Ophthalmic formulation and use of the same

Abstract

To provide reproxalap ophthalmic solution and a method for using the solution for treating a disease or a disorder such as allergic conjunctivitis.SOLUTION: In some embodiments, the present invention relates to an ophthalmic solution containing reproxalap or pharmaceutically acceptable salt thereof and pharmaceutically acceptable filler, in which concentration of reproxalap or pharmaceutically acceptable salt thereof is approximately 0.5%w / v or less and approximately 0.1%w / v or greater. In some embodiments, the reproxalap and a cyclodextrin filler in the ophthalmic solution have a molar ratio of less than 1:2.1. In some embodiments, the concentration of reproxalap or pharmaceutically acceptable salt thereof is approximately 0.2%w / v to approximately 0.3%w / v.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 62 / 824,233, filed March 26, 2019, and U.S. Provisional Application No. 62 / 857,874, filed June 6, 2019, the entire contents of each of which are incorporated herein by reference.

[0002] The present invention relates to ophthalmic solutions comprising reproxalap or a pharma- ceutically acceptable salt thereof for the treatment of diseases or disorders such as allergic conjunctivitis (AC). [Background technology]

[0003] Acute allergic conjunctivitis (AC) is experienced by approximately 40% of the general population (Singh et al., J Allergy Clin Immunol., 2010, 126(4):778-783). AC is associated with type I (immediate) hypersensitivity involving immunoglobulin E (IgE)-mediated release of histamine and other mediators from mast cells and basophils. Mast cell degranulation leads to the release of inflammatory mediators and activation of enzyme cascades that generate proinflammatory mediators (Mishra et al., Recent Pat Inflamm Allergy Drug Discov., 2011, 5(1):26-36). Release of various mediators in the eye leads to inflammation of the conjunctiva that also affects the cornea and eyelids, causing symptoms including itching and burning, tearing, chemosis (conjunctival edema), conjunctival congestion, hyperemia, eyelid edema and mucus secretion.

[0004] The initial symptoms of allergic conjunctivitis, occurring within minutes of allergen exposure, are likely due primarily to the release of histamine (Leonardi, A., Exp Eye Res. 2013, 117:106-17), which is accompanied by a peak in tearing approximately 5 minutes after allergen exposure and a notable decline over 30-40 minutes (Ackerman et al., Ther Adv Chronic Dis., 2016, 7(1):52-67.2016). Shortly after the histamine surge, the symptoms of allergic conjunctivitis are perpetuated by non-histamine inflammatory mediators such as cellular infiltrates, cytokines, leukotrienes, proteases and other factors including aldehydes (Leonardi, A., Exp Eye Res., 2013, 117:106-17). Aldehydes are pro-inflammatory mediators of both allergic (Th2) and autoimmune (Th1) diseases, and elevated levels of toxic aldehydes are associated with allergic conjunctivitis and other ocular and systemic diseases (Bacsi et al., J Allergy Clin Immunol., 2005, 116(4): 836-843; Boldogh et al., J Clin Invest., 2005, 115(8): 2169-2179; Wakamatsu et al., Mol Vis., 2010, 16: 2465-2475).

[0005] Aldehydes are reactive and bind to proteins, carbohydrates, lipids and nucleic acids (Esterbauer et al., Free Radical Biology and Medicine, 1990, 11(1):81-128). Free aldehydes, that is, aldehydes that are not sequestered or otherwise protected by specific metabolic processes, can be toxic, while aldehydes that bind to cellular components can lead to inflammation (Yadav et al., Oxidative Medicine and Cellular Longevity 2013, Volume 2013, Article ID 690545), molecular dysfunction (O'Brien et al., Critical Reviews in Toxicology, 2005, 35(7):609-62) and lipofuscin components in the retina. This can result in the accumulation of indigestible metabolites such as ketamine and ketamine (Boyer et al., J Biol Chem., 2012, 287:22276-86). In biological systems, aldehydes are formed by a variety of processes including the oxidation of alcohols, polyamine and glucose metabolism, and oxidative stress. In some disease states, aldehyde concentrations can be increased. Increased levels of aldehydes, especially malonyldialdehyde (MDA), most commonly thought to result from lipid peroxidation, have been reported in various inflammatory eye diseases, including pterygium, Behçet's disease, Sjögren's syndrome, anterior uveitis, and dry eye disease (Sandikci et al., Acta Dermato-Venereologica, 2003, 83(5):342-6; Cejkova et al., Histology and Histopathology, 2007, 22(9):997-1003; Balci et al., Molecular Vision, 2011, 17:443-7; Turk et al., Ocular Immunology and Inflammation, 2014, 22(2):127-32; Choi et al., Current Eye Research, 2016, 41(9):1143-9). [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Sandikci et al., Acta Dermato-Venereologica (2003) 83(5):342~6 [Non-Patent Document 2] Cejkova et al., Histology and Histopathology (2007) 22(9):997~103 [Non-Patent Document 3] Balci et al., Molecular Vision (2011) 17:443-7 [Non-Patent Document 4] Turk et al., Ocular Immunology and Inflammation (2014) 22(2):127~32 [Non-Patent Document 5] Choi et al., Current Eye Research (2016) 41(9):1143-9 Summary of the Invention [Means for solving the problem]

[0007] Thus, there is an unmet need for improved ophthalmic formulations of drugs that can treat allergic conjunctivitis.

[0008] In some aspects, the present invention relates to an ophthalmic solution comprising reproxalap or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient, wherein the concentration of reproxalap or a pharma- ceutically acceptable salt thereof is about 0.5% w / v or less and about 0.1% w / v or more. In some embodiments, the reproxalap and the cyclodextrin excipient in the ophthalmic solution are in a molar ratio of less than 1:2.1. In some embodiments, the concentration of reproxalap or a pharma- ceutically acceptable salt thereof is about 0.2% w / v to about 0.3% w / v.

[0009] In some embodiments, the ophthalmic solution comprises about 0.25% w / v of a pharma- ceutically acceptable excipient selected from Reproxalap and a cyclodextrin. In some embodiments, the cyclodextrin is about 7% w / v. In some embodiments, the cyclodextrin is about 11% w / v. In some embodiments, the cyclodextrin is sulfobutylether-β-cyclodextrin or hydroxypropyl-β-cyclodextrin.

[0010] In some embodiments, the ophthalmic solution comprises about 0.5% w / v of a pharma- ceutically acceptable excipient selected from reproxalap and a cyclodextrin. In some embodiments, the cyclodextrin is about 9.5% w / v. In some embodiments, the cyclodextrin is sulfobutylether-β-cyclodextrin or hydroxypropyl-β-cyclodextrin.

[0011] In another aspect, the present invention relates to a method for treating allergic conjunctivitis in a subject, comprising topically administering a therapeutically effective amount of the ophthalmic solution of the present invention to either eye of a subject in need thereof. In some embodiments, the allergic conjunctivitis treated is seasonal allergic conjunctivitis. In some embodiments, the allergic conjunctivitis treated is contact conjunctivitis. In some embodiments, the allergic conjunctivitis treated is perennial conjunctivitis.

[0012] In some embodiments of the method, the ophthalmic solution of the present invention is administered to the eye of a subject prior to exposure to an ocular allergen. In some embodiments, the ophthalmic solution is administered to the eye of a subject in need thereof prior to expected or certain exposure to an ocular allergen, for example within the duration of therapeutic effect of 0.25% w / v or 0.5% w / v Reproxalap solution. In some embodiments, the ophthalmic solution is administered 3.5 hours or less, 3 hours or less, 2.5 hours or less, 2 hours or less, 1.5 hours or less, 1 hour or less, 0.5 hours or less, 25 minutes or less, 20 minutes or less, 25 minutes or less, 20 minutes or less, 15 minutes or less, 10 minutes or less, or 5 minutes or less prior to expected or certain exposure to an ocular allergen, or immediately prior to expected or certain exposure to an ocular allergen.

[0013] In some embodiments, the subject treated before expected or certain exposure to eye allergens has a history of allergic conjunctivitis. In some embodiments, the subject treated before expected or certain exposure to eye allergens has a history of allergic conjunctivitis and has a positive allergen skin test for one or more eye allergens. In some embodiments, the subject treated before expected or certain exposure to eye allergens has a previous clinical diagnosis of allergic conjunctivitis. In some embodiments, the subject treated before expected or certain exposure to eye allergens has a previous clinical diagnosis of allergic conjunctivitis and has a positive allergen skin test for one or more eye allergens.

[0014] In some embodiments of the method, the ophthalmic solution of the present invention is administered at or after exposure to eye allergen. In some embodiments, the ophthalmic solution of the present invention is administered immediately after exposure to eye allergen. In some embodiments, the ophthalmic solution of the present invention is administered at or after the onset of allergic conjunctivitis symptoms. In some embodiments, the method for treating allergic conjunctivitis in a subject comprises topically administering the ophthalmic solution of the present invention to the eye of a subject in need thereof at or after exposure to eye allergen or at or after the onset of allergic conjunctivitis symptoms, and the ophthalmic solution is administered 6 times a day, 5 times a day, 4 times a day (QID), 3 times a day (TID), twice a day (BID), once a day (QD) or as needed (PRN). In some embodiments, the method for treating allergic conjunctivitis comprises topically administering the ophthalmic solution of the present invention to the eye of a subject in need thereof at or after exposure to an ocular allergen or at or after the onset of symptoms of allergic conjunctivitis, the ophthalmic solution being administered 6 times a day, 5 times a day, 4 times a day (QID), 3 times a day (TID), 2 times a day (BID), once a day (QD), followed by administration as needed (PRN). In some embodiments of the method, the ophthalmic solution of the present invention is administered 4 times a day (QID), followed by administration as needed (PRN).

[0015] In some embodiments, treatment during or after exposure of the eye to an allergen or during or after the onset of symptoms of allergic conjunctivitis can be further divided into treatment for an initiation phase, an exacerbation phase, and / or a maintenance phase. In some embodiments, the ophthalmic solution is administered six times a day, five times a day, or four times a day (QID) during the initiation and / or exacerbation phase, followed by twice a day (BID), once a day (QD), or as needed (PRN) during the maintenance phase.

[0016] In some embodiments, the method for treating allergic conjunctivitis comprises administering an ophthalmic solution of the present invention to the eye of a subject in need thereof before expected or certain exposure to an ophthalmic allergen, and further comprises administering an ophthalmic solution of the present invention to the eye of the subject at or after exposure to an ophthalmic allergen, or at or after the onset of symptoms of allergic conjunctivitis. In some embodiments, the method for treating allergic conjunctivitis comprises a first treatment phase and a second treatment phase, the first treatment phase comprises administering an ophthalmic solution of the present invention to the eye of a subject in need thereof before expected or certain exposure to an ophthalmic allergen, or just before expected or certain exposure to an ophthalmic allergen, and the second treatment phase comprises administering an ophthalmic solution of the present invention to the eye at or after exposure to an ophthalmic allergen, or at or after the onset of symptoms of allergic conjunctivitis.

[0017] In some embodiments, in the first treatment phase of this two-phase treatment regimen, the ophthalmic solution of the present invention is administered 3.5 hours or less, 3 hours or less, 2.5 hours or less, 2 hours or less, 1.5 hours or less, 1 hour or less, 0.5 hours or less, 25 minutes or less, 20 minutes or less, 25 minutes or less, 20 minutes or less, 15 minutes or less, 10 minutes or less, or 5 minutes or less before expected or certain exposure to an ocular allergen, or immediately before expected or certain exposure to an ocular allergen.

[0018] In some embodiments, in the second treatment phase, the ophthalmic solution of the present invention is administered within 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60 minutes (1 hour), 75 minutes (1.25 hours), 90 minutes (1.5 hours), 105 minutes (1.75 hours), or 120 minutes (2 hours) of exposure to the ocular allergen, or after the onset of symptoms of allergic conjunctivitis. In some embodiments, in the second treatment phase, the ophthalmic solution of the present invention is administered 6 times a day, 5 times a day, 4 times a day (QID), 3 times a day (TID), twice a day (BID), once a day (QD), or as needed (PRN). In some embodiments, during the second treatment phase, the ophthalmic solution of the present invention is administered 6 times a day, 5 times a day, 4 times a day (QID), 3 times a day (TID), twice a day (BID), once a day (QD), followed by administration as needed (PRN). In some embodiments, during the second treatment phase, the ophthalmic solution of the present invention is administered 4 times a day (QID), followed by administration as needed (PRN).

[0019] In some embodiments, the second treatment phase can be further divided into an initiation phase, an exacerbation phase, and / or a maintenance phase of treatment. In some embodiments, the ophthalmic solution is administered six times a day, five times a day, or four times a day (QID) during the initiation and / or exacerbation phase, followed by twice a day (BID), once a day (QD) or as needed (PRN) during the maintenance phase. [Brief description of the drawings]

[0020] [Figure 1] Figure 1 shows the area under the curve calculation (AUC) of ocular pruritus scores (0-4) 10-60 minutes after allergen challenge. SEM = standard error of the mean; ocular pruritus scale 0 (no pruritus) to 4 (pruritus so severe itching that it is impossible to live a normal life).

[0021] [Diagram 2]Figure 2 shows the probability of a 2-point response in ocular pruritus scores over time after allergen challenge. At both concentrations of reproxalap, the results were statistically superior to vehicle in achieving the outcome: p=0.0005 for 0.25% reproxalap; p=0.0169 for 0.5% reproxalap.

[0022] [Diagram 3] Figure 3 shows the probability of an ocular pruritus score of 0 (therapeutic cure) over time after allergen challenge. At both concentrations of reproxalap, the results were statistically superior to vehicle in achieving complete reduction in ocular pruritus. p=0.0006 for 0.25% reproxalap; p=0.0045 for 0.5% reproxalap.

[0023] [Figure 4] Figure 4 shows ocular pruritus scores (0-100) during 200 minutes of allergen exposure in the group chamber model of allergic conjunctivitis. Results are shown for 0.25% w / v reproxalap administered 5 minutes before and 95 minutes after exposure to allergen (ragweed). Treatment with reproxalap shows a statistically significant reduction in ocular pruritus versus vehicle for exposure to allergen over 3 hours.

[0024] [Diagram 5] Figure 5 shows eye redness scores (0-4) during 200 minutes of allergen exposure in the group chamber model of allergic conjunctivitis. Results are shown for 0.25% w / v reproxalap administered 5 minutes before and 95 minutes after exposure to allergen (ragweed). Treatment with reproxalap shows a statistically significant reduction in eye redness versus vehicle for exposure to allergen over 3 hours. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] 1. Overview of Certain Embodiments A topical ophthalmic solution of reproxalap has been developed for the treatment of ocular inflammation. Various strengths of the drug product have completed Phase 1 clinical trials as well as controlled double-blind Phase 2a clinical trials for allergic conjunctivitis, controlled double-blind Phase 2b clinical trials for allergic conjunctivitis, controlled double-blind Phase 2 clinical trials for non-infectious anterior uveitis, Phase 2a clinical trials for dry eye disease, and controlled double-blind Phase 2b clinical trials for dry eye disease. The maximum exposure to reproxalap in these completed clinical trials was a 6-week dosing at a strength of 0.5% w / v to treat subjects with non-infectious anterior uveitis.

