WO2015048526A1 - Treating ocular pain - Google Patents

Abstract

Methods of treating ocular pain are provided, e.g., methods including treating a subject having ocular pain with a composition comprising an IL-1 antagonist.

Description

TREATING OCULAR PAIN

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No. 61/883438, filed on September 27, 2013, and U.S. Provisional Application No. 61/968639, filed on March 21, 2014. The entire content of each of the foregoing applications is hereby incorporated herein by reference.

FIELD OF THE INVENTION

The field of the invention relates to treatment of pain. More particularly, the field relates to treatment of ocular pain using an IL-1 antagonist.

BACKGROUND

The cornea is highly innervated with sensory afferents which transmit various painful stimuli to the central nervous system. Eye pain can arise from a variety of causes, for example, the presence of a foreign body in the eye, inflammation, dry eye disease, accidental trauma, surgical procedures (e.g., photorefractive kertotomy), and post-surgical recovery.

Various therapies are used to treat eye pain, but such therapeutic agents have disadvantages. For example, certain therapeutic agents are typically provided systemically and so may have undesirable effects due to systemic exposure. Examples of such agents are non-steroidal anti-inflammatory drugs (NSAIDs), for example, diclofenac, which can have adverse effects on, e.g., the gastrointestinal tract and kidneys. Other agents such as anesthetics can be administered locally, but also have potential adverse effects. For example, local anesthetics can lead to a neurotrophic cornea that can result in corneal melting or ulceration and may also impair wound healing. Further, they can affect membrane stabilization thereby adversely affecting functions of non-neuronal cells.

Accordingly, there is a need for therapeutic agents that can ameliorate eye pain, e.g., ocular pain, effectively and with an acceptable safety profile.

SUMMARY

The invention relates to the discovery that IL-1 inhibitors can ameliorate eye pain through a mechanism that appears to be independent of their ability to modulate inflammatory responses.

Furthermore, the effect is relatively long lasting. Accordingly, the invention relates to a method of treating ocular pain in a subject. The method includes identifying a subject having ocular pain and administering a therapeutically effective amount of an IL-1 antagonist. In some cases, the ocular pain is not associated with an inflammatory cause. In some cases, the subject is not diagnosed with dry eye disease. In some embodiments, the pain is neuropathic pain. In some embodiments, the pain is is acute pain. In some embodiments, the pain is chronic pain. In certain embodiments, the pain is associated with eye surgery. In some cases, the pain is associated with dry eye disease. In some embodiments, the subject has idiopathic ocular pain, or ocular pain associated with conjunctivitis, corneal abrasion, sty, or chalazion. In some embodiments, the administering comprises discontinuous treatment, e.g., an intermittent or discontinuous treatment as described herein. The IL-1 antagonist is, in some cases, anakinra or P05. In embodiments, the IL-1 antagonist is P05 and the method is effective to improve ocular pain by at least 40% compared with baseline ocular pain.

The invention also relates to a method of treating dry eye using a continuous; or an intermittent or discontinuous treatment regimen. In embodiments, the regimen includes treating a subject having ocular pain with a therapeutically effective amount of an IL-1 antagonist for at least one week followed by discontinuing treatment with the IL-1 antagonist for at least one week, wherein the subject exhibits the same level of dry eye or a decrease in dry eye at the end of the no treatment week compared to the level of dry eye at the end of treatment with the IL-1 antagonist. In some embodiments, dry eye is evaluated using corneal fluorescence staining (CFS) using methods known in the art. In some embodiments, the IL- 1 antagonist is administered for at least 1 week, at least 2 weeks, at least three weeks, at least 4 weeks, at least 5 weeks, or at least six weeks. In some embodiments, the method further includes, after

discontinuing treatment for at least one week, administering a therapeutically effective amount of the IL- 1 antagonist. In some cases, the IL-1 antagonist is anakinra or P05.

The invention also relates to a package comprising an IL-1 antagonist formulated for ocular administration and instructions for a discontinuous treatment regimen as described herein.

In another embodiment, the invention is a method of treating ocular pain in a subject, the method includes administering a therapeutically effective amount of P05 to the subject. In some cases, the subject has an OSDI of 19-100% prior to administration of the P05 and after six weeks of treatment has at least a 46% improvement in OSDI-Pain/Sore Eye score compared to the OSDI-Pain/Sore Eye score prior to treatment. In some embodiments, the subject has an OSDI of 19-50% prior to administration of the P05 and after six weeks of treatment has at least a 61% improvement in OSDI-Pain/Sore Eye score compared to the OSDI-Pain/Sore Eye score prior to treatment.

Also provided herein is a kit or package comprising an IL-1 antagonist formulated for ocular administration and instructions for use according to a discontinuous treatment regimen as described herein. Also provided in a kit or package comprising an IL-1 antagonist, e.g., P05, for treating eye pain by ocular administration and instructions for use according to a discontinuous treatment regimen as described herein. The entire disclosure of each patent document and scientific article referred to herein, and those patent documents and scientific articles cited thereby, is expressly incorporated by reference herein for all purposes.

