suprachoroidal injection into the SCS of the eye of the subject by using any one of the microneedles of the present application.
  • the present disclosure provides a formulation of an integrin antagonist in a concentration of about 20 mg/mL to about 80 mg/mL.
  • the formulation is a carboxymethyl cellulose (CMC)-based aqueous suspension.
  • the methods and devices provided herein are for the treatment of diabetic macular edema (DME), diabetic retinopathy (DR), or macular edema associated with uveitis, such as non-infectious uveitis.
  • DME diabetic macular edema
  • DR diabetic retinopathy
  • macular edema associated with uveitis such as non-infectious uveitis.
  • the compositions and methods provided herein are used to restore or improve visual function.
  • the methods provided herein reduce diabetic macular edema affecting the retina, the tissue that lines the inside of the eye and is the part of the eye primarily responsible for vision, and the choroid, the layer adjacent to the retina that supplies the retina with blood, oxygen and nourishment.
  • Macular edema is the build-up of fluid that can cause abnormal swelling of the macula, the portion of the retina responsible for central vision and color perception. This swelling can rapidly result in deterioration of vision and can eventually lead to blind
  • the non-surgical posterior ocular disorder treatment methods and devices described herein are particularly useful for the local delivery of drugs to the posterior region of the eye, for example, the retinochoroidal tissue, macula, retinal pigment epithelium (RPE) and optic nerve in the posterior segment of the eye.
  • the non-surgical methods and microneedles provided herein can be used to target drug delivery to specific posterior ocular tissues or regions within the eye or in neighboring tissue.
  • the methods described herein deliver drug specifically to the sclera, the choroid, the Brach’s membrane, the retinal pigment epithelium, the subretinal space, the retina, the macula, the optic disk, the optic nerve, the ciliary body, the trabecular meshwork, the aqueous humor, the vitreous humor, and/or other ocular tissue or neighboring tissue in the eye of a human subject in need of treatment.
  • the methods and microneedles provided herein in one embodiment, can be used to target drug delivery to specific posterior ocular tissues or regions within the eye or in neighboring tissue.
  • the drug is an integrin antagonist.
  • the integrin antagonist is MK-0429, SF-0166 (OT-166), JSM-6427, THR-687, AXT-107, SB-267268, JNJ-26076713, cilengitide, lebecetin, or risuteganib.
  • an integrin antagonist e.g., MK-0429, to the suprachoroidal space of one or both eyes for at least one dosing session.
  • Non-surgical administration in one embodiment, is achieved by inserting a microneedle into one or both eyes of the patient, for example the sclera, and injecting or infusing a drug formulation through the inserted microneedle and into the suprachoroidal space of the eye.
  • the effective amount of the drug administered to the SCS provides higher therapeutic efficacy of the drug, compared to the therapeutic efficacy of the drug when the identical dosage is administered intravitreally, topically, intracamerally, parenterally or orally.
  • the microneedle drug delivery methods described herein precisely deliver the drug into the SCS for subsequent local delivery to nearby posterior ocular tissues (e.g., the retina and choroid) in need of treatment.
  • the drug may be released into the ocular tissues from the infused volume (or, e.g., from microparticles or nanoparticles in the drug formulation) for an extended period, e.g., several hours or days or weeks or months, after the non-surgical drug administration has been completed.
  • the drug formulation comprises an integrin antagonist.
  • the SCS drug delivery methods advantageously include precise control of the depth of insertion into the ocular tissue, so that the microneedle tip can be placed into the eye so that the integrin antagonist formulation flows into the suprachoroidal space and into one or more posterior ocular tissues surrounding the SCS, e.g., the choroid and retina.
  • the insertion of the microneedle is in the sclera of the eye.
  • the integrin antagonist flow into the SCS is accomplished without contacting underlying tissues with the microneedle, such as choroid and retina tissues.
  • the methods provided herein achieve delivery of integrin antagonist comprising composition to the suprachoroidal space, thereby allowing drug access to posterior ocular tissues e.g., the choroid and retina) not obtainable via topical, parenteral, intracameral or intravitreal drug delivery.
  • the methods provided herein deliver an integrin antagonist to the posterior ocular tissue for the treatment of a posterior ocular disorder, the suprachoroidal drug dose sufficient to achieve a therapeutic response and/or the frequency of dosing in a human subject treated with the methods provided herein is less than the intravitreal, topical, parenteral or oral integrin antagonist dose or dosing schedule sufficient to elicit the same or substantially the same therapeutic response.