[0026] It has now been discovered that certain topical (ophthalmic) formulations (e.g., solutions) of reproxalap are surprisingly effective in treating allergic conjunctivitis. Without wishing to be bound by theory, it is believed that certain concentrations of reproxalap in combination with excipients and / or ratios of reproxalap to excipients exhibit increased efficacy over previous reproxalap ophthalmic solutions. Furthermore, in some embodiments, the topical formulations of the present disclosure produce reduced instillation site pain and irritation in human patients compared to previously known reproxalap ophthalmic solutions. In some embodiments, reduced instillation site pain and irritation results in increased patient compliance and improved outcomes.

[0027] In some embodiments, the ophthalmic solutions of the present disclosure exhibit improved (e.g., sustained) release of reproxalap compared to previously known ophthalmic solutions of reproxalap. Without wishing to be bound by theory, the ophthalmic solutions of the present disclosure may provide sustained or delayed release of reproxalap due to interactions between reproxalap and excipients. In some embodiments, certain ratios of reproxalap:excipients in the ophthalmic solutions of the present disclosure exhibit increased efficacy.

[0028] In some embodiments, after administration to a patient population, the ophthalmic solution of the present disclosure provides a statistically significant reduction in the ocular pruritus scale in a patient population suffering from allergic conjunctivitis. In some embodiments, after administration to a patient population, the ophthalmic solution of the present disclosure provides a statistically significant (p<0.05) reduction of at least one point in the ocular pruritus scale in a patient population suffering from allergic conjunctivitis. In some embodiments, after administration to a patient population, the ophthalmic solution of the present disclosure provides a statistically significant (p<0.05) reduction of at least two points in the ocular pruritus scale in a patient population suffering from allergic conjunctivitis. The ocular pruritus scale ranges from 0 (no pruritus) to 4 (incapacitating pruritus).

[0029] In some embodiments, the present invention provides an ophthalmic solution comprising reproxalap or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient, wherein the concentration of reproxalap or a pharma- ceutically acceptable salt thereof is about 0.5% w / v or less and 0.1% w / v or more. In some embodiments, the present invention provides a method for treating allergic conjunctivitis in a subject, comprising topically administering to a subject in need thereof an ophthalmic solution described herein.

[0030] In some embodiments, the disclosed ophthalmic solutions include reproxalap and a cyclodextrin excipient in a molar ratio of less than 1:2.1. In some embodiments, the ratio is from 1:2.1 to about 1:25. In some embodiments, the ratio is from about 1:2.2 to 1:20, 1:2.5 to 1:20, 1:2.5 to 1:10, 1:2.75 to 1:10, 1:3 to 1:8, 1:3.5 to 1:7, 1:4 to 1:6, or 1:4 to 1:5. In some embodiments, the ratio is about 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3, 1:3.1, 1:3.2, 1:3.3, 1:3.4, 1:3.5, 1:3.6, 1:3.7, 1:3.8, 1:3.9, 1:4.0, 1: 4.1, 1:4.2, 1:4.3, 1:4.4, 1:4.5, 1:4.6, 1:4.7, 1:4.8, 1:4.9, 1:5.0, 1:5.1, 1:5.2, 1:5.3, 1:5.4, 1:5.5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12, 1:15, 1:20 or 1:25. In some embodiments, the ratio is one of those in Table 1 below, for example, the ratio in Table 1 + / - 10%. In some embodiments, the cyclodextrin is sulfobutylether β-cyclodextrin (SBECD). In some embodiments, the cyclodextrin is hydroxypropyl-β-cyclodextrin (2-hydroxypropyl-β-cyclodextrin:HPCD).

[0031] In some embodiments, the cyclodextrin excipient is one of those described herein, such as sulfobutyl ether β-cyclodextrin (SBECD). [Table 1]

[0032] In some embodiments, the ophthalmic solution comprises about 0.2%-0.4% reproxalap and about 7%-25% w / v of a cyclodextrin excipient such as SBECD or HPCD. In some embodiments, the ophthalmic solution comprises about 0.2%, 0.25%, 0.3%, 0.35% or 0.4% reproxalap and about 7%-25% w / v of a cyclodextrin excipient such as SBECD or HPCD.

[0033] In some embodiments, the ophthalmic solution comprises about 0.25% reproxalap and about 4.7% to about 25% w / v of a cyclodextrin excipient, such as SBECD or HPCD.

[0034] In some embodiments, the ophthalmic solution comprises about 0.25% Reproxalap and about 7%-25% w / v of a cyclodextrin excipient such as SBECD or HPCD.

[0035] In some embodiments, the ophthalmic solution comprises about 0.25% Reproxalap and about 4.75% to about 11% w / v of a cyclodextrin excipient, such as SBECD or HPCD.

[0036] In some embodiments, the ophthalmic solution comprises about 0.5% Reproxalap and about 9.5% to about 11% w / v of a cyclodextrin excipient such as SBECD or HPCD.

[0037] In some embodiments, the ophthalmic solution comprises about 0.25% Reproxalap and about 7% w / v of a cyclodextrin excipient such as SBECD or HPCD.

[0038] In some embodiments, the ophthalmic solution comprises about 0.25% Reproxalap and about 11% w / v of a cyclodextrin excipient such as SBECD or HPCD.

[0039] 2.Definition General terms used herein are defined by the following meanings unless otherwise specified.

[0040] The terms "comprising" and "including" are used herein in their open-ended and non-limiting sense, unless otherwise stated.

[0041] The terms "a" and "an" and "the" and similar references in the context of describing the present invention (particularly in the context of the claims below) are to be construed as encompassing both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. When the plural is used for compounds, salts, and the like, this is to be taken to mean a single compound, salt, or the like.

[0042] The term "pharmacologically acceptable" is defined herein to refer to compounds, biological agents, materials, compositions and / or dosage forms that are suitable, within the scope of sound medical judgment, for contact with the tissues of a subject, e.g., a mammal or human, without excessive toxicity, irritation, allergic response and other problematic complications, and are commensurate with a reasonable benefit / risk ratio.

[0043] The term "treating" or "treatment" as used herein includes treatment that alleviates, reduces or relieves at least one symptom in a subject, or affects the delay of progression of a disease, condition and / or disorder. For example, treatment can be the reduction of one or more signs or symptoms of a disorder, or the complete eradication of a disorder. Also, within the meaning of the present invention, the term "treating" refers to stopping, delaying the onset of a disease (e.g., the period before the clinical manifestation of a disease) and / or reducing the risk of a disease developing or worsening.

[0044] As used herein, the term "subject" or "patient" includes animals such as mammals, e.g., humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In some embodiments, the subject is a human.

[0045] The term "about" or "approximately" has the meaning within 10% of a given value or range. In some embodiments, the term "about" refers to within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a given value.

[0046] As used herein, the term "w / v" refers to the unit of concentration "grams / mL" (weight to volume). For example, 7% w / v is equal to 70 mg / mL.

[0047] Reproxalap has the following structure: [ka]

[0048] Without wishing to be bound to a particular theory, Reproxalap functions as an aldehyde sequestering agent, or "trap," that rapidly binds to aldehydes to form cyclic products.

[0049] 3.Ophthalmic solution The ophthalmic solutions of the present invention comprise a suitable concentration of reproxalap or a pharma- ceutically acceptable salt thereof to effectively treat allergic conjunctivitis without causing particularly severe or intolerable adverse effects. In some embodiments, the present invention provides an ophthalmic solution comprising about 0.1% to about 0.5% w / v of reproxalap or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient, wherein the molar ratio of reproxalap to excipient is about 1:2.1 or less.

[0050] In some embodiments, the excipient is cyclodextrin and the ratio of reproxalap to the excipient is about 1:2.1 to about 1:25.

[0051] In some embodiments, the present invention provides an ophthalmic solution comprising reproxalap or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient, the concentration of reproxalap or a pharma- ceutically acceptable salt thereof being about 0.5% w / v or less and about 0.1% w / v or more. In some embodiments, the ophthalmic solution comprises 0.15-0.45% w / v of reproxalap or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient. In some embodiments, the ophthalmic solution comprises about 0.2-about 0.4% w / v of reproxalap or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient. In some embodiments, the ophthalmic solution comprises about 0.21-about 0.35% w / v of reproxalap or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient. In some embodiments, the ophthalmic solution comprises about 0.22 to about 0.3% w / v of reproxalap or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient. In some embodiments, the ophthalmic solution comprises about 0.22 to about 0.29% w / v of reproxalap or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient. In some embodiments, the ophthalmic solution comprises about 0.25% w / v of reproxalap or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient. In some embodiments, the ophthalmic solution comprises about 0.25% w / v of reproxalap and a pharma- ceutically acceptable excipient selected from cyclodextrins. In some embodiments, the ophthalmic solution comprises about 0.5% w / v of reproxalap and a pharma- ceutically acceptable excipient selected from cyclodextrins.

[0052] In some embodiments, the present invention provides an ophthalmic solution comprising less than 0.5% w / v of reproxalap or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient. In some embodiments, the present invention provides an ophthalmic solution comprising at least 0.1% w / v of reproxalap or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient. In some embodiments, the present invention provides an ophthalmic solution comprising reproxalap or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient, wherein the concentration of reproxalap or a pharma- ceutically acceptable salt thereof is less than 0.5% w / v and is equal to or greater than 0.1% w / v.

[0053] In some embodiments, reproxalap or a pharma- ceutically acceptable salt thereof in the ophthalmic solution of the present invention is at a concentration of less than 0.45% w / v and at least 0.1% w / v. In some embodiments, reproxalap or a pharma- ceutically acceptable salt thereof in the ophthalmic solution of the present invention is at a concentration of less than 0.4% w / v and at least 0.1% w / v. In some embodiments, reproxalap or a pharma- ceutically acceptable salt thereof in the ophthalmic solution of the present invention is at a concentration of less than 0.35% w / v and at least 0.1% w / v. In some embodiments, reproxalap or a pharma- ceutically acceptable salt thereof in the ophthalmic solution of the present invention is at a concentration of less than 0.3% w / v and at least 0.1% w / v. In some embodiments, reproxalap or a pharma- ceutically acceptable salt thereof in the ophthalmic solution of the present invention is at a concentration of less than 0.25% w / v and at least 0.1% w / v. In some embodiments, reproxalap or a pharma- ceutically acceptable salt thereof in the ophthalmic solution of the invention is at a concentration of less than 0.2% w / v and at least 0.1% w / v. In some embodiments, reproxalap or a pharma- ceutically acceptable salt thereof in the ophthalmic solution of the invention is at a concentration of less than 0.15% w / v and at least 0.1% w / v.

[0054] In some embodiments, reproxalap or a pharma- ceutically acceptable salt thereof in the ophthalmic solution of the present invention is at a concentration of 0.5% w / v or less and at least 0.15% w / v. In some embodiments, reproxalap or a pharma- ceutically acceptable salt thereof in the ophthalmic solution of the present invention is at a concentration of 0.5% w / v or less and at least 0.2% w / v. In some embodiments, reproxalap or a pharma- ceutically acceptable salt thereof in the ophthalmic solution of the present invention is at a concentration of 0.5% w / v or less and at least 0.25% w / v. In some embodiments, reproxalap or a pharma- ceutically acceptable salt thereof in the ophthalmic solution of the present invention is at a concentration of 0.5% w / v or less and at least 0.3% w / v. In some embodiments, reproxalap or a pharma- ceutically acceptable salt thereof in the ophthalmic solution of the present invention is at a concentration of 0.5% w / v or less and at least 0.35% w / v. In some embodiments, reproxalap or a pharma- ceutically acceptable salt thereof in the ophthalmic solution of the invention is at a concentration of 0.5% w / v or less and at least 0.4% w / v. In some embodiments, reproxalap or a pharma- ceutically acceptable salt thereof in the ophthalmic solution of the invention is at a concentration of 0.5% w / v or less and at least 0.45% w / v.

[0055] In some embodiments, reproxalap or a pharma- ceutically acceptable salt thereof in the ophthalmic solution of the present invention is at a concentration of about 0.1%-0.5%, 0.15%-0.45% w / v, 0.15%-0.4% w / v, 0.15%-0.35% w / v, 0.15%-0.3% w / v, 0.15%-0.25% w / v, or 0.15%-0.2% w / v. In some embodiments, reproxalap or a pharma-ceutically acceptable salt thereof in the ophthalmic solution of the present invention is at a concentration of about 0.2%-0.45% w / v, 0.2%-0.4% w / v, 0.2%-0.35% w / v, 0.2%-0.3% w / v, or 0.2%-0.25% w / v. In some embodiments, reproxalap or a pharma- ceutically acceptable salt thereof in the ophthalmic solution of the invention is at a concentration of 0.25%-0.45% w / v, 0.25%-0.4% w / v, 0.25%-0.35% w / v, or 0.25%-0.3% w / v. In some embodiments, reproxalap or a pharma-ceutically acceptable salt thereof in the ophthalmic solution of the invention is at a concentration of 0.3%-0.45% w / v, or 0.3%-0.4% w / v.

[0056] In some embodiments, reproxalap or a pharma- ceutically acceptable salt thereof in the ophthalmic solutions of the present invention is at a concentration of about 0.1% w / v, 0.15% w / v, about 0.2% w / v, about 0.25%, about 0.3% w / v, about 0.35% w / v, about 0.4% w / v, about 0.45% w / v or about 0.5% w / v.

[0057] In some embodiments, the aforementioned concentrations of reproxalap may be selected and applied in a treatment regimen comprising an initiation phase, an exacerbation phase, and / or a maintenance phase, as further described herein.

[0058] In some embodiments, the pharma- ceutically acceptable excipient in the ophthalmic solution of the present invention is cyclodextrin. In some embodiments, the cyclodextrin is α-, β-, or γ-cyclodextrin. In some embodiments, the cyclodextrin is a pharma- ceutically acceptable derivative of cyclodextrin, including, but not limited to, hydroxyalkyl derivatives of α-, β-, and γ-cyclodextrin (especially hydroxyethyl and hydroxypropyl derivatives of β-cyclodextrin and γ-cyclodextrin), randomly methylated β-cyclodextrin, sulfobutylether β-cyclodextrin, sulfobutylether γ-cyclodextrin, and so-called branched β- and γ-cyclodextrin derivatives, such as glucosyl-β-cyclodextrin and glucosyl-γ-cyclodextrin. Natural cyclodextrins are used either alone or as mixtures of two or more cyclodextrins, such as, but not limited to, mixtures of gamma-cyclodextrin and the more water soluble hydroxypropyl gamma-cyclodextrin, or gamma-cyclodextrin and sulfobutyl ether gamma-cyclodextrin, or beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin, or beta-cyclodextrin and sulfobutyl ether beta-cyclodextrin.

[0059] In some embodiments, the cyclodextrin in the ophthalmic solution of the present invention is at a concentration of 0-20% w / v. In some embodiments, the cyclodextrin in the ophthalmic solution of the present invention is at a concentration of 1-18% w / v, 1-16% w / v, 1-14% w / v, 2-12% w / v, 4-10% w / v, 5-9% w / v, or 6%-8% w / v. In some embodiments, the cyclodextrin in the ophthalmic solutions of the present invention is at a concentration of about 1% w / v, 2% w / v, 3% w / v, 4% w / v, 5% w / v, 6% w / v, 7% w / v, 8% w / v, 9% w / v, 10% w / v, 11% w / v, 12% w / v, 13% w / v, 14% w / v, 15% w / v, 16% w / v, 17% w / v, 18% w / v, 19% w / v or 20% w / v.