Additional features and advantages of the invention are more particularly described below.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is a graph depicting the results of a clinical trial in which subjects diagnosed with dry eye disease were treated with vehicle (placebo) or an IL-1 antagonist for six weeks and evaluated for corneal fluorescein staining (CFS). Y axis indicates change from baseline CFS scores. X axis is weeks from the start of treatment. The square symbols show the results for vehicle only (placebo) treatment; the circle symbols show the results for treatment with IL-1 antagonist. The values depicted are regular means with the error bars showing standard error of the mean (SEM).

Fig. 2 is a graph depicting the results of a clinical trial for the EE subset of subjects (evaluatable efficacy population) from the clinical trial described in Fig. 1 in which subjects diagnosed with dry eye disease were treated with vehicle (placebo) or an IL-1 antagonist for six weeks and evaluated for corneal fluorescein staining (CFS). Y axis indicates change from baseline CFS scores. X axis is weeks from the start of treatment. The square symbols show the results for vehicle only (placebo) treatment; the circle symbols show the results for treatment with IL-1 antagonist. The values depicted are regular means with the error bars showing standard error of the mean (SEM).

Fig. 3 is a graph depicting the results of a clinical trial in which the EE subjects from the clinical trial diagnosed with dry eye disease were treated with vehicle or an IL-1 antagonist for six weeks and evaluated for pain. Y axis indicates change from baseline pain scores. X axis is weeks from the start of treatment. The square symbols show the results for vehicle only (placebo) treatment; the circle symbols show the results for treatment with IL-1 antagonist. The values depicted are regular means with the error bars showing SEM.

Fig. 4 is a graph depicting the results for the EE subset of subjects having an OSDI of less than 50 and treated with vehicle or an IL-1 antagonist for six weeks and evaluated for pain. Y axis indicates change from baseline pain scores. X axis is weeks from the start of treatment. The square symbols show the results for vehicle only (placebo) treatment; the circle symbols show the results for treatment with IL- 1 antagonist. The values depicted are regular means with the error bars showing SEM.

DETAILED DESCRIPTION

Applicants have discovered that IL-1 antagonists, e.g., P05,can ameliorate eye pain, e.g., ocular pain, through a mechanism that appears to be independent of their ability to modulate inflammatory responses. It has been observed that there is a lack of a consistent correlation between the severity of the lack of tear formation in dry eye disease and ocular pain. For example, certain dry eye patients develop disabling eye irritation with only mild tear instability.

As used herein, pain includes sensation described as pain by a subject and can include, for example, itching, burning, throbbing, stinging, aching, stabbing, or shooting pain. Pain can be evaluated using the OSDI-pain score.

Furthermore, applicants have discovered that, using a biologic antagonist of IL-1 activity, e.g., P05, the effect on e.g., dry eye is surprisingly long lasting. Accordingly, intermittent treatment with an IL-1 antagonist can be effective to treat (e.g., to decrease or prevent increases in) dry eye.

In aspects of the methods disclosed herein, treatment of dry eye is effective with intermittent administration of an IL-1 antagonist. In embodiments, the IL-1 antagonist is administered for a first period (e.g., of at least 1, 2, 3, 4, 5, or 6 weeks) followed by discontinuing treatment for a second period (e.g., of at least 5-10 days, e.g., at least 1 week during which the IL-1 antagonist is not administered), wherein the subject exhibits the same level of dry eye or a decrease in dry eye at the end of the second period compared with the level of dry eye at the end of the first period. In embodiments, the length of the first and second periods are independently selected from at least 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 10 weeks, or 12 weeks).

In embodiments, the IL-1 antagonist is initially administered to a subject for a first period of at least 1-6 weeks (e.g., for a period of at least 1, 2, 3, 4, 5, or 6 weeks) and discontinued for a second period of at least 1 week. In embodiments, following the second period, the IL-1 antagonist is administered for a third period. In embodiments, the third period begins before dry eye recurs or increases in the subject. In embodiments, the third period begins when dry eye recurs or increases. In embodiments, the third period is a period of at least 1-6 weeks (e.g., a period of at least 1, 2, 3, 4, 5, or 6 weeks).

In embodiments, the IL-1 antagonist is administered according to an intermittent treatment regimen, e.g., a first period of treatment with the IL-1 antagonist, followed by a second period during which the IL-1 antagonist is not administered. In embodiments, the length of the first and second periods are independently selected from at least least 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 10 weeks, or 12 weeks. In embodiments, the first period is at least 6 weeks. In embodiments, the second period is at least 5-10 days, e.g., at least 1 week. In embodiments, a treatment regimen is employed in which the first and second periods are repeated iteratively.

One embodiment provided herein is a treatment regimen comprising (i) administering the IL-1 antagonist to a subject for a first period (e.g., a period of at least 1-6 weeks, e.g. at least 6 weeks) and (ii) discontinuing administration of the IL-1 antagonist for a second period of at least 5-10 days, e.g., at least 1 week, wherein (i) and (ii) are repeated for two or more iterations. The treatment regimen can be included in a method of treating dry eye, wherein the method is effective to treat (e.g., to reduce or prevent increases in) dry eye in a subject.

In embodiments, the IL-1 antagonist is P05 and the method is effective to improve dry eye by at least 1, 2, or 3 units compared to baseline as assayed by CFS. In embodiments, the IL-1 antagonist is P05 and the method is effective to improve dry eye by at least 25%, 30%, 40%, 45%, 50%, 55%, or 60% compared with baseline dry eye as assayed, e.g., by CFS.