  • the SCS delivery methods described herein allow for decreased dose, compared to the intravitreal, topical, intracameral parenteral or oral integrin antagonist dose sufficient to elicit the same or substantially the same therapeutic response.
  • the suprachoroidal integrin antagonist dose sufficient to elicit a therapeutic response is 75% or less, or 50% or less, or 25% or less than the intravitreal, topical parenteral or oral dose sufficient to elicit a therapeutic response.
  • the therapeutic response in one embodiment, is a reduction in the severity of a symptom/clinical manifestation of the posterior ocular disorder (diabetic macular edema (DME), diabetic retinopathy (DR), uveitis, macular edema associated with uveitis, macular edema associated with RVO, wet AMD, choroidal neovascularization (CNV), wet AMD associated with CNV) for which the patient is undergoing treatment, or a reduction in number of symptom(s)/clinical manifestation(s) of the posterior ocular disorder for which the patient is undergoing treatment.
  • DME diabetic macular edema
  • DR diabetic retinopathy
  • uveitis macular edema associated with uveitis
  • macular edema associated with RVO macular edema associated with RVO
  • wet AMD choroidal neovascularization
  • CNV choroidal neovascularization
  • AMD choroidal
  • the methods described herein are carried out with a hollow or solid microneedle, for example, a rigid microneedle.
  • a hollow or solid microneedle for example, a rigid microneedle.
  • the term “microneedle” refers to a conduit body having a base, a shaft, and a tip end suitable for insertion into the sclera and other ocular tissue and has dimensions suitable for minimally invasive insertion and drug formulation infusion as described herein. Both the “length” and “effective length” of the microneedle encompass the length of the shaft of the microneedle and the bevel height of the microneedle.
  • the microneedle is an SCS microinjector as described herein.
  • the SCS microinjector comprises a 30-gauge needle that is about 700 pm, about 900 pm, or about 1100 pm in length. In some embodiments, the SCS microinjector comprises a 30-gauge needle that is about 900 pm in length. In some embodiments, the SCS microinjector comprises a 30-gauge needle that is about 700 pm in length. In some embodiments, the SCS microinjector comprises a 28-gauge, a 30-gauge, or a 32-gauge needle.
  • the microneedle has an effective length of about 600 pm, about 700 pm, about 800 pm, about 900 pm, about 1000 pm, about 1100 pm, about 1200 pm, about 1300 pm, about 1400 pm, or about 1500 pm, including any values and ranges therebetween. In some embodiments, the microneedle has an effective length of about 700 pm. In some embodiments, the microneedle has an effective length of about 900 pm. In some embodiments, the microneedle has an effective length of about 1100 pm.
  • the microneedle device may comprise a means for controllably inserting, and optionally retracting, the microneedle into the ocular tissue.
  • the microneedle device may include means of controlling the angle at which at least one microneedle is inserted into the ocular tissue (e.g., by inserting the at least one microneedle into the surface of the ocular tissue at an angle of about 90 degrees).
  • the depth of microneedle insertion into the ocular tissue can be controlled by the length of the microneedle, as well as other geometric features of the microneedle. For example, a flange or other sudden change in microneedle width can be used to limit the depth of microneedle insertion.
  • the microneedle insertion can also be controlled using a mechanical micropositioning system involving gears or other mechanical components that move the microneedle into the ocular tissue a controlled distance and, likewise, can be operated, for example, in reverse, to retract the microneedle a controlled distance.
  • the depth of insertion can also be controlled by the velocity at which the microneedle is inserted into the ocular tissue.
  • the retraction distance can be controlled by the elastic recoil of the ocular tissue into which the microneedle is inserted or by including an elastic element within the microneedle device that pulls the microneedle back a specified distance after the force of insertion is released.
  • the angle of insertion can be directed by positioning the microneedle at a first angle relative to the microneedle base and positioning the base at a second angle relative to the ocular surface.
  • the first angle can be about 90° and the second angle can be about 0°.
  • the angle of insertion can also be directed by having the microneedle protrude from a device housing through a channel in that housing that is oriented at a specified angle.
  • microneedle and/or any of the components included in the embodiments described herein is/are formed and/or constructed of any suitable biocompatible material or combination of materials, including metals, glasses, semi-conductor materials, ceramics, or polymers.
  • suitable metals include pharmaceutical-grade stainless steel, gold, titanium, nickel, iron, gold, tin, chromium, copper, and alloys thereof.
  • the polymer can be biodegradable or non-biodegradable.