[0060] In some embodiments, the pharma- ceutically acceptable excipient in the ophthalmic solution of the present invention is sulfobutylether-β-cyclodextrin, particularly at a particular concentration and in any of the concentration ranges described above, for example, about 7% w / v. In some embodiments, the pharma- ceutically acceptable excipient in the ophthalmic solution of the present invention is hydroxypropyl-β-cyclodextrin, particularly at a particular concentration and in any of the concentration ranges described above, for example, about 7% w / v. In some embodiments, Reproxalap is at a concentration of about 0.25% w / v and the cyclodextrin, such as sulfobutylether-β-cyclodextrin or hydroxypropyl-β-cyclodextrin, is at a concentration of about 7% w / v.

[0061] In some embodiments, the pharma- ceutically acceptable excipient in the ophthalmic solution of the present invention is sulfobutylether-β-cyclodextrin, particularly at a particular concentration and in any of the concentration ranges described above, for example, about 11% w / v. In some embodiments, the pharma-ceutically acceptable excipient in the ophthalmic solution of the present invention is hydroxypropyl-β-cyclodextrin, particularly at a particular concentration and in any of the concentration ranges described above, for example, about 11% w / v. In some embodiments, Reproxalap is at a concentration of about 0.25% w / v and the cyclodextrin, such as sulfobutylether-β-cyclodextrin or hydroxypropyl-β-cyclodextrin, is at a concentration of about 11% w / v.

[0062] In some embodiments, the ophthalmic solution of the present invention comprises a pharma- ceutically acceptable buffering agent, hi some embodiments, the pharma- ceutically acceptable buffering agent is a phosphate buffer, a citrate buffer, a Tris buffer, a histidine buffer, or an acetate buffer.

[0063] In some embodiments, the pharma- ceutically acceptable buffering agent is sodium dihydrogen phosphate. In some embodiments, the pharma-ceutically acceptable buffering agent is sodium dihydrogen phosphate. In some embodiments, the pharma-ceutically acceptable buffering agent is a mixture of sodium dihydrogen phosphate and sodium dihydrogen phosphate. In some embodiments, the ophthalmic solution of the present invention comprises about 0.083% w / v sodium dihydrogen phosphate and about 0.017% w / v sodium dihydrogen phosphate.

[0064] In some embodiments, the ophthalmic solution of the present invention has a pH of about neutral. In some embodiments, the ophthalmic solution of the present invention has a pH of 6.5 to 8. In some embodiments, the ophthalmic solution of the present invention has a pH of 6.9 to 7.7. In some embodiments, the ophthalmic solution of the present invention has a pH of 7.1 to 7.5. In some embodiments, the ophthalmic solution of the present invention has a pH of about 7.3.

[0065] Pharmaceutically acceptable acids and / or bases may be used in the ophthalmic solution to adjust the pH. In some embodiments, the ophthalmic solution of the present invention comprises a pharma- ceutically acceptable acid. In some embodiments, the ophthalmic solution of the present invention comprises a pharma- ceutically acceptable base. In some embodiments, the ophthalmic solution of the present invention comprises a pharma- ceutically acceptable acid and a base. In some embodiments, the pharma- ceutically acceptable acid is hydrochloric acid. In some embodiments, the pharma- ceutically acceptable base is sodium hydroxide.

[0066] In some embodiments, the ophthalmic solution of the present invention comprises a tonicity agent. In some embodiments, the tonicity agent is selected from the group consisting of dextrose, potassium chloride, propylene glycol, and sodium chloride. In some embodiments, the ophthalmic solution of the present invention comprises a tonicity agent at a concentration of less than about 0.5% w / v. In some embodiments, the ophthalmic solution of the present invention comprises a tonicity agent at a concentration of about 0.45%, 0.4%, 0.35%, 0.3%, 0.25%, 0.2%, 0.15%, or 0.1% w / v. In some embodiments, the tonicity agent is sodium chloride.

[0067] In some embodiments, the ophthalmic solution includes specific concentrations of reproxalap, cyclodextrin, phosphate, and sodium chloride. In some embodiments, the ophthalmic solution includes specific concentrations herein (e.g., 0.1% w / v, 0.25% w / v, 0.5% w / v, etc.), 5-9% w / v of cyclodextrin (e.g., sulfobutylether-β-cyclodextrin or hydroxypropyl-β-cyclodextrin), 0.07%-0.09% w / v of sodium phosphate (dibasic), 0.015%-0.19% w / v of sodium phosphate (monobasic), and 0.2-0.3% w / v of sodium chloride. In some embodiments, the ophthalmic solution comprises Reproxalap at a concentration specified herein (e.g., 0.1% w / v, 0.25% w / v, 0.5% w / v, etc.), about 7% w / v of a cyclodextrin (e.g., sulfobutylether-β-cyclodextrin or hydroxypropyl-β-cyclodextrin), 0.07%-0.09% w / v of sodium phosphate (dibasic), 0.015%-0.019% w / v of sodium phosphate (monobasic), and 0.2-0.3% w / v of sodium chloride. In some embodiments, the ophthalmic solution is adjusted to the appropriate pH with sodium hydroxide or HCl.

[0068] In some embodiments, the ophthalmic solution includes specific concentrations of reproxalap, cyclodextrin, phosphate, and sodium chloride. In some embodiments, the ophthalmic solution includes specific concentrations herein (e.g., 0.1% w / v, 0.25% w / v, 0.5% w / v, etc.), 10-14% w / v of cyclodextrin (e.g., sulfobutylether-β-cyclodextrin or hydroxypropyl-β-cyclodextrin), 0.07%-0.09% w / v of sodium phosphate (dibasic), 0.015%-0.19% w / v of sodium phosphate (monobasic), and 0.2-0.3% w / v of sodium chloride. In some embodiments, the ophthalmic solution comprises Reproxalap at a concentration specified herein (e.g., 0.1% w / v, 0.25% w / v, 0.5% w / v, etc.), about 11% w / v of a cyclodextrin (e.g., sulfobutylether-β-cyclodextrin or hydroxypropyl-β-cyclodextrin), 0.07%-0.09% w / v of sodium phosphate (dibasic), 0.015%-0.019% w / v of sodium phosphate (monobasic), and 0.2-0.3% w / v of sodium chloride. In some embodiments, the ophthalmic solution is adjusted to the appropriate pH with sodium hydroxide or HCl.

[0069] In some embodiments, the ophthalmic solution comprises the composition in the Examples of 0.5% Reproxalap Ophthalmic Solution A. In some embodiments, the ophthalmic solution comprises the composition in the Examples of 0.5% Reproxalap Ophthalmic Solution B. In some embodiments, the ophthalmic solution comprises the composition in the Examples of 0.25% Reproxalap Ophthalmic Solution A. In some embodiments, the ophthalmic solution comprises the composition in the Examples of 0.25% Reproxalap Ophthalmic Solution (basic).

[0070] 4. Treatment method In one aspect, the present invention provides a method for treating allergic conjunctivitis in a subject, comprising topically administering to the eye of a subject in need thereof an ophthalmic solution of the present invention, in some embodiments, the concentration of reproxalap in the ophthalmic solution used in the method is as described above.

[0071] In some embodiments, the ophthalmic solutions of the present invention may be administered at different frequencies suitable for effectively treating allergic conjunctivitis, for example, without causing severe or intolerable adverse effects.

[0072] In some embodiments, the allergic conjunctivitis being treated is seasonal allergic conjunctivitis. In some embodiments, the allergic conjunctivitis being treated is contact allergic conjunctivitis. In some embodiments, the allergic conjunctivitis being treated is perennial conjunctivitis.

[0073] In some embodiments, the ophthalmic solution of the present invention may be topically administered to the eye 1-12 times per day. In some embodiments, the ophthalmic solution of the present invention may be topically administered to the eye 1-10 times per day. In some embodiments, the ophthalmic solution of the present invention may be topically administered to the eye 1-8 times per day. In some embodiments, the ophthalmic solution of the present invention may be topically administered to the eye 1-6 times per day. In some embodiments, the ophthalmic solution of the present invention may be topically administered to the eye 1-4 times per day.

[0074] In some embodiments, the methods of the present invention include topically administering the ophthalmic solution of the present invention up to 12 times per day. In some embodiments, the methods of the present invention include topically administering the ophthalmic solution of the present invention up to 11 times per day. In some embodiments, the methods of the present invention include topically administering the ophthalmic solution of the present invention up to 10 times per day. In some embodiments, the methods of the present invention include topically administering the ophthalmic solution of the present invention up to 9 times per day. In some embodiments, the methods of the present invention include topically administering the ophthalmic solution of the present invention up to 8 times per day. In some embodiments, the methods of the present invention include topically administering the ophthalmic solution of the present invention up to 7 times per day. In some embodiments, the methods of the present invention include topically administering the ophthalmic solution of the present invention 6 times per day. In some embodiments, the methods of the present invention include topically administering the ophthalmic solution of the present invention 5 times per day. In some embodiments, the methods of the present invention include topically administering the ophthalmic solution of the present invention 4 times per day (QID). In some embodiments, the methods of the present invention include topically administering the ophthalmic solution of the present invention 3 times per day (TID). In some embodiments, the methods of the present invention include topically administering the ophthalmic solution of the present invention twice per day (BID). In some embodiments, the methods of the invention comprise topical administration of an ophthalmic solution of the invention once daily (QD). In some embodiments, the methods of the invention comprise topical administration of an ophthalmic solution of the invention on an as-needed basis (PRN).

[0075] In one aspect, the present invention provides a method for treating allergic conjunctivitis in a subject, comprising topically administering an ophthalmic solution of the present invention to an eye of the subject. In some embodiments, the method of the present invention comprises topically administering an ophthalmic solution of the present invention four times per day (QID). In some embodiments, the method of the present invention comprises topically administering an ophthalmic solution of the present invention three times per day (TID). In some embodiments, the method of the present invention comprises topically administering an ophthalmic solution of the present invention twice per day (BID). In some embodiments, the method of the present invention comprises topically administering an ophthalmic solution of the present invention once per day (QD). In some embodiments, the method of the present invention comprises topically administering an ophthalmic solution of the present invention as needed (PRN).

[0076] In some embodiments, the method of treating allergic conjunctivitis comprises topically administering an ophthalmic solution of the present invention four times a day (QID), three times a day (TID), twice a day (BID), or once a day (QD) to the eye of a subject in need thereof, followed by administration as needed (PRN) to the subject. In some embodiments, the method of treating allergic conjunctivitis comprises topically administering an ophthalmic solution of the present invention four times a day (QID), followed by administration as needed (PRN).

[0077] In some embodiments, the method of treating allergic conjunctivitis comprises topically administering the ophthalmic solution of the present invention to the eye of a subject in need thereof before expected or certain exposure to an ocular allergen. In some embodiments, the ophthalmic solution is topically administered to the eye before expected or certain exposure to an ocular allergen, for example, within the duration of therapeutic effect of a 0.25% w / v or 0.5% w / v Reproxalap solution. In some embodiments, the ophthalmic solution of the present invention is administered 3.5 hours or less, 3 hours or less, 2.5 hours or less, 2 hours or less, 1.5 hours or less, 1 hour or less, 0.5 hours or less, 25 minutes or less, 20 minutes or less, 25 minutes or less, 20 minutes or less, 15 minutes or less, 10 minutes or less, or 5 minutes or less before expected or certain exposure to an ocular allergen, or immediately before exposure to an ocular allergen. In some embodiments, the ophthalmic solution of the present invention is administered 1.5 hours or less, 1 hour or less, 0.5 hours or less, 25 minutes or less, 20 minutes or less, 25 minutes or less, 20 minutes or less, 15 minutes or less, 10 minutes or less, or 5 minutes or less prior to expected or certain exposure to an ocular allergen. In some embodiments, the ophthalmic solution of the present invention is administered 0-0.5 hours, 0-1 hour, 0-1.5 hours, 0-2 hours, 0-2.5 hours, 0-3 hours, 0-3.5 hours prior to expected or certain exposure to an ocular allergen. In some embodiments, the ophthalmic solution of the present invention is administered 0.5-1 hour, 0.5-1.5 hours, 0.5-2 hours, 0.5-2.5 hours, 0.5-3 hours, 0.5-3.5 hours prior to expected or certain exposure to an ocular allergen. In some embodiments, the ophthalmic solution of the present invention is administered 1 to 1.5 hours, 1 to 2 hours, 1 to 2.5 hours, 1 to 3 hours, or 1 to 3.5 hours prior to expected or certain exposure to an ocular allergen. In some embodiments, the ophthalmic solution of the present invention is administered 1.5 to 2 hours, 1.5 to 2.5 hours, 1.5 to 3 hours, or 1.5 to 3.5 hours prior to expected or certain exposure to an ocular allergen.In some embodiments, the ophthalmic solution of the present invention is administered ~2.5 hours, 2-3 hours, 2-3.5 hours prior to expected or certain exposure to an ocular allergen, hi some embodiments, the ophthalmic solution of the present invention is administered 2.5-3 hours or 2.5-3.5 hours prior to expected or certain exposure to an ocular allergen.

[0078] In some embodiments, the method for treating allergic conjunctivitis comprises topically administering the ophthalmic solution of the present invention to the eye of a subject in need thereof one, two, three, four, five, six, seven or eight times prior to expected or certain exposure to an ocular allergen. In some embodiments, the method for treating allergic conjunctivitis comprises topically administering the ophthalmic solution of the present invention to the eye of a subject in need thereof one, two, three, four, five, six, seven or eight times prior to expected or certain exposure to an ocular allergen. In some embodiments, the ophthalmic solution when administered two or more times is administered over a period of 3.5 hours, 3 hours, 2.5 hours, 2 hours, 1.5 hours, 1 hour or 0.5 hours prior to expected or certain exposure to an ocular allergen. In some embodiments, the ophthalmic solution when administered once is administered 1.5 hours or less, 1 hour or less, 0.5 hours or less, 25 minutes or less, 20 minutes or less, 25 minutes or less, 20 minutes or less, 15 minutes or less, 10 minutes or less, or 5 minutes or less before expected or certain exposure to eye allergen, or immediately before expected or certain exposure to eye allergen.In some embodiments, each administration of the ophthalmic solution involves one or two doses (e.g., drops) of the ophthalmic solution.In some embodiments, each administration of the ophthalmic solution involves a single dose (e.g., one drop) of the ophthalmic solution.