In embodiments, an IL-1 antagonist is effective to treat ocular pain. In embodiments, the IL-1 antagonist is P05 and the method is effective to improve ocular pain by at least 25%, 30%, 40%, 45%, 50%, 55%, or 60% compared with baseline ocular pain as assayed, e.g., by the pain/sore eye question in the OSDI. In embodiments, the method is effective to improve ocular pain by at least 45%. In embodiments, ocular pain is assessed using the OSDI-pain/sore eye question.

In embodiments, the subject has a baseline OSDI of 19-100. In some such embodiments, the method is effective to improve ocular pain by at least 25%, 30%, 40%, or 45%.

In embodiments, the subject has a baseline OSDI less than 50, e.g., 19-49. In some such embodiments, the method is effective to improve ocular pain by at least 40, 45, 50, 55, or 60%. In some embodiments, the method is effective to improve ocular pain by at least 38%-61% compared to baseline, e.g., at least 40%-60%.

In embodiments, during periods of treatment with the IL-1 antagonist, the IL-1 antagonist is administered to the subject (e.g., administered to the eye of the subject, e.g., topically administered to the eye) 1-10 times per day (e.g., two, three, four, or five times per day). In embodiments, the IL-1 antagonist is administered ad libitum. In embodiments, the IL-1 antagonist is administered at least one per day, optionally with further administration ad libitum.

In embodiments, the IL-1 antagonist comprises P05, e.g., at a concentration of 1-50 mg/ml (e.g., 5-20 mg/ml).

IL-1 antagonists

In general, an IL-1 antagonist is a molecule that can specifically bind to an IL-1, an IL-1R, or a complex containing an IL-1 and an IL-1R. "Specifically binds" means that a molecule preferentially binds to a selected molecule and does not display significant binding to other molecules. In addition, an IL-1 antagonist can inhibit at least one IL-1 associated activity, for example, the ability to inhibit IL-6 expression in a cell line that can express IL-6 in response to exposure to an IL-1. IL-1 antagonists suitable for treating ocular pain include biologic therapeutics such as anakinra, which is a genetically engineered, non-glycosylated IL-IRa, and P05, a genetically engineered polypeptide containing sequences derived from an IL-IRa and sequences derived from an IL-Ιβ (see USSN 13/812582, issued as U.S. Patent No. 8,853,150 for a description of P05 and other biologic IL-1 antagonists).

Formulation and treatment

An IL-1 antagonist that is useful for treating ocular pain is typically formulated in a format suitable for administration to the eye, e.g., topical administration or intraocular administration. Such formulations are known in the art. In general, a biologic IL-1 antagonist is formulated such that the concentration of IL-1 antagonist is at least 0.5 mg/ml, at leastl mg/ml, at least 5 mg/ml, at leastlO mg/ml, at least 15 mg/ml, at least 20 mg/ml, at least 30 mg/ml, at least 40 mg/ml, or at least 50 mg/ml. In general, the formulation is at a pH that is comfortable for delivery to the eye, e.g., pH 6.5-7.6. Formulations are delivered in a therapeutically effective amount. A "therapeutically effective amount" of an agent described herein can vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the compound to elicit a desired response in the individual, e.g., amelioration of at least one disorder parameter, or amelioration of at least one symptom of the disorder (and optionally, the effect of any additional agents being administered). A therapeutically effective amount is also one in which any toxic or detrimental effects of the composition are outweighed by the therapeutically beneficial effects. A composition as described herein is generally administered in a therapeutically effective amount.

The topical formulation can be a liquid formulation or semi-solid, for example, a topical formulation can include an aqueous solution, an aqueous suspension, an ointment or a gel. An ophthalmic IL-1 antagonist formulation can be topically applied to the front of the eye, under the upper eyelid, on the lower eyelid and in the cul-de-sac. Typically, the ophthalmic formulation is sterile. An IL-1 antagonist ophthalmic formulation can contain one or more pharmaceutical excipients suitable for the preparation of ophthalmic formulations. Examples of such excipients are preserving agents, buffering agents, chelating agents, antioxidant agents and salts for regulating the osmotic pressure. Ophthalmic formulations, including both ointments and suspensions, typically have a viscosity that is suited for the selected route of administration. In some embodiments, the ophthalmic formulation has a viscosity from about

25 centipoise to about 30,000 centipoise.

In some embodiments, the formulation is a liquid formulation comprising a polymer. Such a polymer can be used to improve the bioavailability, raise viscosity, or reduce drainage from the eye of a liquid formulation. Suitable polymers include, but are not limited to, those described in Wagh et al.