  • suitable biocompatible, biodegradable polymers include polylactides, polyglycolides, polylactide-co-glycolides (PLGA), polyanhydrides, polyorthoesters, polyetheresters, polycaprolactones, polyesteramides, poly(butyric acid), poly(valeric acid), polyurethanes and copolymers and blends thereof.
  • Representative non-biodegradable polymers include various thermoplastics or other polymeric structural materials known in the fabrication of medical devices.
  • Biodegradable microneedles can provide an increased level of safety compared to non-biodegradable ones, such that they are essentially harmless even if inadvertently broken off into the ocular tissue.
  • the dose has a delivered volume of at least about 20 pL, at least about 50 uL, at least about 100 pL, at least about 200 pL or at least about 500 pL.
  • the amount of therapeutic formulation delivered into the suprachoroidal space from the devices described herein is from about 10 pL to about 200 pL, e.g., from about 50 pL to about 150 pL, including any values or ranges therebetween.
  • from about 10 pL to about 500 pL, e.g., from about 50 pL to about 250 pL, including any values or ranges therebetween is non-surgically administered to the suprachoroidal space.
  • about 100 pL of the integrin antagonist formulation is delivered into the suprachoroidal space from the devices.
  • the integrin antagonist formulation comprises the integrin antagonist at a concentration of about 10 mg/mL to about 80 mg/mL or about 20 mg/mL to about 80 mg/mL (e.g., about 20 mg/mL, about 25 mg/mL, about 30 mg/mL, about 35 mg/mL, about 40 mg/mL, about 45 mg/mL, about 50 mg/mL, about 55 mg/mL, about 60 mg/mL, about 65 mg/mL, about 70 mg/mL, about 75 mg/mL, or about 80 mg/mL, including all values and ranges therebetween).
  • a concentration of about 10 mg/mL to about 80 mg/mL or about 20 mg/mL to about 80 mg/mL e.g., about 20 mg/mL, about 25 mg/mL, about 30 mg/mL, about 35 mg/mL, about 40 mg/mL, about 45 mg/mL, about 50 mg/mL, about 55 mg/mL, about 60 mg/mL, about
  • the integrin antagonist formulation comprises the integrin antagonist at a concentration of about 10 mg/mL to about 80 mg/mL. In some embodiments, the integrin antagonist formulation comprises the integrin antagonist at a concentration of about 20 mg/mL to about 50 mg/mL. In some embodiments, the integrin antagonist formulation comprises the integrin antagonist at a concentration of about 30 mg/mL.
  • the administration provides the mean integrin antagonist concentration of about 500 ng/mL to about 1000 ng/mL (e.g., about 500 ng/mL, about 600 ng/mL, about 700 ng/mL, about 800 ng/mL, about 900 ng/mL, or about 1000 ng/mL, including all values and ranges therebetween) in the central retina on day 112 following administration.
  • the mean integrin antagonist concentration of about 500 ng/mL to about 1000 ng/mL (e.g., about 500 ng/mL, about 600 ng/mL, about 700 ng/mL, about 800 ng/mL, about 900 ng/mL, or about 1000 ng/mL, including all values and ranges therebetween) in the central retina on day 112 following administration.
  • the administration provides the mean integrin antagonist concentration of about 0.1 ng/mL to about 500 ng/mL (e.g., about 0.1 ng/mL, about 0.25 ng/mL, about 0.5 ng/mL, about 1 ng/mL, about 2 ng/mL, about 4 ng/mL, about 6 ng/mL, about 8 ng/mL, about 10 ng/mL, about 15 ng/mL, about 20 ng/mL, about 25 ng/mL, about 30 ng/mL, about 35 ng/mL, about 40 ng/mL, about 45 ng/mL, about 50 ng/mL, about 60 ng/mL, about 70 ng/mL, about 80 ng/mL, about 90 ng/mL, about 100 ng/mL, about 200 ng/mL, about 300 ng/mL, about 400 ng/mL, or about 500 ng/mL, about 600 ng/mL, or
  • the administration provides the mean integrin antagonist concentration of about 800 ng/mL to about 1200 ng/mL (e.g., about 800 ng/mL, about 900 ng/mL, about 1000 ng/mL, about 1100 ng/mL, or about 1200 ng/mL, including all values and ranges therebetween) in the peripheral retina on day 112 following administration.
  • the mean integrin antagonist concentration of about 800 ng/mL to about 1200 ng/mL (e.g., about 800 ng/mL, about 900 ng/mL, about 1000 ng/mL, about 1100 ng/mL, or about 1200 ng/mL, including all values and ranges therebetween) in the peripheral retina on day 112 following administration.