[0079] In some embodiments, the subject to be treated that is selected for treatment before expected or certain exposure to eye allergens has a history of allergic conjunctivitis. In some embodiments, the subject to be treated that is selected for treatment before expected or certain exposure to eye allergens has a history of allergic conjunctivitis and has a positive allergen skin test for one or more eye allergens, particularly the eye allergens to which the subject is expected to be exposed. In some embodiments, the subject to be treated before expected or certain exposure to eye allergens has a previous clinical diagnosis of allergic conjunctivitis. In some embodiments, the subject to be treated before expected or certain exposure to eye allergens has a previous clinical diagnosis of allergic conjunctivitis and has a positive allergen skin test for one or more eye allergens, particularly the eye allergens to which the subject is expected to be exposed.In allergen skin tests, allergens, particularly hazel (e.g. Corylus avellana), alder (e.g. Alnus incana), birch (e.g. Betula alba), plane tree (e.g. Platanus vulgaris), cypress (e.g. Cupressus sempervirens), grass mix (e.g. Poa pratensis, Dactilis glomerata, Lolium perenne, Phleum pratense, Festuca pratensis, Helictotrichon pretense), olive (e.g. Olea europaea), mugwort (e.g. Artemisia vulgaris), ragweed (e.g. Ambrosia artemisiifolia), Alternaria (e.g. Alternaria A panel of airborne allergens may be used, including allergens from species such as Dermatophagoides alternata (tenuis), Cladosporium (e.g., Cladosporium herbarum), Aspergillus (e.g., Aspergillus fumigatus), Parietaria, cat, dog, Dermatophagoides pteronyssinus, Dermatophagoides farinae, and Blatella germanica.

[0080] In some embodiments, the method for treating allergic conjunctivitis in a subject comprises administering an ophthalmic solution of the present invention to an eye of a subject in need thereof at or after exposure to an ocular allergen. In some embodiments, the method for treating allergic conjunctivitis in a subject comprises administering an ophthalmic solution of the present invention to an eye of a subject in need thereof immediately after exposure to an ocular allergen. In some embodiments, the method for treating allergic conjunctivitis comprises administering an ophthalmic solution of the present invention to an eye of a subject in need thereof at or after the onset of symptoms of allergic conjunctivitis. In some embodiments, the method for treating allergic conjunctivitis comprises administering an ophthalmic solution of the present invention to an eye of a subject in need thereof immediately after the onset of symptoms of allergic conjunctivitis. In some embodiments, the method for treating allergic conjunctivitis comprises administering an ophthalmic solution of the present invention to an eye of a subject in need thereof before the maximum severity of symptoms of allergic conjunctivitis is reached. In some embodiments, the severity of symptoms of allergic conjunctivitis may be measured using the scoring of ocular itching, conjunctival redness, and ocular tearing as used in the examples below or known in the art. In some embodiments, scoring of the severity of allergic conjunctivitis symptoms is described in Ciolino et al., Clinical Ophthalmology, 2015, 9:765-772; Abelson et al., J Ocular Pharmacol., 1998, 14(6):533-542; and McLaurin et al., Clinical Sci., 2015, 34(10):1245-1251, all of which are incorporated herein by reference. In some embodiments, treatment upon or after exposure to an ocular allergen and / or after onset of allergic conjunctivitis symptoms may further include an onset phase, an exacerbation phase, and / or a maintenance phase, as further discussed herein.

[0081] In some embodiments, a method for treating allergic conjunctivitis in a subject comprises administering an ophthalmic solution of the present invention to an eye of a subject in need thereof up to 5 minutes or less, 10 minutes or less, 15 minutes or less, 20 minutes or less, 25 minutes or less, 30 minutes or less, 35 minutes or less, 40 minutes or less, 45 minutes or less, 50 minutes or less, 60 minutes (1 hour) or less, 75 minutes (1.25 hours) or less, 90 minutes (1.5 hours) or less, 105 minutes (1.75 hours) or less, or 120 minutes (2 hours) or less after exposure to an ocular allergen or onset of symptoms of allergic conjunctivitis. In some embodiments, a method for treating allergic conjunctivitis in a subject comprises administering an ophthalmic solution of the present invention to an eye of a subject in need thereof up to 5 minutes or less, 10 minutes or less, 15 minutes or less, 20 minutes or less, 25 minutes or less, 30 minutes or less, 35 minutes or less, 40 minutes or less, 45 minutes or less, 50 minutes or less, 60 minutes (1 hour) or less, 75 minutes (1.25 hours) or less, or 90 minutes (1.5 hours) or less after exposure to an ocular allergen or onset of symptoms of allergic conjunctivitis. In some embodiments of the method, the ophthalmic solution of the present invention is administered about 0-5 minutes, 0-10 minutes, 0-15 minutes, 0-20 minutes, 0-25 minutes, 0-30 minutes, 0-35 minutes, 0-40 minutes, 0-45 minutes, 0-50 minutes, 0-60 minutes, 0-75 minutes, 0-90 minutes, 0-105 minutes, or 0-120 minutes after exposure to an ocular allergen or onset of symptoms of allergic conjunctivitis. In some embodiments of the method, the ophthalmic solution of the present invention is administered about 5-10 minutes, 5-15 minutes, 5-20 minutes, 5-25 minutes, 5-30 minutes, 5-35 minutes, 5-40 minutes, 5-45 minutes, 5-50 minutes, 5-60 minutes, 5-75 minutes, 5-90 minutes, 5-105 minutes, or 5-120 minutes after exposure to an ocular allergen or onset of symptoms of allergic conjunctivitis.In some embodiments of the method, the ophthalmic solution of the present invention is administered about 10-15 minutes, 10-20 minutes, 10-25 minutes, 10-30 minutes, 10-35 minutes, 10-40 minutes, 10-45 minutes, 10-50 minutes, 10-60 minutes, 10-75 minutes, 10-90 minutes, 10-105 minutes, or 10-120 minutes after exposure to an ocular allergen or onset of symptoms of allergic conjunctivitis. In some embodiments of the method, the ophthalmic solution of the present invention is administered within 15-20 minutes, 15-25 minutes, 15-30 minutes, 15-35 minutes, 15-40 minutes, 15-45 minutes, 15-50 minutes, 15-60 minutes, 15-75 minutes, 15-90 minutes, 15-105 minutes, or 15-120 minutes after exposure to an ocular allergen or onset of symptoms of allergic conjunctivitis. In some embodiments of the method, the ophthalmic solution of the present invention is administered within 20-25 minutes, 20-30 minutes, 20-35 minutes, 20-40 minutes, 20-45 minutes, 20-50 minutes, 20-60 minutes, 20-75 minutes, 20-90 minutes, 20-105 minutes, or 20-120 minutes after exposure to the ocular allergen or onset of symptoms of allergic conjunctivitis. In some embodiments of the method, the ophthalmic solution of the present invention is administered within 25-30 minutes, 25-35 minutes, 25-40 minutes, 25-45 minutes, 25-50 minutes, 25-60 minutes, 25-75 minutes, 25-90 minutes, 25-105 minutes, or 25-120 minutes after exposure to the ocular allergen or onset of symptoms of allergic conjunctivitis. In some embodiments of the method, the ophthalmic solution of the present invention is administered up to 30-35 minutes, 30-40 minutes, 30-45 minutes, 30-50 minutes, 30-60 minutes, 30-75 minutes, 30-90 minutes, 30-105 minutes, or 30-120 minutes after exposure to the ocular allergen or onset of symptoms of allergic conjunctivitis. In some embodiments of the method, the ophthalmic solution of the present invention is administered up to 35-40 minutes, 35-45 minutes, 35-50 minutes, 35-60 minutes, 35-75 minutes, 35-90 minutes, 35-105 minutes, or 35-120 minutes after exposure to the ocular allergen or onset of symptoms of allergic conjunctivitis. In some embodiments of the method, the ophthalmic solution of the present invention is administered within 40 to 45 minutes, 40 to 50 minutes, 40 to 60 minutes, 40 to 75 minutes, 40 to 90 minutes, 40 to 105 minutes, or 40 to 120 minutes after exposure of the eye to the allergen or onset of symptoms of allergic conjunctivitis.In some embodiments of the method, the ophthalmic solution of the present invention is administered up to 45-50 minutes, 45-60 minutes, 45-75 minutes, 45-90 minutes, 45-105 minutes, or 45-120 minutes after exposure to the ocular allergen or onset of symptoms of allergic conjunctivitis. In some embodiments of the method, the ophthalmic solution of the present invention is administered up to 50-60 minutes, 50-75 minutes, 50-90 minutes, 50-105 minutes, or 50-120 minutes after exposure to the ocular allergen or onset of symptoms of allergic conjunctivitis. In some embodiments of the method, the ophthalmic solution of the present invention is administered up to 60-75 minutes, 60-90 minutes, 60-105 minutes, or 60-120 minutes after exposure to the ocular allergen or onset of symptoms of allergic conjunctivitis. In some embodiments of the method, the ophthalmic solution of the present invention is administered up to 75-90 minutes, 75-105 minutes, or 75-120 minutes after exposure to the ocular allergen or onset of symptoms of allergic conjunctivitis. In some embodiments of the method, the ophthalmic solution of the present invention is administered up to 90-105 minutes, or 90-120 minutes after exposure to the ocular allergen or onset of symptoms of allergic conjunctivitis.

[0082] In some embodiments, a method for treating allergic conjunctivitis in a subject comprises topically administering an ophthalmic solution of the present invention to the eye of a subject in need thereof upon or after exposure of the eye to an allergen or upon or after the onset of symptoms of allergic conjunctivitis, wherein the ophthalmic solution is administered up to 12 times per day, up to 11 times per day, up to 10 times per day, up to 9 times per day, up to 8 times per day, up to 7 times per day, up to 6 times per day, up to 5 times per day, up to 4 times per day, up to 3 times per day, up to 2 times per day, or once per day. In some embodiments, the method for treating allergic conjunctivitis in a subject comprises topically administering the ophthalmic solution of the present invention to the eye of a subject in need thereof at or after exposure to an ocular allergen or at or after the onset of symptoms of allergic conjunctivitis, and the ophthalmic solution is administered 12 times a day, 11 times a day, 10 times a day, 9 times a day, 8 times a day, 7 times a day, 6 times a day, 5 times a day, 4 times a day (QID), 3 times a day (TID), twice a day (BID), once a day (QD). In some embodiments, the method for treating allergic conjunctivitis in a subject comprises topically administering the ophthalmic solution of the present invention to any eye of a subject in need thereof at or after exposure to an ocular allergen or after the onset of symptoms of allergic conjunctivitis, and the ophthalmic solution is administered as needed (PRN). In some embodiments, the method for treating allergic conjunctivitis in a subject comprises topically administering the ophthalmic solution of the present invention to the eye of a subject in need thereof at or after exposure to an ocular allergen or at or after the onset of symptoms of allergic conjunctivitis, the ophthalmic solution being administered four times a day (QID), three times a day (TID), twice a day (BID), once a day (QD) or as needed (PRN).In some embodiments, the method for treating allergic conjunctivitis comprises topically administering the ophthalmic solution of the present invention to the eye of a subject in need thereof at or after exposure to an ocular allergen or at or after the onset of symptoms of allergic conjunctivitis, the ophthalmic solution being administered six times a day, five times a day, four times a day (QID), three times a day (TID), twice a day (BID), once a day (QD), followed by administration as needed (PRN).In some embodiments, the method for treating allergic conjunctivitis comprises topically administering the ophthalmic solution of the present invention to the eye of a subject in need thereof at or after exposure to an ocular allergen or at or after the onset of symptoms of allergic conjunctivitis, the ophthalmic solution being administered four times a day (QID), three times a day (TID), twice a day (BID), once a day (QD), followed by administration as needed (PRN) to the subject. In some embodiments, the ophthalmic solution of the present invention is administered four times a day (QID), followed by administration as needed (PRN).

[0083] In some embodiments, the method for treating allergic conjunctivitis comprises topically administering an ophthalmic solution of the present invention to the eye of a subject in need thereof at or after exposure to an ocular allergen or at or after the onset of symptoms of allergic conjunctivitis, each administration being every 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, or 4 hours. In some embodiments, the method for treating allergic conjunctivitis comprises topically administering an ophthalmic solution of the present invention to the eye of a subject in need thereof at or after exposure to an ocular allergen or at or after the onset of symptoms of allergic conjunctivitis, each administration being every 1-1.5 hours, 1-2 hours, 1-2.5 hours, 1-3 hours, 1-3.5 hours, or 1-4 hours. In some embodiments, the method for treating allergic conjunctivitis comprises topically administering an ophthalmic solution of the present invention to the eye of a subject in need thereof at or after exposure to an ocular allergen or at or after the onset of symptoms of allergic conjunctivitis, each administration being every 1.5-2 hours, 1.5-2.5 hours, 1.5-3 hours, 1.5-3.5 hours, or 1.5-4 hours. In some embodiments, the method for treating allergic conjunctivitis comprises topically administering an ophthalmic solution of the present invention to the eye of a subject in need thereof at or after exposure to an ocular allergen or at or after the onset of symptoms of allergic conjunctivitis, each administration being every 2-2.5 hours, 2-3 hours, 2-3.5 hours, or 2-4 hours. In some embodiments, the method for treating allergic conjunctivitis comprises topically administering the ophthalmic solution of the present invention to the eye of a subject in need thereof at or after exposure of the eye to an allergen or at or after the onset of symptoms of allergic conjunctivitis, with each administration being every 3-3.5 hours or 3-4 hours.

[0084] In some embodiments, a method for treating allergic conjunctivitis comprises topically administering an ophthalmic solution of the present invention to the eye of a subject in need thereof at or after exposure of the eye to an allergen or at or after the onset of symptoms of allergic conjunctivitis, wherein the ophthalmic solution is administered twice daily (BID) with each administration being 60 minutes (1 hour), 90 minutes (1.5 hours), 120 minutes (2 hours), 150 minutes (2.5 hours), 180 minutes (3 hours), 210 minutes (3.5 hours), or 240 minutes (4 hours) apart. In some embodiments, a method for treating allergic conjunctivitis comprises topically administering an ophthalmic solution of the present invention to the eye of a subject in need thereof at or after exposure of the eye to an allergen or at or after the onset of symptoms of allergic conjunctivitis, wherein the ophthalmic solution is administered three times a day (TID) with each administration being 60 minutes (1 hour), 90 minutes (1.5 hours), 120 minutes (2 hours), 150 minutes (2.5 hours), 180 minutes (3 hours), 210 minutes (3.5 hours), or 240 minutes (4 hours) apart. In some embodiments, a method for treating allergic conjunctivitis comprises topically administering an ophthalmic solution of the present invention to the eye of a subject in need thereof at or after exposure of the eye to an allergen or at or after the onset of symptoms of allergic conjunctivitis, wherein the ophthalmic solution is administered four times daily (QID) with each administration being 60 minutes (1 hour), 90 minutes (1.5 hours), 120 minutes (2 hours), 150 minutes (2.5 hours), 180 minutes (3 hours), 210 minutes (3.5 hours), or 240 minutes (4 hours) apart. In some embodiments, a method for treating allergic conjunctivitis comprises topically administering an ophthalmic solution of the present invention to the eye of a subject in need thereof at or after exposure of the eye to an allergen or at or after the onset of symptoms of allergic conjunctivitis, wherein the ophthalmic solution is administered twice daily (BID), with each administration spaced 60 minutes (1 hour), 90 minutes (1.5 hours), or 120 minutes (2 hours) apart.