(Asian J Pharm, 2: 12-17, 2008). In non-limiting examples, the polymer is sodium hyaluronase, chitosan, a cyclodextrin (e.g., hydroxypropyl- -cyclodextrin), polygalactoronic acid, xyloglucan, xanthan gum, gellan gum, a thiomer, a poly(ortho ester) (e.g., Einmahl, Adv Drug Deliv Rev 53:45-73, 2001), or a tamarind seed polysaccharide (e.g., Ghelardi et al., Antimicrob Agents Chemother 48:3396-3401, 2004). In some embodiments, a formulation comprising an IL-1 antagonist composition for ophthalmic delivery can comprise one or more of surfactants, adjuvants, buffers, antioxidants, tonicity adjusters, preservatives (e.g., EDTA, BAK (benzalkonium chloride), sodium chlorite, sodium perborate, polyquaterium-1), thickeners or viscosity modifiers (e.g., carboxymethyl cellulose, hydroxymethyl cellulose, polyvinyl alcohol, polyethylene glycol, glycol 400, propylene glycol hydroxymethyl cellulose, hydroxypropyl-guar, hyaluronic acid, and hydroxypropyl cellulose) and the like. Additives in the formulation may include, but are not limited to, sodium chloride, sodium bicarbonate, sorbic acid, methyl paraben, propyl paraben, chlorhexidine, castor oil, and sodium perborate.

In some embodiments, purified or deionized water is used in the composition. The pH can be adjusted by adding any physiologically and ophthalmically acceptable pH adjusting acids, bases or buffers to within the range of about 5.0 to 8.5, e.g., pH 6.5, pH 7.0, pH 7.3, pH, 7.4, pH 7.5, or pH 7.6. Ophthalmically acceptable examples of acids include acetic, boric, citric, lactic, phosphoric, hydrochloric, and the like, and examples of bases include sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, tromethamine, trishydroxymethylamino-methane, and the like. Examples of salts and buffers that can be used in a formulation include citrate/dextrose, sodium bicarbonate, ammonium chloride and mixtures of the aforementioned acids and bases.

In some embodiments, the osmotic pressure of the ophthalmic composition may be from about 10 milliosmolar (mOsM) to about 400 mOsM, for example, 200 to 400 mOsM, or 220 to 370 mOsM. Generally, the osmotic pressure can be adjusted using physiologically and ophthalmically acceptable salts or excipients. In some embodiments, sodium chloride is included in a formulation, for example, sodium chloride is present in a formulation in a concentration ranging from 0.01% to 1% by weight, or from 0.05% to 0.45% by weight, based on the total weight of the composition. Equivalent amounts of one or more salts made up of cations such as potassium, ammonium and the like and anions such as chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, bisulfate, sodium bisulfate, ammonium sulfate, and the like can also be used in addition to or instead of sodium chloride to achieve osmolalities within the desired range. In some embodiments, a sugar such as mannitol, dextrose, sorbitol, glucose and the like is also used to adjust osmolality.

In some embodiments, the methods involve forming or supplying a depot of the agent in contact with the external surface of the eye. A depot refers to a source of agent that is not rapidly removed by tears or other eye clearance mechanisms. This allows for continued, sustained high concentrations of agent be present in the fluid on the external surface of the eye by a single application. In some embodiments, the depot can remain for up to eight hours or more. In some embodiments, the ophthalmic depot formulation includes, but is not limited to, aqueous polymeric suspensions, ointments, and solid inserts. In some embodiments, a semi-solid composition is a liquid formulation that increases in viscosity upon application to the eye, typically due to the presence of a polymer in the liquid formulation for which an increase is viscosity occurs with a change in temperature, pH, or electrolyte concentration. The polymer can be, for example, cellulose acetophthalate, polyacrylic acid, gellan gum, hyaluronase, chitosan, salts of alginic acid (e.g., sodium alginate), or a block copolymer of ethylene oxide and propylene oxide (e.g., Pluronic®, BASF; poloxamer). In some embodiment, the polyacrylic acid is cross- linked acrylic acid (e.g., Carbopol®). In some embodiments, the semi-solid composition comprises a mixture of carbopol and a block copolymer of ethylene oxide and propylene oxide; a mixture of methyl cellulose and hydroxy ethyl cellulose; or a mixture of polyethylene glycol and a block copolymer of ethylene oxide and propylene oxide.

In some embodiments, the IL-1 antagonist containing ophthalmic formulation is an ointment or gel. In some embodiments, the ophthalmic formulation is an oil-based delivery vehicle. For example, the formulation can comprises a petroleum or lanolin base to which the IL-1 antagonist composition is added (for example at 0.1 to 2%), and excipients. Common bases can include, but are not limited to, mineral oil, petrolatum and combinations thereof. In some embodiments, the ointment is applied as a ribbon onto the lower eyelid.

In some cases, the ophthalmic composition is an ophthalmic insert. For example, the ophthalmic insert is biologically inert, soft, bio-erodible, viscoelastic, stable to sterilization after exposure to therapeutic agents, resistant to infections from air borne bacteria, bio-erodible, biocompatible, and/or viscoelastic. In some embodiments, the insert comprises an ophthalmically acceptable matrix, e.g., a polymer matrix. The matrix is typically a polymer and the IL-1 antagonist composition is dispersed within the matrix or bonded to the polymer matrix. In some embodiments, the agent is slowly released from the matrix through dissolution or hydrolysis of a covalent bond. In some embodiments, the polymer is bioerodible (soluble) and the dissolution rate thereof can control the release rate of the agent dispersed therein. In another form, the polymer matrix is a biodegradable polymer that breaks down such as by hydrolysis to thereby release the agent bonded thereto or dispersed therein. In further embodiments, the matrix and agent can be surrounded with an additional polymeric coating to further control release. In some embodiments, the insert comprises a biodegradable polymer such as polycaprolactone (PCL), an ethylene/vinyl acetate copolymer (EVA), polyalkyl cyanoacrylate, polyurethane, a nylon, or poly(dl- lactide-co-glycolide) (PLGA), or a copolymer of any of these. In some cases, the agent is dispersed into the matrix material or dispersed amongst the monomer composition used to make the matrix material prior to polymerization. In some embodiments, the amount of agent is from about 0.1 to about 50% or from about 2 to about 20%. The biodegradable or bioerodible polymer matrix can be used so that the spent insert does not have to be removed from the eye. As the biodegradable or bioerodible polymer is degraded or dissolved, the agent is released.