  • the administration provides the mean integrin antagonist concentration of about 0.1 ng/mL to about 1000 ng/mL (e.g., about 0.1 ng/mL, about 0.25 ng/mL, about 0.5 ng/mL, about 1 ng/mL, about 2 ng/mL, about 4 ng/mL, about 6 ng/mL, about 8 ng/mL, about 10 ng/mL, about 15 ng/mL, about 20 ng/mL, about 25 ng/mL, about 30 ng/mL, about 35 ng/mL, about 40 ng/mL, about 45 ng/mL, about 50 ng/mL, about 60 ng/mL, about 70 ng/mL, about 80 ng/mL, about 90 ng/mL, about 100 ng/mL, about 200 ng/mL, about 300 ng/mL, about 400 ng/mL, about 500 ng/mL, about 600 ng/mL
  • the mean integrin antagonist concentration is maintained in the central retina or peripheral retina for at least 1 to 12 months or at least 1 to 6 months (e.g., at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months, including any values or ranges therebetween) following a single administration of the integrin antagonist formulation to the SCS.
  • the mean integrin antagonist concentration is maintained in the central retina or peripheral retina for at least 2 months following a single administration of the integrin antagonist formulation to the SCS.
  • the mean integrin antagonist concentration is maintained in the central retina or peripheral retina for at least 3 months following a single administration of the integrin antagonist formulation to the SCS.
  • the mean integrin antagonist concentration is maintained in the central retina or peripheral retina for at least 4 months following a single administration of the integrin antagonist formulation to the SCS.
  • the efficacy of the method is measured by measuring the patient’s mean change from baseline in macula thickness at one or more time points after the patient is treated. For example, at one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, or more, including all durations in between, after treatment, e.g., with an anti-inflammatory drug delivered non-surgically to the SCS, mean change from baseline in retinal thickness and/or macula thickness is measured. A decrease in retina thickness and/or macula thickness is one measurement of treatment efficacy of the methods provided herein.
  • a patient treated by one of the methods provided herein for example with one of the devices described herein experiences a decrease in retinal thickness from baseline (e.g., retinal thickness such as central retinal thickness (CRT) or central subfield thickness (CST) prior to treatment), at any given time point after at least one dosing session (single session or multiple dosing sessions), of at least about 20 pm, or at least about 40 pm, or at least about 50 pm, or at least about 100 pm, or at least about 125 pm, or at least about 150 pm, or at least about 175 pm. or at least about 200 pm, or from about 50-100 pm, or from about 75-200 pm, or from about 100-150 pm, or from about 150-200 pm, and all values in between.
  • the patient experiences a > 5%, > 10%, > 15%, > 20%, > 25%, > 25%, > 30%, > 35%, or > 40%, decrease in retinal thickness (e.g., CST) subsequent to at least one dosing session.
  • the decrease in retinal thickness is measured about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, or longer after at least one dosing session. In another embodiment, the decrease in retinal thickness is measured 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, or longer after at least one dosing session.
  • a decrease in retinal thickness is sustained by the patient for at least about 2 weeks, at least about 1 month or 4 weeks, at least about 2 months or 8 weeks, at least about 3 months or 12 weeks, at least about 6 months or 24 weeks, at least about 8 months or 36 weeks, at least about 9 months or 36 weeks, at least about 12 months or 48 weeks, or longer after each dosing session.
  • the therapeutic response is a change from baseline in macula thickness at one or more time points after the patient is treated. For example, at one week, two weeks, three weeks, one month, two months, three months, four months or more, including all durations in between, after a dosing session, e.g., with an integrin antagonist MK- 0429 delivered non-surgically to the SCS, change from baseline in macula thickness is measured.
  • a decrease in macula thickness is one measurement of therapeutic response (e.g., by about 10%, or about 20%, or about 30%, or about 40%, or about 50%, or about 60% and more, including all values in between).
  • Efficacy in another embodiment, is assessed via a visual acuity measurement at one and/or two months post-treatment (e.g., by measuring the mean change in best corrected visual acuity (BCVA) from baseline, z.e., prior to treatment).
  • BCVA best corrected visual acuity
  • a patient treated by one or more of the methods provided herein experiences an improvement in BCVA from baseline, at any given time point (e.g., 2 weeks after administration, 4 weeks after administration, 2 months after at least one dosing session, 3 months after administration), 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 in between, as compared to the patient’s BVCA prior to the at least one dosing session.