[0085] In some embodiments, each administration of the ophthalmic solution at or after exposure to an ocular allergen or at or after the onset of symptoms of allergic conjunctivitis involves one or two doses (e.g., drops) of the ophthalmic solution. In some embodiments, each administration of the ophthalmic solution involves a single dose (e.g., one drop) of the ophthalmic solution. In some embodiments, each administration of the ophthalmic solution involves two doses (e.g., two drops) of the ophthalmic solution.

[0086] In some embodiments, the subject selected for treatment at or after exposure to eye allergens or at or after the onset of symptoms of allergic conjunctivitis has a history of allergic conjunctivitis.In some embodiments, the subject selected for treatment at or after exposure to eye allergens or at or after the onset of symptoms of allergic conjunctivitis has a history of allergic conjunctivitis and is positive in allergen skin test for one or more eye allergens, particularly eye allergens to which the subject is expected to be exposed.In some embodiments, the subject selected for treatment at or after exposure to eye allergens or at or after the onset of symptoms of allergic conjunctivitis has been clinically diagnosed with allergic conjunctivitis in the past.In some embodiments, the subject selected for treatment at or after exposure to eye allergens or at or after the onset of symptoms of allergic conjunctivitis has been clinically diagnosed with allergic conjunctivitis in the past and is positive in allergen skin test for one or more eye allergens, particularly eye allergens to which the subject is expected to be exposed. In some embodiments, the standard allergen skin test uses a panel of allergens, such as those described above.

[0087] In some embodiments, the method for treating allergic conjunctivitis comprises administering the ophthalmic solution of the present invention to the eye of a subject in need thereof before expected or certain exposure to an ophthalmic allergen, and further comprises administering the ophthalmic solution of the present invention at or after exposure to an ophthalmic allergen or at or after the onset of symptoms of allergic conjunctivitis. This treatment protocol results in a two-phase treatment regimen, the first phase being administration before expected or certain exposure to an ophthalmic allergen, and the second phase being administration at or after exposure to an ophthalmic allergen or at or after the onset of symptoms of allergic conjunctivitis. In some embodiments, the method for treating allergic conjunctivitis comprises a first treatment phase comprising administering the ophthalmic solution before expected or certain exposure of the subject to an ophthalmic allergen, and a second treatment phase comprising administering the ophthalmic solution at or after exposure of the subject to an ophthalmic allergen or at or after the onset of symptoms of allergic conjunctivitis. In some embodiments, the second treatment phase may further comprise treatment of an onset phase, an exacerbation phase, and / or a maintenance phase as discussed herein.

[0088] In some embodiments, in the first treatment phase (administration of the ophthalmic solution of the present invention to the eye of a subject in need thereof prior to expected or certain exposure to an ophthalmic allergen), the ophthalmic solution is administered topically to the eye prior to expected or certain exposure to an ophthalmic allergen, for example, within the duration of therapeutic effect of a 0.25% w / v or 0.5% w / v Reproxalap solution. In some embodiments, in the first treatment phase, the ophthalmic solution of the present invention is administered 3.5 hours or less, 3 hours or less, 2.5 hours or less, 2 hours or less, 1.5 hours or less, 1 hour or less, 0.5 hours or less, 25 minutes or less, 20 minutes or less, 25 minutes or less, 20 minutes or less, 15 minutes or less, 10 minutes or less, or 5 minutes or less prior to expected or certain exposure to an ophthalmic allergen, or immediately prior to exposure to an ophthalmic allergen. In some embodiments, the ophthalmic solution of the present invention is administered 0-0.5 hours, 0-1 hour, 0-1.5 hours, 0-2 hours, 0-2.5 hours, 0-3 hours, 0-3.5 hours before expected or certain exposure to an ocular allergen. In some embodiments, the ophthalmic solution of the present invention is administered 0.5-1 hour, 0.5-1.5 hours, 0.5-2 hours, 0.5-2.5 hours, 0.5-3 hours, 0.5-3.5 hours before expected or certain exposure to an ocular allergen. In some embodiments, the ophthalmic solution of the present invention is administered 1-1.5 hours, 1-2 hours, 1-2.5 hours, 1-3 hours, 1-3.5 hours before expected or certain exposure to an ocular allergen. In some embodiments, the ophthalmic solution of the present invention is administered 1.5-2 hours, 1.5-2.5 hours, 1.5-3 hours, 1.5-3.5 hours before expected or certain exposure to an ocular allergen. In some embodiments, the ophthalmic solution of the present invention is administered 2-2.5 hours, 2-3 hours, 2-3.5 hours prior to expected or certain exposure to an ophthalmic allergen, hi some embodiments, the ophthalmic solution of the present invention is administered 2.5-3 hours or 2.5-3.5 hours prior to expected or certain exposure to an ophthalmic allergen.

[0089] In some embodiments, in the first treatment phase (administering the ophthalmic solution of the present invention to the eye of a subject in need thereof prior to expected or certain exposure to an ophthalmic allergen), the ophthalmic solution of the present invention is administered 1, 2, 3, 4, 5, 6, 7 or 8 times prior to expected or certain exposure to an ophthalmic allergen. In some embodiments, in the first treatment phase, the ophthalmic solution of the present invention is administered 1, 2, 3, 4, 5, 6, 7 or 8 times prior to expected or certain exposure to an ophthalmic allergen. In some embodiments, in the first treatment phase, the ophthalmic solution of the present invention is administered 1, 2, 3, 4, 5, 6, 7 or 8 times prior to expected or certain exposure to an ophthalmic allergen. In some embodiments, in the first treatment phase, the ophthalmic solution of the present invention is administered 1, 2, 3, 4 times prior to expected or certain exposure to an ophthalmic allergen. In some embodiments, in the first treatment phase, the ophthalmic solution of the present invention is administered 1, 2, 3, 4 times prior to expected or certain exposure to an ophthalmic allergen. In some embodiments, the ophthalmic composition when administered twice or more times is administered 3.5 hours, 3 hours, 2.5 hours, 2 hours, 1.5 hours, 1 hour or 0.5 hours before expected or certain exposure to ocular allergen. In some embodiments of the first treatment phase, the ophthalmic solution when administered once is administered 1.5 hours or less, 1 hour or less, 0.5 hours or less, 25 minutes or less, 20 minutes or less, 25 minutes or less, 20 minutes or less, 15 minutes or less, 10 minutes or less, or 5 minutes or less before expected or certain exposure to ocular allergen, or immediately before expected or certain exposure to ocular allergen. In some embodiments, each administration of the ophthalmic solution in the first treatment phase is accompanied by one or two doses (e.g., drops) of the ophthalmic solution. In some embodiments, each administration of the ophthalmic solution in the first treatment phase is accompanied by a single dose (e.g., one drop) of the ophthalmic solution. In some embodiments, each administration of the ophthalmic solution of the first treatment phase involves two doses (eg, two drops) of the ophthalmic solution.

[0090] In some embodiments, in the second treatment phase (administering the ophthalmic solution of the present invention to the eye of a subject in need thereof at or after exposure to an ocular allergen or during or after the onset of symptoms of allergic conjunctivitis), the ophthalmic solution of the present invention is administered within 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60 minutes (1 hour), 75 minutes (1.25 hours), 90 minutes (1.5 hours), 105 minutes (1.75 hours), or 120 minutes (2 hours) after exposure to an ocular allergen or after the onset of symptoms of allergic conjunctivitis. In some embodiments, in the second treatment phase, the ophthalmic solution of the present invention is administered within 0-5 minutes, 0-10 minutes, 0-15 minutes, 0-20 minutes, 0-25 minutes, 0-30 minutes, 0-35 minutes, 0-40 minutes, 0-45 minutes, 0-50 minutes, 0-60 minutes, 0-75 minutes, 0-90 minutes, 0-105 minutes, or 0-120 minutes after exposure of the eye to an allergen or after onset of symptoms of allergic conjunctivitis. In some embodiments of the method, the ophthalmic solution of the present invention is administered within 5-10, 5-15, 5-20, 5-25, 5-30, 5-35, 5-40, 5-45, 5-50, 5-60, 5-75, 5-90, 5-105, or 5-120 minutes after exposure to an ocular allergen or after onset of symptoms of allergic conjunctivitis. In some embodiments of the method, the ophthalmic solution of the present invention is administered within 10-15, 10-20, 10-25, 10-30, 10-35, 10-40, 10-45, 10-50, 10-60, 10-75, 10-90, 10-105, or 10-120 minutes after exposure to an ocular allergen or after onset of symptoms of allergic conjunctivitis. In some embodiments of the method, the ophthalmic solution of the present invention is administered within 15-20 minutes, 15-25 minutes, 15-30 minutes, 15-35 minutes, 15-40 minutes, 15-45 minutes, 15-50 minutes, 15-60 minutes, 15-75 minutes, 15-90 minutes, 15-105 minutes, or 15-120 minutes after exposure of the eye to the allergen or after onset of symptoms of allergic conjunctivitis.In some embodiments of the method, the ophthalmic solution of the present invention is administered within 20-25 minutes, 20-30 minutes, 20-35 minutes, 20-40 minutes, 20-45 minutes, 20-50 minutes, 20-60 minutes, 20-75 minutes, 20-90 minutes, 20-105 minutes, or 20-120 minutes after exposure to an ocular allergen or after onset of symptoms of allergic conjunctivitis. In some embodiments of the method, the ophthalmic solution of the present invention is administered within 25-30 minutes, 25-35 minutes, 25-40 minutes, 25-45 minutes, 25-50 minutes, 25-60 minutes, 25-75 minutes, 25-90 minutes, 25-105 minutes, or 25-120 minutes after exposure to an ocular allergen or after onset of symptoms of allergic conjunctivitis. In some embodiments of the method, the ophthalmic solution of the present invention is administered within 30-35 minutes, 30-40 minutes, 30-45 minutes, 30-50 minutes, 30-60 minutes, 30-75 minutes, 30-90 minutes, 30-105 minutes, or 30-120 minutes after exposure to an ocular allergen or onset of symptoms of allergic conjunctivitis. In some embodiments of the method, the ophthalmic solution of the present invention is administered within 35-40 minutes, 35-45 minutes, 35-50 minutes, 35-60 minutes, 35-75 minutes, 35-90 minutes, 35-105 minutes, or 35-120 minutes after exposure to an ocular allergen or onset of symptoms of allergic conjunctivitis. In some embodiments of the method, the ophthalmic solution of the present invention is administered within 40-45 minutes, 40-50 minutes, 40-60 minutes, 40-75 minutes, 40-90 minutes, 40-105 minutes, or 40-120 minutes after exposure to an ocular allergen or onset of symptoms of allergic conjunctivitis. In some embodiments of the method, the ophthalmic solution of the present invention is administered within 45-50 minutes, 45-60 minutes, 45-75 minutes, 45-90 minutes, 45-105 minutes, or 45-120 minutes after exposure to an ocular allergen or onset of symptoms of allergic conjunctivitis. In some embodiments of the method, the ophthalmic solution of the present invention is administered within 50-60 minutes, 50-75 minutes, 50-90 minutes, 50-105 minutes, or 50-120 minutes after exposure to an ocular allergen or onset of symptoms of allergic conjunctivitis. In some embodiments of the methods, the ophthalmic solution of the present invention is administered within 60 to 75 minutes, 60 to 90 minutes, 60 to 105 minutes, or 60 to 120 minutes after exposure of the eye to an allergen or after the onset of symptoms of allergic conjunctivitis.In some embodiments of the method, the ophthalmic solution of the present invention is administered within 75-90 minutes, 75-105 minutes, or 75-120 minutes after exposure to an ocular allergen or after onset of symptoms of allergic conjunctivitis. In some embodiments of the method, the ophthalmic solution of the present invention is administered within 90-105 minutes, or 90-120 minutes after exposure to an ocular allergen or after onset of symptoms of allergic conjunctivitis.

[0091] In some embodiments, in the second treatment phase, the ophthalmic solution of the present invention is administered up to 8 times a day, up to 7 times a day, up to 6 times a day, up to 5 times a day, up to 4 times a day, up to 3 times a day, up to 2 times a day, or once a day. In some embodiments, in the second treatment phase, the ophthalmic solution of the present invention is administered 8 times a day, 7 times a day, 6 times a day, 5 times a day, 4 times a day (QID), 3 times a day (TID), 2 times a day (BID), or once a day (QD). In some embodiments, in the second treatment phase, the ophthalmic solution of the present invention is administered as needed (PRN). In some embodiments, in the second treatment phase, the ophthalmic solution of the present invention is administered 8 times a day, 7 times a day, 6 times a day, 5 times a day, 4 times a day (QID), 3 times a day (TID), 2 times a day (BID), once a day (QD), followed by administration as needed (PRN). In some embodiments of the method, the ophthalmic solution of the present invention is administered four times daily (QID) followed by administration as needed (PRN).

[0092] In some embodiments, in the second treatment phase, each administration is every 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, or 4 hours. In some embodiments of the method, each administration is every 1-1.5 hours, 1-2 hours, 1-2.5 hours, 1-3 hours, 1-3.5 hours, or 1-4 hours. In some embodiments of the method, each administration is every 1.5-2 hours, 1.5-2.5 hours, 1.5-3 hours, 1.5-3.5 hours, or 1.5-4 hours. In some embodiments of the method, each administration is every 2-2.5 hours, 2-3 hours, 2-3.5 hours, or 2-4 hours. In some embodiments of the method, each administration is every 3-3.5 hours, or 3-4 hours.

[0093] In some embodiments, during the second treatment phase, the ophthalmic solution of the present invention is administered twice daily (BID) with each administration spaced 60 minutes (1 hour), 90 minutes (1.5 hours), 120 minutes (2 hours), 150 minutes (2.5 hours), 180 minutes (3 hours), 210 minutes (3.5 hours), or 240 minutes (4 hours). In some embodiments of the method, the ophthalmic solution of the present invention is administered three times daily (TID) with each administration spaced 60 minutes (1 hour), 90 minutes (1.5 hours), 120 minutes (2 hours), 150 minutes (2.5 hours), 180 minutes (3 hours), 210 minutes (3.5 hours), or 240 minutes (4 hours). In some embodiments of the method, the ophthalmic solution of the present invention is administered four times daily (QID) with each administration spaced 60 minutes (1 hour), 90 minutes (1.5 hours), 120 minutes (2 hours), 150 minutes (2.5 hours), 180 minutes (3 hours), 210 minutes (3.5 hours), or 240 minutes (4 hours). In some embodiments of the method, the ophthalmic solution of the present invention is administered twice daily (BID) with each administration spaced 60 minutes (1 hour), 90 minutes (1.5 hours), or 120 minutes (2 hours).

[0094] In some embodiments, in the second treatment phase, each administration of the ophthalmic solution at or after exposure to an ocular allergen or at or after the onset of symptoms of allergic conjunctivitis is accompanied by one or two doses (e.g., drops) of the ophthalmic solution. In some embodiments, in the second treatment phase, each administration of the ophthalmic solution is accompanied by a single dose (e.g., one drop) of the ophthalmic solution. In some embodiments, in the second treatment phase, each administration of the ophthalmic solution is accompanied by two doses (e.g., two drops) of the ophthalmic solution.