In further embodiments, the ophthalmic insert comprises a polymer, including, but are not limited to, those described in Wagh, et al., Asian J Pharm 2: 12-17 (2008), which is incorporated herein by reference in its entirety. In some embodiments, the insert comprises a polymer selected from

polyvinylpyrrolidone (PVP), an acrylate or methacrylate polymer or copolymer (e.g., Eudragit® family of polymers (Evonik, Essen, Germany), hydroxymethyl cellulose, polyacrylic acid, poly(amidoamine) dendrimers, poly(dimethylsiloxane), polyethylene oxide, poly(lactide-co-glycolide), poly(2- hydroxyethylmethacrylate), polyvinyl alcohol), or poly (propylene fumarate). In some embodiments, the insert comprises Gelfoam®. In some embodiments, the insert is a polyacrylic acid of 450 kDa-cysteine conjugate.

The insert can comprise a core that contains the IL-1 antagonist composition and an outer tube (e.g., as described in U.S. Patent Pub. No. 20040009222). In some cases, the outer tube can be permeable, semi-permeable, or impermeable to the drug. In some embodiments, the core includes a polymer matrix that does not have a significant effect on the rate of IL-1 antagonist composition release. In some cases, the outer tube, the polymer matrix of the core, or both is bioerodible. The co-extruded product can be segmented into drug delivery devices. In some embodiments, the device is uncoated so that the respective ends are open, or the device is coated with, for example, a layer that is permeable to the IL-1 antagonist composition, semi-permeable to the IL-1 antagonist composition, or is bioerodible. In certain

embodiments, the IL-1 antagonist composition and at least one polymer are admixed in powder form.

In some embodiments, the ophthalmic composition is an ophthalmic film. Polymers suitable for such films include, but are not limited to, those described in Wagh, et al. {supra). In some embodiments, the film is a soft-contact lens, for example, a lens composed of copolymers of Ν,Ν-diethylacrylamide and methacrylic acid cross-linked with ethyleneglycol dimethacrylate.

In certain embodiments, the IL-1 antagonist is in an insert that is in a tubular form, and may be segmented.

In some embodiments, the IL-1 antagonist composition is formulated in a therapeutically effective amount, coated by or dispersed in a polymer matrix, such that the IL-1 antagonist composition is in granular or particulate form. In some embodiments, the IL-1 antagonist composition is released from the formulation as drug from the granules dissolves into or within the matrix, diffuses through the matrix, and is released into the surrounding physiological fluid. In some embodiments, the rate of release is limited primarily by the rate of dissolution of the IL-1 antagonist composition from the granules/particles into the matrix; the steps of diffusion through the matrix and dispersion into the surrounding fluid are primarily not release-rate-limiting. In certain embodiments, the polymer matrix is non-bioerodible, while in other embodiments it is bioerodible. Exemplary non-bioerodible polymer matrices can be formed from polyurethane, polysilicone, poly(ethylene-co-vinyl acetate) (EVA), polyvinyl alcohol, and derivatives and copolymers thereof. Exemplary bioerodible polymer matrices can be formed from polyanhydride, polylactic acid, polyglycolic acid, polyorthoester, polyalkylcyanoacrylate, and derivatives and copolymers thereof.

In some cases, the IL-1 antagonist composition is formulated in a collagenous material. For example, the insert can be a soluble ophthalmic drug insert (e.g., a polymeric oval film that can be introduced in the upper conjuctival sac for drug delivery; an elliptical insert such as OCUSERT® (pilocarpine ocular therapeutic system, Alza Corporation) which is made of ethylene vinyl acetate;

Lacrisert®, a rod shaped insert made of cellulose; New Ophthalmic Drug Delivery Systems (NODS), made of poly(vinyl alcohol); or an inserts described in Fabrizio (Adv Drug Deliv Rev 16: 95-106, 1998). In some cases, the insert comprises collagen, gelatin, or a polymer, wherein the polymer is selected from polycaprolactone (PCL), an ethylene/vinyl acetate copolymer (EVA), polyalkyl cyanoacrylate, polyurethane, a nylon, poly(dl-lactide-co-glycolide) (PLGA), or a copolymer of any of these. In some cases, the insert is implanted under the upper eyelid. In some cases, the insert is implanted in the posterior segment of the eye, in the choroidal space, or in the sclera. In some embodiments, the insert is implanted intravitreally or sub-retinally. In some embodiments, the insert is injected sub-retinally. Examples of such methods of administration and techniques for their preparation are set forth in Remington's: The Practice of Science of Pharmacy, 20^th edition (Lippincott Williams & Wilkins, 2006), which is incorporated herein by reference in its entirety.