  • any given time point e.g., 2 weeks after administration, 4 weeks after administration, 2 months after at least one dosing session, 3 months after administration
  • the patient gains about 5 letters or more, about 10 letters or more, about 15 letters or more, about 20 letters or more, about 25 letters or more in a BCVA measurement after a dosing regimen is complete, for example a monthly dosing regimen, compared to the patient’ s BCVA measurement prior to undergoing treatment.
  • the patient gains from about 5 to about 30 letters, 10 to about 30 letters, from about 15 letters to about 25 letters or from about 15 letters to about 20 letters in a BCVA measurement upon completion of at least one dosing session, compared to the patient’s BCVA measurement prior to the at least one dosing session.
  • the BCVA gain is about 2 weeks, about 1 month, about 2 months, about 3 months or about 6 months after the at least one dosing session. In another embodiment, the 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 at least one dosing session.
  • the BCVA is based on the Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity charts.
  • EDRS Early Treatment of Diabetic Retinopathy Study
  • the patient subjected to a treatment method substantially maintains his or her vision subsequent to the treatment (e.g., a single dosing session or multiple dosing sessions), as measured by losing fewer than 15 letters in a best-corrected visual acuity (BCVA) measurement, compared to the patient’s BCVA measurement prior to undergoing treatment.
  • the patient loses fewer than 10 letters, fewer than 8 letters, fewer than 6 letters or fewer than 5 letters in a BCVA measurement, compared to the patient’s BCVA measurement prior to undergoing treatment.
  • Decrease in vitreous haze can also be used as a measure of the method’s efficacy.
  • Decreases in vitreous haze can be qualitatively and/or quantitatively determined by techniques such as, but not limited to, photographic grading, a scoring system, a multi-point scale, a multi- step scale (e.g. a multi-step logarithmic scale, manual screening by one or more examiners, and/or the like).
  • the decrease in vitreous haze is present about 2 weeks, about 1 month, about 2 months, about 3 months or about 6 months after at least one dosing session.
  • the decrease in retinal thickness is present 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 at least one dosing session.
  • a decrease in vitreous haze is experienced by the patient and is present 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 dosing session.
  • the methods provided herein allow for greater integrin antagonist retention in the eye compared to other drug delivery methods, for example, a greater amount of integrin antagonist is retained in the eye when delivered via the methods provided herein as compared to the same dose delivered via intracameral, sub-tenon, intravitreal, topical, parenteral or oral drug delivery methods.
  • the intraocular elimination half-life (ti/2) of the integrin antagonist when delivered via the methods described herein is greater than the intraocular ti/2 of the drug when the same integrin antagonist dose is administered intravitreally, intracamerally, topically, parenterally or orally.
  • the intraocular ti/2 of the drug when administered via the non-surgical SCS drug delivery methods provided herein is from about 1.1 times to about 10 times longer, or from about 1.25 times to about 10 times longer, or from about 1.5 times to about 10 times longer, or about 2 times to about 5 times longer, than the intraocular ti/2 of the drug when the identical dosage is administered topically, intracamerally, sub-tenonally, intravitreally, orally or parenterally.
  • the intraocular Cmax of the integrin antagonist when delivered via the methods described herein, is greater than the intraocular Cmax of the drug when the same integrin antagonist dose is administered intravitreally, intracamerally, sub- tenonally, topically, parenterally or orally.
  • the intraocular Cmax of the integrin antagonist when administered via the non-surgical SCS integrin antagonist delivery methods provided herein is at least 1.1 times greater, or at least 1.25 times greater, or at least 1.5 times greater, or at least 2 times greater, or at least 5 times greater, than the intraocular Cmax of the integrin antagonist when the identical dose is administered topically, intracamerally, intravitreally, orally or parenterally.
  • the intraocular Cmax of the integrin antagonist when administered via the non-surgical SCS drug delivery methods provided herein is about 1 to about 2 times greater, or about 1.25 to about 2 times greater, or about 1 to about 5 times greater, or about 1 to about 10 times greater, or about 2 to about 5 times greater, or about 2 to about 10 times greater, than the intraocular Cmax of the integrin antagonist when the identical dose is administered topically, intracamerally, sub-tenonally, intravitreally, orally or parenterally.
  • the mean intraocular area under the curve (AUCo-t) of the integrin antagonist when administered to the SCS via the methods described herein, is greater than the intraocular AUCo-t of the integrin antagonist, when administered intravitreally, intracamerally, sub-tenonally, topically, parenterally or orally.