[0095] In some embodiments, a method for treating allergic conjunctivitis includes a first treatment phase and a second treatment phase, the first treatment phase includes administering an ophthalmic solution before the subject's expected or certain exposure to an ocular allergen, and the second treatment phase includes administering an ophthalmic solution at or after the subject's exposure to an ocular allergen, or at or after the onset of symptoms of allergic conjunctivitis, wherein the subject selected for treatment has a history of allergic conjunctivitis. In some embodiments, the subject selected for treatment has a history of allergic conjunctivitis and has a positive allergen skin test for one or more ocular allergens, particularly the ocular allergens to which the subject is expected to be exposed. In some embodiments, the subject selected for treatment has a clinical diagnosis of allergic conjunctivitis in the past. In some embodiments, the subject selected for treatment has a clinical diagnosis of allergic conjunctivitis in the past and has a positive allergen skin test for one or more ocular allergens, particularly the ocular allergens to which the subject is expected to be exposed. In some embodiments, the standard allergen skin test uses a panel of allergens, such as those described above.

[0096] In some embodiments, the methods of the present invention comprise topically administering an ophthalmic solution of the present invention at different strengths (eg, different reproxalap concentrations and different administration frequencies as described herein).

[0097] In some embodiments, the methods of the present invention comprise topically administering an ophthalmic solution comprising about 0.25% w / v reproxalap or a pharma- ceutically acceptable salt thereof four times per day, three times per day, or twice per day.

[0098] In some embodiments, the methods of the present invention comprise topically administering an ophthalmic solution comprising about 0.30% w / v of reproxalap or a pharma- ceutically acceptable salt thereof four times per day, three times per day, or twice per day.

[0099] In some embodiments, the methods of the present invention comprise topically administering an ophthalmic solution comprising about 0.35% w / v reproxalap or a pharma- ceutically acceptable salt thereof four times per day, three times per day, or twice per day.

[0100] In some embodiments, the methods of the present invention comprise topically administering an ophthalmic solution comprising about 0.4% w / v reproxalap or a pharma- ceutically acceptable salt thereof four times per day, three times per day, or twice per day.

[0101] In some embodiments, the methods of the present invention comprise topically administering an ophthalmic solution comprising about 0.45% w / v reproxalap or a pharma- ceutically acceptable salt thereof four times per day, three times per day, or twice per day.

[0102] In some embodiments, the methods of the present invention comprise topically administering an ophthalmic solution comprising about 0.5% w / v reproxalap or a pharma- ceutically acceptable salt thereof four times per day, three times per day, or twice per day.

[0103] In some embodiments, the methods of the invention involve topical administration of an ophthalmic solution comprising 0.3% to 0.4% w / v reproxalap or a pharma- ceutically acceptable salt thereof four times per day, three times per day, or twice per day.

[0104] In some embodiments, the methods of the invention involve topical administration of an ophthalmic solution comprising 0.2% to 0.4% w / v reproxalap or a pharma- ceutically acceptable salt thereof four times per day, three times per day, or twice per day.

[0105] In some embodiments, the method of the present invention includes two or more phases of treatment, including an initiation phase, an exacerbation phase, and / or a maintenance phase. In some embodiments, the different phases of treatment may include administration of different strengths of reproxalap, different administration frequencies, or a combination of different strengths of reproxalap and different administration frequencies. In some embodiments, the initiation phase of treatment begins upon onset of symptoms of allergic conjunctivitis. In some embodiments, the initiation phase of treatment begins when symptoms of allergic conjunctivitis are in the worsening of signs and / or symptoms of the disease. In some embodiments, the initiation and / or exacerbation phase of treatment may be for up to 1 week, up to 2 weeks, up to 3 weeks, up to 4 weeks, up to 6 weeks, up to 8 weeks, or up to 12 weeks. In some embodiments, the maintenance phase may be for up to 1 week, up to 2 weeks, up to 3 weeks, up to 4 weeks, up to 6 weeks, up to 8 weeks, or up to 12 weeks or longer, e.g., until symptoms of allergic conjunctivitis are reduced or resolved.

[0106] In some embodiments, the method of the present invention comprises two or more phases, and the ophthalmic solution of the present invention is topically administered in different phases at different intensities. In some embodiments, the method of the present invention comprises an initiation phase and a maintenance phase, and the ophthalmic solution is topically administered in the initiation phase at a higher intensity than in the maintenance phase. In some embodiments, the treatment cycle of the method of the present invention comprises multiple phases, including an exacerbation phase, during which signs and / or symptoms worsen.

[0107] In some embodiments, the method of the invention comprises two or more phases, and the ophthalmic solution of the invention is topically administered in different phases at different strengths, hi some embodiments, the method of the invention comprises an initiation phase, and the ophthalmic solution is topically administered at a high strength in the initiation phase, at a lower strength in the maintenance phase, and at a high strength during an exacerbation of signs and / or symptoms of the disease.

[0108] In some embodiments, the ophthalmic solution administered during the initiation phase comprises a higher concentration of reproxalap or a pharma- ceutically acceptable salt thereof than the ophthalmic solution administered during the maintenance phase. In some embodiments, the ophthalmic solution administered during the initiation or progression phase and the ophthalmic solution administered during the maintenance phase comprise a concentration of reproxalap or a pharma- ceutically acceptable salt thereof selected from the group consisting of about 0.5% w / v, 0.45% w / v, 0.4% w / v, 0.35% w / v, 0.3% w / v, 0.25% w / v, 0.2% w / v, 0.15% w / v, and 0.1% w / v.

[0109] In some embodiments, an ophthalmic solution of about 0.5% w / v of reproxalap is administered during the onset or progression phase, and less than 0.5% w / v of reproxalap is administered during the maintenance phase. In some embodiments, an ophthalmic solution of about 0.4% w / v, 0.35% w / v, 0.3% w / v, 0.25% w / v, 0.2% w / v, 0.15% w / v, or 0.1% w / v of reproxalap is administered during the maintenance phase.

[0110] In some embodiments, an ophthalmic solution of about 0.5% w / v to about 0.4% reproxalap is administered during the onset or progression phase, and less than 0.4% w / v reproxalap is administered during the maintenance phase. In some embodiments, an ophthalmic solution of about 0.35% w / v, 0.3% w / v, 0.25% w / v, 0.2% w / v, 0.15% w / v, or 0.1% w / v reproxalap is administered during the maintenance phase.

[0111] In some embodiments, an ophthalmic solution of about 0.5% w / v to about 0.3% reproxalap is administered during the onset or progression phase, and less than 0.3% w / v reproxalap is administered during the maintenance phase. In some embodiments, an ophthalmic solution of about 0.25% w / v, 0.2% w / v, 0.15% w / v, or 0.1% w / v reproxalap is administered during the maintenance phase.

[0112] In some embodiments, an ophthalmic solution of about 0.4% w / v to about 0.3% reproxalap is administered during the onset or progression phase, and less than 0.3% w / v reproxalap is administered during the maintenance phase. In some embodiments, an ophthalmic solution of about 0.25% w / v, 0.2% w / v, 0.15% w / v, or 0.1% w / v reproxalap is administered during the maintenance phase.

[0113] In some embodiments, an ophthalmic solution of about 0.3% w / v to about 0.2% reproxalap (e.g., 0.3%, 0.25% or 0.2% w / v) is administered during the onset or progression phase, and 0.25% w / v or less reproxalap is administered during the maintenance phase. In some embodiments, an ophthalmic solution of about 0.25% w / v, 0.2% w / v, 0.15% w / v or 0.1% w / v reproxalap is administered during the maintenance phase.

[0114] In some embodiments, the ophthalmic solution of the present invention is topically administered at a higher daily frequency in the onset phase and / or progression phase than in the maintenance phase. In some embodiments, the ophthalmic solution of the present invention is topically administered 5 times a day in the onset phase, followed by 4 times, 3 times, 2 times, 1 time or as needed in the maintenance phase. In some embodiments, the ophthalmic solution of the present invention is topically administered 4 times a day (QID) in the onset phase or progression phase, followed by 3 times a day (TID), twice a day (BID), once a day (QD) or as needed (PRN) in the maintenance phase. In some embodiments, the ophthalmic solution of the present invention is topically administered 3 times a day (TID) in the onset phase or progression phase, followed by 2 times a day (BID) or once a day (QD) or as needed (PRN) in the maintenance phase. In some embodiments, the ophthalmic solution of the present invention is topically administered twice a day (BID) in the onset phase or progression phase, followed by 1 time a day (QD) or as needed (PRN) in the maintenance phase.

[0115] In some embodiments, the ophthalmic solutions of the present invention used in the initiation and maintenance phases have the same concentration of reproxalap (e.g., 0.5%, 0.4%, 0.3%, 0.25% or 0.2% w / v) when the dosing frequency differs between the initiation and maintenance phases.

[0116] In some embodiments, the ophthalmic solution administered during the onset or progression phase has a higher concentration of reproxalap and is administered more frequently than the ophthalmic solution administered during the maintenance phase.

[0117] In some embodiments, the present invention provides a method for treating allergic conjunctivitis in a subject comprising topically administering to the subject an ophthalmic solution comprising about 0.4% w / v of reproxalap or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient, wherein the ophthalmic solution is administered at a higher strength for an onset or exacerbation phase, followed by a lower strength for a maintenance phase, each of the onset phase, exacerbation phase, and maintenance phase being as described herein.

[0118] In some embodiments, a multi-phasic treatment cycle may include an initiation or progression phase of up to 1 week, up to 2 weeks, up to 3 weeks, up to 4 weeks, up to 6 weeks, up to 8 weeks, or up to 12 weeks, followed by a maintenance phase with an ophthalmic solution containing about 0.5%, 0.4% or 0.35% w / v, 0.25% (e.g., 0.5%-0.35% w / v) reproxalap or a pharma- ceutically acceptable salt thereof. In some embodiments, an ophthalmic solution containing about 0.5%, 0.4% or 0.35% w / v, 0.25% (e.g., 0.5%-0.35% w / v) reproxalap or a pharma- ceutically acceptable salt thereof is administered four times a day (QID) during the initiation or progression phase, followed by three times a day (TID), twice a day (BID), or once a day (QD) during the maintenance phase. In some embodiments, an ophthalmic solution comprising about 0.5%, 0.4%, or 0.35% w / v, 0.25% (e.g., 0.5%-0.35% w / v) reproxalap or a pharma- ceutically acceptable salt thereof is administered three times daily (TID) during the onset or exacerbation phase, followed by twice daily (BID) or once daily (QD) during the maintenance phase.

[0119] In some embodiments, an ophthalmic solution containing about 0.4%, 0.35% or 0.3% w / v (e.g., 0.4%-0.3% w / v) reproxalap or a pharma- ceutically acceptable salt thereof is administered four times a day (QID) during the onset or progression phase, followed by three times a day (TID), twice a day (BID) or once a day (QD) during the maintenance phase. In some embodiments, an ophthalmic solution containing about 0.4%, 0.35% or 0.3% w / v (e.g., 0.4%-0.3% w / v) reproxalap or a pharma- ceutically acceptable salt thereof is administered three times a day (TID) during the onset or progression phase, followed by twice a day (BID) or once a day (QD) during the maintenance phase.

[0120] In some embodiments, an ophthalmic solution containing about 0.3%, 0.25% or 0.2% w / v (e.g., 0.3%-0.2% w / v) reproxalap or a pharma- ceutically acceptable salt thereof is administered four times a day (QID) during the onset or progression phase, followed by three times a day (TID), twice a day (BID) or once a day (QD) during the maintenance phase. In some embodiments, an ophthalmic solution containing about 0.3%, 0.25% or 0.2% w / v (e.g., 0.3%-0.2% w / v) reproxalap or a pharma- ceutically acceptable salt thereof is administered three times a day (TID) during the onset or progression phase, followed by twice a day (BID) or once a day (QD) during the maintenance phase.

[0121] In some embodiments, the present invention provides a method for treating allergic conjunctivitis in a subject comprising topically administering to the subject an ophthalmic solution comprising 0.35%-0.45% w / v reproxalap or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient, wherein the ophthalmic solution is administered at a higher strength for an onset or exacerbation phase, followed by a lower strength for a maintenance phase, each of the onset, exacerbation and maintenance phases being as described herein. In some embodiments, the multi-phase treatment cycle of the ophthalmic solution comprising 0.35%-0.45% w / v reproxalap or a pharma- ceutically acceptable salt thereof is up to 12 weeks. In some embodiments, an ophthalmic solution containing 0.35%-0.45% w / v reproxalap or a pharma- ceutically acceptable salt thereof is administered four times a day (QID) during the onset or progression phase, followed by three times a day (TID), twice a day (BID), or once a day (QD) during the maintenance phase. In some embodiments, an ophthalmic solution containing 0.35%-0.45% w / v reproxalap or a pharma- ceutically acceptable salt thereof is administered three times a day (TID) during the onset or progression phase, followed by twice a day (BID) or once a day (QD) during the maintenance phase.

[0122] In some embodiments, a treatment regimen with an ophthalmic solution of the present invention results in a statistically significant reduction in the ocular pruritus scale in a patient population suffering from allergic conjunctivitis. In some embodiments, a treatment regimen with an ophthalmic solution of the present invention results in a statistically significant (p<0.05) reduction of at least one point in the ocular pruritus scale in a patient population suffering from allergic conjunctivitis. In some embodiments, a treatment regimen with an ophthalmic solution of the present invention results in a statistically significant (p<0.05) reduction of at least two points in the ocular pruritus scale in a patient population suffering from allergic conjunctivitis. The ocular pruritus scale ranges from 0 (no pruritus) to 4 (incapacitating pruritus).

[0123] In some embodiments, the present invention provides a method for treating a certain subject with allergic conjunctivitis.In some embodiments, the subject with allergic conjunctivitis is 18 years old or older.In some embodiments, the subject with allergic conjunctivitis has a history of allergic conjunctivitis for at least 6 months before receiving the treatment of the present invention.In some embodiments, the subject with allergic conjunctivitis has a history of or desires to use eye drops for symptoms within 6 months before receiving the treatment of the present invention.

[0124] In some embodiments, the present invention provides methods for treating a subject having allergic conjunctivitis, comprising identifying a subject who meets one or more of the following criteria for at least one eye prior to receiving a treatment of the present invention (e.g., screening performed about 1 and / or 2 weeks prior to receiving the treatment): Schirmer test score ≤10mm and ≥1mm; · Tear film breakup time (TFBUT) is ≦5 seconds; · Fluorescein corneal staining score of ≥2 in at least one region (e.g., inferior, superior, or central); A total fluorescein corneal staining score based on the sum of the lower, upper, and central regions is ≥ 4; and Total Lissamine Green conjunctival score ≥ 2 based on the combined temporal and nasal areas.

[0125] In some embodiments, the present invention provides methods for treating a subject with allergic conjunctivitis, comprising screening to exclude subjects with one or more of the following conditions for at least one eye, prior to receiving the treatment of the present invention: · Having clinically significant slit lamp findings, which may include active blepharitis, meibomian gland dysfunction (MGD), eyelid margin inflammation or active ocular allergy that may require therapeutic treatment;· Having ongoing ocular infection (bacterial, viral or fungal) or active ocular inflammation;· Having previously undergone laser in situ keratomileusis (LASIK) surgery within the past 12 months;· Having any surgery of the eye and / or eyelid planned over the study period or having had any surgery of the eye within 6 months; Have a known allergy and / or sensitivity to the ophthalmic solution of the present invention or any of its components.