In some embodiments, the aqueous agent concentration is from about 0.002 μg/mL to about 0.01 μg/mL or from about 0.01 μg /mL, to about 0.05 μg /mL, or less than about 0.05 μg /mL. In some embodiments, the agent is released at a rate of about 1 μg /day to about 50 μg /day, or from about 1 μg /day to about 10 μg /day. In some embodiments, the insert further comprises an additional therapeutic agent, as detailed above, e.g., fluocinolone acetonide (such as that found in the ophthalmic insert Retisert®).

An IL-1 antagonist composition can be provided in an aqueous polymeric suspension. In some embodiments, the IL-1 antagonist composition or a polymeric suspending agent is suspended in an aqueous medium (e.g., having the properties as described above). Examples of polymeric suspending agents include, but are not limited to, dextrans, polyethylene glycols, polyvinylpyrolidone, polysaccharide gels, Gelrite®, cellulosic polymers like hydroxypropyl methylcellulose, and carboxy-containing polymers such as polymers or copolymers of acrylic acid, as well as other polymeric demulcents. In some embodiments, the polymeric suspending agent is a water swellable, water insoluble polymer, especially a cross-linked carboxy-containing polymer. In some embodiments, the polymeric suspending agent comprises from at least about 90% to about 99.9%, or from about 95% to about 99.9%, by weight based on the total weight of monomers present, of one or more carboxy-containing monoethylenically unsaturated monomers. In some embodiments, the carboxy-containing monoethylenically unsaturated monomer includes acrylic acid, methacrylic acid, ethacrylic acid, methylacrylic acid (crotonic acid), cis- .alpha.-methylcrotonic acid (angelic acid), trans-a-methylcrotonic acid (tiglic acid), a-butylcrotonic acid, .alpha.-phenylacrylic acid, a-benzylacrylic acid, a-cyclohexylacrylic acid, phenylacrylic acid (cinnamic acid), coumaric acid (o-hydroxycinnamic acid), and umbellic acid (p-hydroxycoumaric acid). In some embodiments, the polymer is cross-linked by a polyfunctional crosslinking agent (e.g., a difunctional crosslinking agent). In some embodiments, the crosslinking agent is contained in an amount of from about 0.01% to about 5%, or from about 0.1% to about 5.0%, or from about 0.2% to about 1%, based on the total weight of monomers present. In some embodiments, the crosslinking agents are nonpolyalkenyl polyether difunctional crosslinking monomers such as divinyl glycol, 2,3-dihydroxyhexa-l,5-diene, 2,5- dimethyl-l,5-hexadiene, divinylbenzene, N,N-diallylacrylamide, N,N-diallymethacrylamide; polyalkenyl polyether crosslinking agents containing two or more alkenyl ether groupings per molecule, e.g., alkenyl ether groupings containing terminal H₂C=C groups, prepared by etherifying a polyhydric alcohol containing at least four carbon atoms and at least three hydroxyl groups with an alkenyl halide such as allyl bromide or the like, e.g., polyallyl sucrose, polyallyl pentaerythritol, or the like; diolefinic non- hydrophilic macromeric crosslinking agents having molecular weights of from about 400 to about 8,000, such as insoluble diacrylates and polyacrylates and methacrylates of diols and polyols, diisocyanate hydroxyalkyl acrylate or methacrylate reaction products of isocyanate terminated prepolymers derived from polyester diols, polyether diols or polysiloxane diols with hydroxyalkylmethacrylates, and the like.

In some embodiments, the cross-linked polymers are made from a carboxy-containing monoethylenically unsaturated monomer or monomers as the sole monoethylenically unsaturated monomer present, together with a crosslinking agent or agents. In some embodiments, the polymers are ones in which up to about 40%, and preferably from about 0% to about 20% by weight, of the carboxy- containing monoethylenically unsaturated monomer or monomers has been replaced by one or more non- carboxyl-containing monoethylenically unsaturated monomer or monomers containing only