  • the intraocular AUCo-t of the integrin antagonist when administered via the non-surgical SCS drug delivery methods provided herein is at least 1.1 times greater, or at least 1.25 times greater, or at least 1.5 times greater, or at least 2 times greater, or at least 5 times greater, than the intraocular AUCo-t of the integrin antagonist when the identical dose is administered topically, intracamerally, sub-tenonally, intravitreally, orally or parenterally.
  • the intraocular AUCo-t of the integrin antagonist when administered via the non-surgical SCS integrin antagonist delivery methods provided herein is about 1 to about 2 times greater, or about 1.25 to about 2 times greater, or about 1 to about 5 times greater, or about 1 to about 10 times greater, or about 2 to about 5 times greater, or about 2 to about 10 times greater, than the intraocular AUCo-t of the integrin antagonist when the identical dose is administered topically, intracamerally, sub-tenonally, intravitreally, orally or parenterally.
  • the intraocular time to peak concentration (tmax) of the integrin antagonist when administered to the SCS via the methods described herein, is greater than the intraocular tmax of the integrin antagonist, when the same integrin antagonist dose is administered intravitreally, intracamerally, topically, parenterally or orally.
  • therapeutic response is measured at a time point postadministration, for example 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks 24 weeks, 30 weeks, 36 weeks, 42 weeks, 48 weeks, or longer post-treatment, and all values in between.
  • the therapeutic efficacy of the drug formulations delivered by the methods described herein and the therapeutic response of the human subject can be assayed by standard means in the art, as known to those of skill in the art.
  • the therapeutic efficacy of any particular drug can be assessed by measuring the response of the human subject after administration of the drug; a drug with a high therapeutic efficacy will show a greater amelioration and/or discontinuation of symptoms than a drug with a lower therapeutic efficacy.
  • the efficacy of the integrin antagonist formulations provided herein can be measured, for example, by observing changes in pain intensity, changes in ocular lesions (size or number), intraocular pressure, fluid accumulation, inflammation (e.g., by measuring changes in the hackett/McDonald ocular score), ocular hypertension, and/or visual acuity.
  • the efficacy of the therapeutic formulation is measured by observing changes in the measurements according to the Hackett/McDonald ocular scores, inflammation, visual acuity, and/or edema.
  • the efficacy of the therapeutic integrin antagonist formulation is measured, for example, by observing changes in the measurements according to the Hackett/McDonald ocular scores, inflammation, visual acuity, and/or edema.
  • an integrin antagonist that treats, prevents and/or ameliorates diabetic macular edema is used in conjunction with the devices and methods described herein and is delivered to the suprachoroidal space of the eye.
  • the integrin antagonist is MK-0429, SF-0166 (OT-166), JSM-6427, THR-687, AXT-107, SB-267268, JNJ- 26076713, cilengitide, lebecetin, or risuteganib.
  • one or more of the diabetic macular edema treating drugs described above is combined with one or more agents listed above or herein or with other agents known in the art.
  • the integrin antagonist is MK-0429.
  • the “therapeutic formulation” delivered via the methods and devices provided herein in one embodiment is an aqueous solution or suspension, and comprises an effective amount of the drug or therapeutic agent, for example, a cellular suspension.
  • the therapeutic formulation is a fluid drug formulation.
  • the “drug formulation” is a formulation of a drug, which typically includes one or more pharmaceutically acceptable excipient materials known in the art.
  • the term “excipient” refers to any non-active ingredient of the formulation intended to facilitate handling, stability, dispersibility, wettability, release kinetics, and/or injection of the drug.
  • the excipient may include or consist of water or saline.
  • the therapeutic substance in one embodiment is formulated with one or more polymeric excipients to limit therapeutic substance migration and/or to increase viscosity of the formulation.
  • a polymeric excipient may be selected and formulated to act as a viscous gel-like material in-situ and thereby spread into a region of the suprachoroidal space and uniformly distribute and retain the drug.
  • the polymer excipient in one embodiment is selected and formulated to provide the appropriate viscosity, flow and dissolution properties.
  • carboxymethylcellulose is used in one embodiment to form a gel -like material in the suprachoroidal space.
  • the viscosity of the polymer in one embodiment is enhanced by appropriate chemical modification to the polymer to increase associative properties such as the addition of hydrophobic moieties, the selection of higher molecular weight polymer or by formulation with appropriate surfactants.
  • Water soluble polymers that are physiologically compatible are suitable for use as polymeric excipients in the therapeutic formulations described herein, and for delivery via the methods and devices described herein include but are not limited to synthetic polymers such as polyvinylalcohol, polyvinylpyrollidone, polyethylene glycol, polyethylene oxide, polyhydroxyethylmethacrylate, polypropylene glycol and propylene oxide, and biological polymers such as cellulose derivatives, chitin derivatives, alginate, gelatin, starch derivatives, hyaluronic acid, chondroiten sulfate, dermatin sulfate, and other glycosoaminoglycans, and mixtures or copolymers of such polymers.