[0126] As described herein, the ophthalmic solutions of the present invention can achieve increased efficacy in subjects with allergic conjunctivitis. Thus, in some embodiments, the present invention provides a method for treating a subject with allergic conjunctivitis, comprising topically administering to the subject an ophthalmic solution of the present invention.

[0127] In some embodiments, the present invention provides a method for treating allergic conjunctivitis in a subject, comprising topically administering to the subject an ophthalmic solution as described herein, wherein the ophthalmic solution is administered three times a day (TID), twice a day (BID) or once a day (QD). In some embodiments, an ophthalmic solution comprising about 0.25% w / v of reproxalap or a pharma- ceutically acceptable salt thereof is administered three times a day (TID). In some embodiments, an ophthalmic solution comprising about 0.25% w / v of reproxalap or a pharma-ceutically acceptable salt thereof is administered twice a day (BID). In some embodiments, an ophthalmic solution comprising about 0.25% w / v of reproxalap or a pharma-ceutically acceptable salt thereof is administered once a day (QD).

[0128] In topical ophthalmic administration, each administration comprises one or more aliquots of the composition (e.g., ophthalmic solution). In some embodiments, the aliquots are administered as drops, applied, for example, using an eye dropper or squeeze vial, in estimated volumes. In some embodiments, one or more drops, up to two, three, four drops are applied topically to each of one or both eyes at each administration. In some embodiments, each administration comprises sequential administration, for example, a first administration of one or more aliquots (e.g., one or more drops), a first period to allow for absorption of the composition, followed by a second administration of one or more aliquots (e.g., one or more drops). In some embodiments, one drop provides a single dose of ophthalmic solution. In some embodiments, the volume of the topical administration is about 25uL to about 75uL. In some embodiments, the volume of the topical administration is about 30uL to about 60uL. In some embodiments, the volume of the topical administration is about 50uL. In some embodiments, the volume of one drop of the ophthalmic solution of the present invention is approximately 30uL to 50uL. In some embodiments, a drop of an ophthalmic solution of the present invention has a volume of approximately 50 uL.

[0129] In some embodiments, the ophthalmic solution of the present disclosure is co-administered with an additional therapeutic agent. In some embodiments, the additional therapeutic agent is an agent disclosed in WO2017147617 or WO2017196881, each of which is incorporated herein by reference in its entirety. In some embodiments, the additional therapeutic agent is an antihistamine, a mast cell inhibitor, or an anti-inflammatory agent. Exemplary antihistamines include levocabastine, olopatadine, and ketotifen fumarate, among others. In some embodiments, the anti-inflammatory agent is a steroid, a nonsteroidal anti-inflammatory compound, antimetabolite, an immunosuppressant antibiotic, an alkylating agent, or an anti-inflammatory cytokine antibody. Exemplary steroid compounds include cortisol, cortisone, prednisone, prednisolone (e.g., prednisolone acetate), methylprednisone, triamcinolone, betamethasone, dexamethasone, and their prodrugs, among others. Exemplary nonsteroidal anti-inflammatory compounds include acetylsalicylic acid, diflunisal, salsalate, ibuprofen, dexbuprofen, naioxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, nabumetone, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, phenylbutazone, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid and celecoxib, among others.Exemplary antimetabolites include azathioprine, mercaptopurine, leflunomide, mycophenolic acid and mycophenolate mofetil and methotrexate, among others. Exemplary anti-inflammatory antibiotics include cyclosporine, tacrolimus, rapamycin and their derivatives, among others. Exemplary anti-inflammatory antibodies include antibodies targeting inflammatory cytokines, such as antibodies against TNFα, IL-1, IL-4, IL-5 and IL-17, among others.

[0130] In another aspect, a method is further provided herein for evaluating the safety, efficacy, comparability, or bioequivalence of an aldehyde-trapping compound for treating allergic conjunctivitis using an EEC chamber protocol. In some embodiments, the method for evaluating the safety, efficacy, comparability, or bioequivalence of an aldehyde-trapping compound for treating allergic conjunctivitis includes placing a test subject in an EEC chamber, administering one or more test allergens, administering a test aldehyde-trapping compound or a composition thereof, and evaluating the severity of symptoms of allergic conjunctivitis. In some embodiments, the symptoms for evaluating the severity of allergic conjunctivitis include one or more of ocular itching, ocular tearing, and conjunctival redness, among others. In some embodiments, the test aldehyde-trapping compound or a composition thereof is administered before and / or at or after the start of exposure of the test subject to the allergen. In some embodiments, the method is used to evaluate the comparability or bioequivalence of an ophthalmic composition containing 0.25% w / v or 0.5% w / v reproxalap. EXAMPLES

[0131] The following examples are intended to illustrate the present invention and should not be construed as limiting thereof. Reproxalap can be synthesized, for example, as previously reported in WO2006 / 127945, the entire contents of which are incorporated herein by reference.

[0132] Abbreviation CAE: Controlled Hazardous Environment GMP: Manufacturing management and quality control regulations for pharmaceuticals and quasi-drugs ICH: International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use OD: Right eye OS: Left eye OU: Both eyes PRN: As needed QD: Once a day QID: 4 times a day QS: Appropriate amount

[0133] Example 1: A Multicenter, Double-Blind, Randomized, Parallel-Group, Vehicle-Controlled Phase 3 Clinical Trial to Evaluate the Safety and Efficacy of Reproxalap Ophthalmic Solution (0.25% and 0.5%) Compared to Vehicle in the Conjunctival Allergen Challenge (Ora-CAC®) Model of Acute Allergic Conjunctivitis. This double-blind, randomized, vehicle-controlled, multicenter, parallel-group, conjunctival allergen challenge phase 3 study evaluated the efficacy and safety of 0.25% and 0.5% concentrations of reproxalap topical ophthalmic solution compared with vehicle in 318 patients (approximately 100 per arm) with seasonal allergic conjunctivitis. The primary efficacy outcome measure was the area under the curve assessment of ocular pruritus scores (on a 0-4 scale) 10-60 minutes after allergen challenge, and the key secondary outcome measure was the 2-point responder rate, a measure of clinical relevance.

[0134] The primary objective of the study was a statistically significant improvement versus vehicle in the primary endpoint of area under the curve for ocular pruritus scores 10-60 minutes after allergen challenge (p<0.0001 and p=0.0025, respectively).

[0135] The secondary objective of the study was a statistically significant improvement versus vehicle in the significant secondary responder analysis of a 2-point improvement in ocular pruritus score (0-4 scale) (p=0.0005 and p=0.0169, respectively).

[0136] Relative to vehicle-treated patients, patients treated with 0.25% and 0.5% reproxalap demonstrated a statistically significant reduction in ocular pruritus as assessed by the area under the curve of ocular pruritus scores (p<0.0001 and p=0.0025, respectively, Figure 1). The 2-point responder rates for 0.25% and 0.5% reproxalap were statistically higher than those of vehicle-treated patients (p=0.0005 and p=0.0169, respectively, Figures 2 and 3), confirming the clinical relevance of the observed improvements in the primary endpoint. Both concentrations of reproxalap demonstrated an anti-inflammatory profile that was significantly different from standard-of-care antihistamine therapy and supported a differentiated mechanism of action for the treatment of allergic conjunctivitis.

[0137] Consistent with previous clinical trials of Reproxalap, no adverse events were observed except for mild, transient instillation site irritation.

[0138] No findings were observed in the following safety assessments: visual acuity (ETDRS chart), intraocular pressure (contact tonometry), slit-lamp biomicroscopy, and dilated fundus examination.

[0139] Duration

[0140] The study consisted of four visits (screening visit, visit 1, visit 2, and visit 3) over a period of approximately 3 to 9 weeks.

[0141] Screening Duration: Screening was approximately 3-9 weeks in duration. At Visit 1, subjects underwent titration of ocular allergen challenge using the allergen that elicited a positive skin test reaction. Subjects with a positive reaction after CAC underwent confirmatory CAC at Visit 2 using the same allergen as qualified at Visit 1.

[0142] Treatment Period: Treatment begins after subject randomization at Visit 3. At this visit, subjects receive their in-hospital dose of treatment.

[0143] Inclusion criteria

[0144] Each subject: · Must be 18 years of age or older of any gender and race; · Must have a positive history of ocular allergy and confirmed by allergy skin testing at the screening visit, or a positive skin test reaction to seasonal allergens (grasses, ragweed, and / or trees) within the past 24 months; Must be able and willing to avoid all prohibited medications during the study and during appropriate washout periods; Must be able and willing to discontinue contact lens wear for at least 72 hours prior to Visit 1 and throughout the study; ·The calculated visual acuity in each eye, measured using an ETDRS chart, must be 0.7 logMAR or greater; · must agree to undergo urine pregnancy tests administered at screening and termination visits (for women deemed to be of childbearing potential, including all women who have had menarche and have not experienced menopause [defined by amenorrhea for more than 12 consecutive months] or successful surgical sterilization [hysterectomy, bilateral tubal ligation, or bilateral oophorectomy]), not be breastfeeding, and agree to use a medically acceptable form of birth control for the duration of the study; · Bilateral CAC responses (ocular pruritus ≥ 2.5 and conjunctival redness ≥ 2) must be positive within 10 (± 2) minutes of instillation of the final allergen titration at Visit 1; and · Bilateral CAC responses (ocular pruritus ≥ 2.5 and conjunctival redness ≥ 2) must be positive at at least 2 of the first 3 time points after challenge at Visit 2.

[0145] Exclusion criteria

[0146] Each subject: Must not have any known contraindications or sensitivities to the use of the investigational product or any of its components: · Must not have any ocular condition that, in the opinion of the investigator, may affect the subject's safety or study parameters (including, but not limited to, a diagnosis of narrow-angle glaucoma, clinically significant blepharitis, follicular conjunctivitis, iritis, pterygium or dry eye); ·must not have a history of ocular surgical intervention within 3 months prior to Visit 1 or during the study and / or refractive surgery within 6 months prior to Visit 1, or have any ocular or systemic surgery planned during the study or within 30 days thereafter; · Must not have a known history of retinal detachment, diabetic retinopathy or active retinal disease;· Must not have an active ocular infection (bacterial, viral or fungal), the presence of any active uveitis, or a positive history of ocular herpes or ocular herpes infection at the time of any visit; -Do not use any of the following prohibited medications during the indicated period prior to Visit 1 and during the study: 〇72 hours ■ For whole body or eyes 1 Antihistamines, H 1 Antihistamines / Mast Cell Stabilizers, H 1 Antihistamine-vasoconstrictor drug combinations 〇7th Decongestants Monoamine oxidase inhibitors ■ All other topical ophthalmic preparations (including artificial tears) ■ Eyelid scrub ■ Topical prostaglandins or prostaglandin derivatives ■ Ophthalmic, topical or systemic nonsteroidal anti-inflammatory medications (NSAIDs); pediatric aspirin (81 mg) is permitted as long as a stable dose is maintained for at least 30 days prior to Visit 1 and continues to be maintained for the duration of the study. 〇14th ■ Inhaled, ophthalmic, topical or systemic corticosteroids or mast cell stabilizers 〇45 days ■ Depot corticosteroids 〇2 months ■ Immunotherapeutic agents (treatment must be maintained constant for at least 2 months; neither the immunotherapeutic agent nor its dosage should be changed during the clinical trial) (Note: currently available over-the-counter anti-allergy eye drops (e.g., antihistamine / vasoconstrictor combination products) may be administered to subjects by trained study personnel at the completion of Visits 1, 2, and 3 and after completion of all evaluations.) ■Having any significant illness that, in the investigator's judgment, could be expected to interfere with the subject's health or study parameters and / or expose the subject to unnecessary risk (including, but not limited to, poorly controlled hypertension, poorly controlled diabetes, history of status asthmaticus, history of organ transplant, history of persistent moderate or severe asthma, history of moderate or severe allergic asthmatic reactions to any of the test allergens, any autoimmune disease requiring treatment or severe cardiovascular disease or arrhythmia); ■ Develop signs or symptoms of clinically active allergic conjunctivitis (defined as the presence of any pruritus or redness >1 [greater than 1] in the conjunctival vascular bed) in either eye at the start of Visit 1, 2, or 3; ■ Having a history of glaucoma, ocular hypertension, or intraocular pressure (IOP) greater than 24 mm Hg at visit 1; ■ used an investigational drug or medical device within 30 days of the study or was concurrently enrolled in another investigational product study; ■ Women who are currently pregnant, planning to become pregnant, breastfeeding, not using a medically acceptable form of birth control throughout the duration of the study, or have a positive urine pregnancy test at Visit 1.

[0147] statistical analysis

[0148] The primary efficacy variable of area under the curve (AUC10-60) for ocular pruritus score (on a scale of 0-4) 10-60 minutes after challenge will be measured at Visit 3. A generalized linear model was fitted to the Visit 3 AUC10-60 data, including treatment as the main effect and, if useful, baseline information from Visit 2 as one or more covariates. The model was used to evaluate two contrasts: a) mean AUC10-60 of reproxalap ophthalmic solution 0.5% versus mean AUC10-60 of vehicle ophthalmic solution, and b) mean AUC10-60 of reproxalap ophthalmic solution 0.25% versus mean AUC10-60 of vehicle ophthalmic solution. The primary efficacy analysis was performed in the intention-to-treat (ITT) population.

[0149] A GEE was used to evaluate the key secondary endpoint (intended to be used for U.S. NDA approval) of within-subject 2-point response (i.e., 2-point reduction in pruritus score from 5 minutes after Visit 2 CAC at 20–60 minutes after Visit 3 CAC) using treatment, Visit 3 post-CAC measurement time, treatment × time interaction, and Visit 2 baseline information as one or more covariates if available. The model was used to evaluate odds ratios for Reproxalap ophthalmic solution 0.5% vs. vehicle ophthalmic solution, and Reproxalap ophthalmic solution 0.25% vs. vehicle ophthalmic solution between combined Visit 3 post-CAC time points for the ITT population, utilizing the estimated covariance matrix within the GEE to accommodate missing data. Significance levels for these contrasts were adjusted for multiplicity using the Hochberg procedure to avoid false discoveries (see FDA, Multiple Endpoints in Clinical Trials, Draft Guidance for Industry, January 2017).

[0150] Phase 3 AC formulation: 0.5% Reproxalap Ophthalmic Solution A Composition of 0.5% Reproxalap Ophthalmic Solution A [Table 2]

[0151] Phase 3 AC formulation: 0.5% Reproxalap Ophthalmic Solution B Composition of 0.5% Reproxalap Ophthalmic Solution B [Table 3]

[0152] Phase 3 AC formulation: 0.25% Reproxalap Ophthalmic Solution A Composition of 0.25% Reproxalap Ophthalmic Solution A [Table 4-1] [Table 4-2]

[0153] Phase 3 AC formulation: 0.25% Reproxalap ophthalmic solution (basic) Composition of 0.25% Reproxalap Ophthalmic Solution B [Table 5]

[0154] In some embodiments, a basic ophthalmic solution is provided above. Additional excipients may be added to the basic ophthalmic solution as needed.