physiologically and ophthalmically innocuous substituents, including acrylic and methacrylic acid esters such as methyl methacrylate, ethyl acrylate, butyl acrylate, 2-ethylhexylacrylate, octyl methacrylate, 2- hydroxyethylmethacrylate, 3-hydroxypropylacrylate, and the like, vinyl acetate, N-vinylpyrrolidone, and the like (see Mueller et al. U.S. Pat. No. 4,548,990, the entire contents of which are incorporated herein by reference, for a more extensive listing of such additional monoethylenically unsaturated monomers). In some embodiments, the polymers include polycarbophil (Noveon AA-1), Carbopol®, and DuraSite®. In some embodiments, the cross-linked polymers are prepared by suspension or emulsion polymerizing the monomers, using conventional free radical polymerization catalysts, to a dry particle size of not more than about 50 μ in equivalent spherical diameter. In some embodiments, the average dry particle size is from about 1 to about 30 μ or from about 3 to about 20 μ in equivalent spherical diameter. In some embodiments, the polymer particles are obtained by mechanically milling larger polymer particles. In further embodiments, such polymers will have a molecular weight from about 250,000 to about 4,000,000 or from 3,000,000,000 to 4,000,000,000. In other embodiments, the particles of cross-linked polymer are monodisperse, meaning that they have a particle size distribution such that at least about 80%, about 90% or about 95%, of the particles fall within a 5 μ band of major particle size distribution. In further embodiments, the monodisperse particle size means that there is no more than about 20%, about 10%, or about 5% particles of a size below 1 μ In some embodiments, the aqueous polymeric suspension comprises from about 0.05 to about 1%, from about 0.1 to about 0.5%, or from about 0.1 to about 0.5%, of the agent and from about 0.1 to about 10%, from about 0.5 to about 6.5%, from about 0.5 to about 2.0%, from about 0.5% to about 1.2%, from about 0.6 to about 0.9%, or from about 0.6 to about 0.8% of a polymeric suspending agent. Although referred to in the singular, it should be understood that one or more species of polymeric suspending agent can be used with the total amount falling within the stated ranges. In one embodiment, the amount of insoluble lightly cross-linked polymer particles, the pH, and the osmotic pressure can be correlated with each other and with the degree of crosslinking to give a composition having a viscosity in the range of from about 500 to about 100,000 centipoise, and preferably from about 1,000 to about 30,000 or about 1,000 to about 10,000 centipoise, as measured at room temperature (about 25°C.) using a Brookfield Digital LVT Viscometer equipped with a number 25 spindle and a 13R small sample adapter at 12 rpm. In some embodiments, the viscosity is from about 10 to about 400 centipoise, from about 10 to about 200 centipoise, or from about 10 to about 25 centipoise.

In some embodiments, the aqueous polymeric suspensions may be formulated so that they retain the same or substantially the same viscosity in the eye that they had prior to administration to the eye. In some embodiments, they may be formulated so that there is increased gelation upon contact with tear fluid. For instance, when a formulation containing DuraSite® or other similar polyacrylic acid-type polymer is administered to the eye at a pH of less than about 6.7, the polymer may swell upon contact with tear fluid since it has a higher pH (around 7). This gelation or increase in gelation may lead to entrapment of the suspended particles, thereby extending the residence time of the composition in the eye. In some embodiments, the agent is released slowly as the suspended particles dissolve over time. In some embodiments, this delivery route increases patient comfort and increased agent contact time with the eye tissues, thereby increasing the extent of drug absorption and duration of action of the formulation in the eye. The agents contained in these drug delivery systems will be released from the gels at rates that depend on such factors as the drug itself and its physical form, the extent of drug loading and the pH of the system, as well as on any drug delivery adjuvants, such as ion exchange resins compatible with the ocular surface, which may also be present.

In some embodiments, treatment includes administering a pharmaceutical IL-1 antagonist composition to a patient, the composition comprising the IL-1 antagonist composition and a

pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical compositions comprise, as the active ingredient, one or more of the agents above in combination with one or more pharmaceutically acceptable carriers (excipients). In making the compositions of the invention, the agent is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semisolid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the formulations for topical administration to the eye are generally in the form of suspensions, emulsions, solutions, ointments containing, for example, up to 10% by weight of the active compound, sterile solutions, and sterile packaged powders that can be hydrated.

In certain embodiments, the treatment is not continuous, e.g., a patient in need of treatment is administered an IL-1 antagonist at least once per day for, e.g., at least one week, two weeks, three weeks, four weeks, five weeks, six weeks, eight weeks, two months, three months, six months, or more, then is not treated with the IL-1 antagonist for, e.g., one week, two weeks, three weeks, four weeks, five weeks, six weeks, eight weeks, two months, three months, six months, or more, or until there is a recurrence of an unacceptable level of pain, at which time the IL-1 antagonist is again administered (recommenced). In some cases, the treatment with the IL-1 antagonist is recommenced before an unacceptable level of pain is reported, e.g., to prophylactically avoid or diminish pain . The advantages of this regimen are that it limits the amount of exposure of the patient to the therapeutic agent, limits the amount of manipulation of the eye, and can be an economic benefit in that less drug is required by the patient. During the period of administration of the IL-1 antagonist, the antagonist can be administered, e.g., once per day, twice per day, three times per day or more.

The amount and frequency of an IL-1 antagonist composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions can be administered to a patient already suffering from a disease associated with ocular pain or having idiopathic ocular pain in an amount sufficient to cure or at least partially ameliorate the ocular pain. Effective doses may be determined by the judgment of the attending clinician and will depend on the condition being treated and on factors such as the severity of the disease, the age, weight and general condition of the patient, and the like. EQUIVALENTS

All technical features can be individually combined in all possible combinations of such features.

The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting on the invention described herein.

EXAMPLE

The following non-limiting examples further illustrate embodiments of the inventions described herein.

Example 1 : Clinical treatment of ocular pain with an IL-1 antagonist

A double -masked clinical trial was conducted in which subjects diagnosed with dry eye disease and having an ocular surface disease index (OSDI) of 19 to 100 were treated with vehicle only for one week then treated with vehicle or a biologic IL-1 antagonist (P05) at a concentration of 5 mg/ml or 20 mg/ml three times per day for six weeks with a final examination one week after termination of the treatment arms of the trial (i.e., at week 7). Subjects were examined bi-weekly during the trial. Corneal fluorescein staining (CFS) was used as one assay of dry eye disease. A decrease in CFS staining from baseline indicates an improvement in a physical sign of disease.