  • the polymeric excipient is selected in one embodiment to allow dissolution over time, with the rate controlled by the concentration, molecular weight, water solubility, crosslinking, enzyme lability and tissue adhesive properties of the polymer.
  • a viscosity modifying agent is present in a therapeutic formulation delivered by one of the methods and/or devices described herein.
  • the viscosity modifying agent is polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose or hydroxypropyl cellulose.
  • the formulation comprises a gelling agent such as poly(hydroxymethy1methacry1ate), poly(N-vinylpyrrolidone), polyvinyl alcohol or an acrylic acid polymer such as Carbopol.
  • the integrin antagonist formulation comprises carboxymethyl cellulose.
  • the integrin antagonist formulation comprises one or more pharmaceutically acceptable excipients selected from sodium carboxymethylcellulose, polysorbate 80, sodium chloride, sodium phosphate (monobasic or dibasic anhydrous), potassium chloride, calcium chloride, magnesium chloride, or sodium acetate.
  • the integrin antagonist formulation comprises one or more pharmaceutically acceptable excipients selected from sodium carboxymethylcellulose, polysorbate 80, sodium chloride, or sodium phosphate (monobasic or dibasic anhydrous).
  • the integrin antagonist formulation comprises about 0.05 % w/v to about 0.5 % w/v, about 0.1 % w/v to about 0.4 % w/v, or about 0.2 % w/v sodium carboxymethylcellulose and about 0.001 % w/v to about 0.01 % w/v, about 0.002 % w/v to about 0.008 % w/v, or about 0.005 % w/v polysorbate 80.
  • the integrin antagonist formulation is an aqueous suspension.
  • the formulation is lyophilized and resuspended to yield an aqueous suspension.
  • the integrin antagonist is formulated as a suspension of microparticles.
  • the integrin antagonist in the formulations described herein has a Dio of 1.5 nm or less, about 1 nm to about 2 nm, or about 1 nm to about 1.3 nm, including any values or ranges therebetween.
  • the integrin antagonist in the formulations described herein has a D50 of 2 nm or less, about 1 nm to about 3 nm, about 1.2 nm to about 2 nm, about 1.2 nm to about 1.5 nm, or about 1.3 nm to about 1.5 nm, including any values or ranges therebetween.
  • the integrin antagonist in the formulations described herein has a D90 of 2 nm or less, about 1.5 nm to about 4 nm, about 1.5 nm to about 3 nm, or about 1.5 nm to about 2 nm, including any values or ranges therebetween.
  • a method of treating a posterior ocular disorder in a subj ect in need thereof comprising non- surgically administering an effective amount of an integrin antagonist formulation to the suprachoroidal space (SCS) of the eye of the human subject in need thereof.
  • SCS suprachoroidal space
  • integrin antagonist is MK-0429, SF-0166 (OT-166), JSM-6427, THR-687, AXT-107, SB-267268, JNJ-26076713, cilengitide, lebecetin, or risuteganib. 3. The method of embodiment 1 or 2, wherein the effective amount of the integrin antagonist is about 2 mg to about 12 mg.
  • the integrin antagonist formulation comprises the integrin antagonist at a concentration of about 20 mg/mL to about 80 mg/mL.
  • the posterior ocular disorder is diabetic macular edema (DME), diabetic retinopathy (DR), macular edema, macular edema associated with uveitis, or age-related macular degeneration (AMD).
  • DME diabetic macular edema
  • DR diabetic retinopathy
  • AMD age-related macular degeneration
  • CMC carboxymethyl cellulose
  • Eyes were collected for histology on day 112 for all 3 dose levels in PK study 2.
  • An 8-mm biopsy punch was used to collect the central retina and central RCS around the optic nerve head.
  • Ocular tissues were homogenized and analyzed for drug levels using a liquid chromatography tandem mass spectroscopy (MS-MS) system.
  • Ocular tolerability As shown in FIGS. 2-4, no signs of toxicity or intraocular inflammation were observed in rabbits during 16-week study. Similar trends were observed in PK study 1 at a lower dose (2 mg of CLS-301).
  • the injected CLS-301 formulation achieved pharmacologically meaningful and durable CLS-301 levels in the retina.