[0155] Phase 3 AC Composition of Vehicle Ophthalmic Solution Composition of vehicle ophthalmic solution [Table 6]

[0156] Generally, the vehicle used is the same as the AC formulation, except that it does not contain reproxalap. In some embodiments, if the AC formulation does not contain sodium phosphate and / or sodium chloride, the vehicle formulation does not contain sodium phosphate and / or sodium chloride.

[0157] Example 2 Clinical Trial Evaluating Reproxalap Ophthalmic Solution in Subjects with Seasonal Allergic Conjunctivitis Using an Environmental Exposure Chamber (EEC) A clinical trial evaluated the feasibility of using an environmental exposure chamber (EEC) to assess the activity of reproxalap ophthalmic solution (0.25% and 0.5%) in an allergic conjunctivitis population.

[0158] The study used an EEC with exposure to airborne ragweed pollen to evaluate the safety, tolerability, and pharmacodynamic activity of Reproxalap ophthalmic solution (0.25% and 0.5%) compared to vehicle ophthalmic solution in treating seasonal allergic conjunctivitis in subjects allergic to ragweed. An EEC is a chamber, e.g., a room, that provides a reproducible challenge with airborne allergens at controlled levels, as well as control of environmental factors such as humidity and temperature (Devillier et al., Allergy, 2011, 66(2):163-9; Goldstein et al., Eye & Contact Lens, 2015, 41(3):145-155; Jacobs et al., J Allergy Clin Immunol., 2012, 130:122-7). EEC chambers have been used in Phase 3 trials to provide real-life conditions for natural allergen exposure (Pfaar et al., Allergy, 2017, 73(Suppl 104):5-23). ​​EEC chambers allow for better assessment of dose-response, onset of action, and magnitude of treatment effect, as well as lower variability in outcomes and reduced confounding factors that are further controlled in this study by constraining the timing of EEC assessments relative to work schedules.

[0159] Inclusion / exclusion criteria included, among others: A history of moderate to severe ragweed-induced allergic conjunctivitis A positive skin prick test for ragweed pollen within the past year before a medical screening visit Positive bilateral CAC reaction to ragweed allergen (ocular pruritus and redness score ≥ 2) within 10 minutes of instillation of the final titration of allergen at Visit 2 - Signs and symptoms of allergic conjunctivitis in both eyes (ocular itching and redness ≥ 1) for ≥ 4 days during the artificial tear induction period in the week prior to Visit 3.

[0160] The EEC clinical research facility was designed with the capacity and control to expose participants to airborne ragweed pollen particles and to maintain target temperature and relative humidity throughout. The EEC contained 100% fresh, HEPA-filtered clean air, into which commercially available air-dried, non-defatted ragweed (Ambrosia artemesiifolia) pollen (Greer Laboratories, Lenoir, NC) was introduced and circulated throughout the room with tightly controlled humidity and temperature as previously described (Ronborg et al., Allergy, 1996, 51(2):82-88). Continuous monitoring and feedback adjustment of measured pollen release allowed for the study to be performed. The wind-borne ragweed pollen count was maintained at 3500 ± 500 particles per cubic meter. The controlled time-course pollen challenge allowed for the assessment of subject responses at any time point throughout the challenge process.

[0161] Patients underwent medical and EEC screening as highlighted above for inclusion / exclusion criteria. Skin prick testing was performed to a standard panel of test allergens including cat, dust, ragweed, grass or tree pollen. Results must be positive (i.e., wheal 3 mm larger than negative control) to at least one test allergen and must include ragweed to proceed to the screening EEC visit.

[0162] For the EEC treatment session, patients were randomized into three treatment groups: (A) treatment with Reproxalap 0.25% ophthalmic solution, (B) treatment with 0.5% ophthalmic solution, and (C) vehicle treatment. For the EEC treatment session, medication was administered 5 minutes before and 95 minutes after entering the chamber. Patients remained in the EEC for approximately 215 minutes. After leaving the EEC, patients were monitored for ocular itching and tearing for up to approximately 60 minutes. Conjunctival redness, as assessed by personnel, was assessed up to approximately 60 minutes after leaving the chamber. Patients were subjected to three sessions in the EEC chamber, with each EEC session separated by a washout period of approximately 2 weeks to ensure sufficient clearance of responses caused by allergen exposure in the EEC and to allow mast cells to recover.

[0163] A standard 9-point (i.e., 0-4 with 0.5 unit increments) and standard VAS scale (0-100 mm) was used for subject-reported ocular itching. A 4-point scale (0-3) was used for subject-rated ocular tearing. A standard 9-point (i.e., 0-4 with 0.5 unit increments) grading scale was used for personnel-rated conjunctival redness.

[0164] Figure 4 shows ocular pruritus scores (0-100) during 200 minutes of allergen exposure in EEC. Treatment with 0.25% w / v Reproxalap shows a statistically significant reduction in ocular pruritus versus vehicle for exposure to allergen over 3 hours.

[0165] Figure 5 shows eye redness scores (0-4) during 200 minutes of allergen exposure in EEC. Treatment with 0.25% w / v Reproxalap shows a statistically significant reduction in eye redness versus vehicle for exposure to allergen over 3 hours.

[0166] While a number of embodiments of the invention have been described, it will be apparent that the inventors' basic examples may be modified to provide other embodiments that utilize the compounds and methods of the invention. It will therefore be understood that the scope of the invention is to be defined by the appended claims rather than the specific embodiments that have been represented by way of example.

[0167] All publications, patents, patent applications, and other documents cited in this application are incorporated by reference herein in their entirety for all purposes to the same extent as if each individual publication, patent, patent application or other document was individually indicated to be incorporated by reference for all purposes. The present invention provides, for example, the following items. (Item 1) A method for treating allergic conjunctivitis in a subject comprising topically administering to the eye of a subject in need thereof a therapeutically effective amount of an ophthalmic solution comprising reproxalap or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient, wherein the concentration of reproxalap or a pharma- ceutically acceptable salt thereof is about 0.5% w / v or less and at least 0.1% w / v, and wherein the ophthalmic solution comprises reproxalap and a cyclodextrin excipient in a molar ratio of less than 1:2.1. (Item 2) 2. The method of claim 1, wherein the reproxalap and the cyclodextrin excipient are present in a molar ratio of reproxalap:cyclodextrin excipient of 1:2.1 to about 1:25. (Item 3) 3. The method according to claim 1 or 2, wherein the cyclodextrin is α-, β- or γ-cyclodextrin, or a pharma- ceutically acceptable derivative of cyclodextrin selected from hydroxyalkyl derivatives of α-, β- and γ-cyclodextrin, randomly methylated β-cyclodextrin, sulfobutyl ether β-cyclodextrin, sulfobutyl ether γ-cyclodextrin, and branched β- and γ-cyclodextrin derivatives, or a mixture of two or more cyclodextrins. (Item 4) 4. The method according to any one of items 1 to 3, wherein the cyclodextrin excipient is hydroxypropyl β-cyclodextrin (HPCD). (Item 5) 4. The method according to any one of items 1 to 3, wherein the cyclodextrin excipient is sulfobutyl ether β-cyclodextrin (SBECD). (Item 6) The method according to any one of claims 1 to 5, wherein the ophthalmic solution comprises about 0.25% reproxalap and about 4.75% to about 11% w / v of the cyclodextrin excipient. 6. The method of any one of items 1 to 5, wherein the ophthalmic solution comprises about 0.25% reproxalap and about 7% w / v of the cyclodextrin excipient. (Item 8) 6. The method of any one of items 1 to 5, wherein the ophthalmic solution comprises about 0.25% reproxalap and about 11% w / v of the cyclodextrin excipient. (Item 9) 6. The method of any one of items 1 to 5, wherein the ophthalmic solution comprises about 0.5% reproxalap and about 9.5% to about 11% w / v of the cyclodextrin excipient. (Item 10) 10. The method according to any one of items 1 to 9, wherein the ophthalmic solution further comprises a tonicity agent and a phosphate buffer. (Item 11) 11. The method of any one of items 1 to 10, wherein the administration is prior to expected or certain exposure of the subject to an ocular allergen. (Item 12) 12. The method of claim 11, wherein the administration is 3.5 hours or less, 3 hours or less, 2.5 hours or less, 2 hours or less, 1.5 hours or less, 1 hour or less, 0.5 hours or less, 25 minutes or less, 20 minutes or less, 25 minutes or less, 20 minutes or less, 15 minutes or less, 10 minutes or less, or 5 minutes or less prior to the expected or certain exposure to the eye allergen. (Item 13) 13. The method of claim 12, wherein said administering is immediately prior to said anticipated or certain exposure to said eye allergen. (Item 14) 13. The method of claim 12, wherein the administration is 1.5 hours or less prior to the expected or certain exposure to the eye allergen. (Item 15) 15. The method of any one of items 11 to 14, wherein the ophthalmic solution is administered 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7 or up to 8 times prior to the expected or certain exposure to an ocular allergen. (Item 16) Item 17. The method of item 15, wherein each administration involves one or two doses of the ophthalmic solution. 17. The method according to any one of items 11 to 16, wherein the subject to be treated has a medical history of suffering from allergic conjunctivitis. (Item 18) 18. The method according to any one of items 11 to 17, wherein the subject to be treated has a positive skin test to one or more eye allergens. (Item 19) 18. The method according to any one of items 11 to 17, wherein the subject to be treated has a history of allergic conjunctivitis and a positive skin test to one or more eye allergens. (Item 20) 18. The method according to any one of items 11 to 17, wherein the subject to be treated has previously been diagnosed with allergic conjunctivitis and has a positive skin test to one or more eye allergens. The method described. (Item 21) 11. The method of any one of items 1 to 10, wherein said administering is at or after exposure of said subject to an ocular allergen or at or after the onset of symptoms of allergic conjunctivitis. (Item 22) 22. The method of claim 21, wherein the administration is at or after exposure of the subject to an ocular allergen. (Item 23) 22. The method of claim 21, wherein the administration is at or after the onset of symptoms of allergic conjunctivitis. (Item 24) 24. The method of claim 23, wherein the administration is prior to reaching maximum severity of symptoms of allergic conjunctivitis. (Item 25) 25. The method of any one of items 21 to 24, wherein the ophthalmic solution is administered up to 12 times per day, up to 10 times per day, up to 8 times per day, up to 6 times per day, up to 5 times per day, up to 4 times per day, up to 3 times per day, up to 2 times per day, once per day or as needed upon or after exposure of the subject to an ocular allergen or upon or after the onset of symptoms of allergic conjunctivitis. (Item 26) 26. The method of item 25, wherein the ophthalmic solution is administered 12 times a day, 10 times a day, 8 times a day, 6 times a day, 5 times a day, 4 times a day (QID), 3 times a day (TID), twice a day (BID), once a day (QD) or as needed (PRN). (Item 27) 25. The method of any one of items 21-24, wherein the ophthalmic solution is administered 12 times per day, 10 times per day, 8 times per day, 6 times per day, 4 times per day (QID), 3 times per day (TID), twice per day (BID) or once per day (QD), followed by administration as needed (PRN). (Item 28) 28. The method according to items 25 to 27, wherein with each administration more than once a day, the administrations are separated by 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours or 5 hours. (Item 29) 29. The method according to items 25 to 28, wherein each administration involves one or two doses of the ophthalmic solution. (Item 30) 2. The method of claim 1, wherein the treatment comprises a first treatment phase comprising administering the ophthalmic solution prior to expected or certain exposure of the subject to an ocular allergen, and a second treatment phase comprising administering the ophthalmic solution at or after exposure of the subject to an ocular allergen, or at or after the onset of symptoms of allergic conjunctivitis. (Item 31) 31. The method of claim 30, wherein the first treatment phase comprises administering the ophthalmic solution 3.5 hours or less, 3 hours or less, 2.5 hours or less, 2 hours or less, 1.5 hours or less, 1 hour or less, 0.5 hours or less, 25 minutes or less, 20 minutes or less, 25 minutes or less, 20 minutes or less, 15 minutes or less, 10 minutes or less, or 5 minutes or less prior to the expected or certain exposure to the ocular allergen. (Item 32) 32. The method of claim 31, wherein the first treatment phase comprises administering the ophthalmic solution immediately prior to the expected or expected exposure to the ocular allergen. (Item 33) 32. The method of claim 31, wherein the first treatment phase comprises administering the ophthalmic solution 1.5 hours or less prior to the expected or certain exposure to the ocular allergen. (Item 34) 34. The method of any one of items 30 to 33, wherein the first treatment phase comprises administering the compound once, twice, three or four times prior to the expected or certain exposure to an ocular allergen. (Item 35) 35. The method of claim 34, wherein each administration is one or two doses of the ophthalmic solution. (Item 36) 36. The method of any one of items 30 to 35, wherein the second treatment phase is during or after exposure of the subject to an ocular allergen. (Item 37) 36. The method according to any one of items 30 to 35, wherein the second treatment phase is at or after the onset of symptoms of allergic conjunctivitis. (Item 38) 36. The method of any one of items 30 to 35, wherein the second treatment phase comprises administering the ophthalmic solution before the maximum severity of symptoms of allergic conjunctivitis is reached. (Item 39) 39. The method of any one of items 30-38, wherein the second treatment phase comprises administering the ophthalmic solution 8 times per day, 7 times per day, 6 times per day, 5 times per day, 4 times per day (QID), 3 times per day (TID), twice per day (BID), once per day (QD) or as needed (PRN). (Item 40) 39. The method of any one of items 30-38, wherein the second treatment phase comprises administering the ophthalmic solution 8 times per day, 7 times per day, 6 times per day, 5 times per day, 4 times per day (QID), 3 times per day (TID), twice per day (BID), once per day (QD), followed by administration as needed (PRN). (Item 41) 41. The method according to any one of items 1 to 10 and 21 to 40, wherein the treatment comprises an initiation phase, an exacerbation phase and / or a maintenance phase. (Item 42) 42. The method of claim 41, wherein the onset phase or the exacerbation phase comprises administering the ophthalmic solution five or four times a day (QID). (Item 43) 43. The method of item 41 or 42, wherein the maintenance phase comprises administering the ophthalmic solution four times a day (QID), three times a day (TID), twice a day (BID), once a day (QD) or as needed (PRN). (Item 44) 44. The method of claim 43, wherein the maintenance phase comprises administering the ophthalmic solution twice daily (QID). (Item 45) The method according to items 39-40 and 42-44, wherein with each administration more than once a day, the administrations are separated by 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours or 5 hours. (Item 46) 46. ​​The method according to any one of items 39 to 45, wherein each administration involves one or two doses of said ophthalmic solution. (Item 47) 47. The method of any one of items 1-46, wherein after administration to the subject, the ophthalmic solution results in a statistically significant reduction in the patient's Ocular Itch Scale compared to no treatment or vehicle treatment. (Item 48) Item 49. The method according to item 47, wherein the reduction in the ocular itch score is at least 1 point. 48. The method of item 47, wherein the reduction in ocular itch score is at least 2 points. (Item 50) 50. The method of any one of items 1 to 49, further comprising administering an additional therapeutic agent for treating allergic conjunctivitis.

Claims

[Claim 1] The invention described in the specification.

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