Over the six treatment weeks, CFS generally decreased, indicating an improvement in this observable disease sign in the entire cohort of subjects (ITT population) and the evaluatable efficacy population (EE population, which excludes subjects with major protocol deviations) (Fig. 1 and Fig. 2). Surprisingly, unlike the data for the pain, CFS scores were improved compared to vehicle for subjects in the treatment arms (i.e., receiving the IL-1 antagonist) for at least for one week after the termination of the treatment arm of the study. This was also observed for the EE subjects. Improvement over baseline continued for up to twelve weeks (the length of the trial).

Subjects' eye pain generally improved over the six weeks of treatment with the IL-1 antagonist. With respect to the OSDI-pain/sore eye question, subjects receiving P05 (efficacy evaluable), improved from baseline by up to 46% (0.9 units) in OSDI/pain at six weeks, with improvement reported as early as two weeks (Fig. 3). In an analysis of subjects having an initial OSDI of 19-49 (EE 50 population), as evaluated using OSDI-pain/sore eye, pain improved by as much as 61% (0.9 units) (Fig. 4).

Corneal esthesiometry demonstrated that P05 did not change corneal sensation (as assayed by estheiometry) from baseline over the six week treatment. This indicates that perceived pain is not associated with corneal sensation for P05 treatment.

These data indicate that ocular pain and physical signs of disease are not necessarily linked and an IL-1 antagonist can be an appropriate treatment for ocular pain independent of signs of physical disease. Further, the data demonstrate that the effect of IL-1 antagonist dry eye can persist after the termination of treatment with the IL-1 antagonist.

The data also indicate that P05 improves eye pain to a greater extent than an IL-IRa inhibitor (anakinra). Data from an earlier single center study of subjects with dry eye disease related to meibomian gland disease were treated with topical IL-IRa, three times daily for 12 weeks. In this trial, symptoms were also assessed using OSDI scores. Analysis of the data from the earlier study demonstrated that IL-1 inhibition improved ocular pain from baseline by 37% and 36% in OSDI-Pain/Sore Eye at 6 and 12 weeks. The data provided herein demonstrate that a chimeric IL-1 inhibitor, P05, caused an improvement in pain by 46% in subjects having an OSDI or 19-100 and by 61% in subjects having an OSDI of less than 50. These data demonstrate that P05 can be used to treat eye pain and is more effective than topical IL-IRa.

Importantly, in the P05 trial, corneal esthesiometry showed that P05 did not change corneal sensation (as measured by esthesiometry) from baseline over the 6 week treatment. These data demonstrate that P05 can be used in a method of treating eye pain and/or dry eye without affecting corneal sensation.

Other embodiments are within the scope of the following claims.

Claims

What is claimed is:

1. A method of treating dry eye using a intermittent treatment regimen, wherein the intermittent treatment regimen comprises

a. treating a subject having dry eye with a therapeutically effective amount of an IL-1 antagonist for at least one week followed by;

b. discontinuing treatment with the IL-1 antagonist for at least one week, wherein the subject exhibits the same level of dry eye or a decrease in dry eye at the end of the no treatment week compared to the level of dry eye at the end of treatment with the IL-1 antagonist.

2. The method of claim 1, wherein the IL-1 antagonist is administered for at least 1 week, at least 2 weeks, at least three weeks, at least 4 weeks, at least 5 weeks, or at least six weeks.

3. The method of claim 1 or claim 2, further comprising

c. following (b) administering a therapeutically effective amount of the IL-1 antagonist.

4. The method of any one of claims 1, 2, or 3, wherein the IL-1 antagonist is anakinra or P05.

5. A package comprising an IL-1 antagonist formulated for ocular administration and

instructions for a discontinuous treatment regimen.

6. A method of treating ocular pain in a subject, the method comprising

a. identifying a subject having ocular pain related to a non-inflammatory cause; and b. administering a therapeutically effective amount of an IL-1 antagonist.

7. The method of claim 6, wherein the subject is not diagnosed with dry eye disease.

8. The method of claim 6, wherein the pain is neuropathic pain

9. The method of claim 6, wherein the pain is acute pain.

10. The method of claim 6, wherein the pain is chronic pain

11. The method of claim 6, wherein the pain is associated with eye surgery.

12. The method of claim 6, wherein the pain is associated with dry eye disease.

13. The method of claim 6, wherein the subject has idiopathic ocular pain, or ocular pain

associated with conjunctivitis, corneal abrasion, sty, or chalazion.

14. The method of claim 6, wherein the administering comprises discontinuous treatment.

15. The method of any one of claim 4-13, wherein the IL-1 antagonist is anakinra or P05.

16. A method of treating ocular pain in a subject, the method comprising administering a

therapeutically effective amount of P05 to the subject.

17. The method of claim 16, wherein the subject has an OSDI of 19-100% prior to administration of the P05 and after six weeks of treatment has at least a 46% improvement in OSDI- Pain/Sore Eye score compared to the OSDI-Pain/Sore Eye score prior to treatment.

18. The method of claim 16, wherein the subject has an OSDI of 19-49% prior to administration of the P05 and after six weeks of treatment has at least a 61% improvement in OSDI- Pain/Sore Eye score compared to the OSDI-Pain/Sore Eye score prior to treatment.