  • the mean CLS-301 levels in the central retina were maintained 30-to 550-folds higher than the in-vitro IC50 values (0.5-5 ng/mL, blocking of cell adhesion to vitronectin) for at least 4 months.
  • the mean drug levels in the central retina (674 ng/gm) and peripheral retina (955 ng/gm) were 1-2 orders of magnitude higher than in-vitro IC50 values.
  • SC injected CLS-301 exhibited high dose-depot level in RCS for the entire duration of the study.
  • CLS-301 has a potential to be a long-acting delivery system via SC administration. Only sporadic low drug levels were detected in vitreous humor and aqueous humor, and negligible amount of CLS-301 was detected in systemic plasma. This compartmentalized ocular drug distribution after SC administration may avoid any potential off-target ocular side effects.
  • Integrin antagonist formulations for delivery to the suprachoroidal space [0068] Study Design'. Integrin antagonist MK-0429 is delivered to the suprachoroidal space using the methods and devices provided herein. The MK-0429 formulation, in one embodiment, is delivered in a volume of 100 pL for total administrated dose of 2, 4, 6, or 8 mg MK-0429 per administration.
  • a suspension formulation of CLS-301 was evaluated for its safety, ocular tolerability, and pharmacokinetics following a single bilateral suprachoroidal administration in rabbits.
  • the CLS-301 suspension formulation was lyophilized at the end of the manufacturing process and stored frozen. On the day of dosing, the frozen formulation was reconstituted to an aqueous suspension by adding water for injection (WFI) with appropriate volume to achieve the target final concentration of 30 mg/mL.
  • WFI water for injection
  • Dutch-belted pigmented rabbits were dosed (O.lmL/eye) bi-laterally via suprachoroidal injection.
  • the ocular tolerability was assessed during the study for up to 84 days. The ocular samples and blood were collected for drug analysis at predetermined timepoints.
  • the formulation was generally tolerated in rabbits. Drug levels were detectable in both central and peripheral retina (target tissue) 24 hours post-dose with drug concentrations in the peripheral retina decreasing significantly by days 14 and 28. The drug levels were below the lower limit of quantitation (LLOQ) (central retina, 1 ng/mL; and peripheral retina, 0.25 ng/mL) on day 54, and day 84. Similarly, the drug levels in the central RPE/choroid/sclera (RCS) and peripheral RCS were detectable at 24 hours, day 14 and day 28 with drug concentrations decreasing over time. The drug levels were below LLOQ (0.25 ng/mL) on day 54, and day 84. There were no detectable drug levels in the vitreous humor or plasma at any time point.
  • LLOQ lower limit of quantitation
  • RCS central RPE/choroid/sclera
  • the manufacturing and processing steps are as follows: i) prepare vehicle (CMC+salts) ii) dissolve API (e.g., integrin antagonist) in portion of vehicle iii) combine dissolved API with remaining vehicle iv) pre-bulk inprocess test sampling v) aseptic-bulk filtration vi) filter and lyophilize.
  • API e.g., integrin antagonist
  • OCT optical coherent tomography
  • PK In the retina, CLS-301 was detectable in both central and peripheral retina 24 hours post-dose with drug concentrations in the peripheral retina decreasing significantly by days 14 and 28. The drug levels were below the lower limit of quantitation (LLOQ) (central retina, 1 ng/mL; and peripheral retina, 0.25 ng/mL) on day 54, and day 84.
  • LLOQ lower limit of quantitation
  • RCS central RPE/choroid/sclera
  • peripheral RCS was detectable at 24 hours, day 14, and day 28 with drug concentrations decreasing over time. The drug levels were below LLOQ (0.25 ng/mL) on day 54, and day 84. There were no detectable drug levels in the vitreous humor or plasma at any time point.

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Abstract

La présente invention concerne des méthodes, des dispositifs et des compositions permettant de traiter l'œdème maculaire diabétique (DME) par administration non chirurgicale d'une composition d'antagoniste de l'intégrine à l'espace suprachoroïdien (SCS) de l'œil.
PCT/US2024/025876 2023-04-24 2024-04-23 Méthodes de traitement de troubles oculaires avec une composition d'antagoniste de l'intégrine WO2024226533A1 (fr)

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Citations (3)

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WO2007100745A2 (fr) * 2006-02-22 2007-09-07 Iscience Interventional Corporation Appareil et formules pour délivrance suprachoroïdiene d'un médicament
WO2014074823A1 (fr) * 2012-11-08 2014-05-15 Clearside Biomedical, Inc. Procédés et dispositifs pour le traitement de maladies oculaires chez des sujets humains
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