Alpha-2 adrenergic agonists for improving vision

Abstract

Disclosed herein are methods of improving visual acuity, field of view, and other visual function indicators comprising administering an alpha-2 adrenergic agonist to a mammal in need thereof.

Description

[0001] Cross Reference to Related Applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 483,843, filed February 8, 2023, which is incorporated by reference in its entirety. BACKGROUND

[0003] Alpha-2 adrenergic agonists are a class of compounds that have been used to treat a variety of conditions including hypertension, attention deficit disorders, certain pain conditions, and most recently as adjunctive agents for sedation in anesthesiology. In ophthalmology, alpha-2 agonists are primarily used to lower intraocular pressure (IOP) in patients with glaucoma.

[0004] In the eye, alpha-2 adrenergic receptors are expressed not only in the ciliary body, iris, and other anterior segment structures, but also in the retina. In addition to the ability of alpha-2 agonists to lower IOP, these compounds have been investigated as neuroprotective agents to reduce vision loss in patients with glaucoma. It is important to note that many alpha-2 agonists reduce pupil size (miosis), and this creates a pinhole effect that improves depth of field and can improve near vision and reduce visual aberrations caused by irregularities in the surface of the eye. In fact, many of these miotic compounds are being investigated for the treatment of presbyopia (a condition of decreased ability to focus at near distances) and as a means to treat visual blur after eye surgery by reducing pupil size (Kesler et al.) (Edwards et al.). However, by reducing pupil size, these treatments also reduce the amount of light entering the eye and can reduce distance vision and limit the field of view. The FDA warns that miotics (i.e., drugs that reduce pupil size) can cause patients to experience temporary dim or dark vision and notes that patients should be advised to exercise caution when driving at night or other activities that are hazardous in low light (FDA Prescribing Information for Vuity® Pilocarpine Hydrochloride Ophthalmic Solution 1.25%). Patients with many ophthalmic diseases including age-related macular degeneration and glaucoma have severe difficulty seeing, especially in dim light. (See Appendix References). Any therapy that meaningfully reduces pupil size will reduce the amount of light entering the eye and can exacerbate this deficiency.

[0005] While there are multiple medications approved to lower IOP in patients with glaucoma, there is no treatment that protects or improves visual function in patients with the disease. Studies have shown that low luminance visual acuity is an early clinical marker of central retinal functional changes compared to standard visual acuity measurements, and macular damage in mild to moderate glaucoma is associated with decreased visual function under low luminance conditions (Blumberg et al. 2019). Furthermore, visual complaints are more common in patients with glaucoma in the absence of optimal luminance, especially under low luminance (Bierings et al. 2018). These low luminance visual measurements are more representative of the real lighting conditions people experience on a cloudy day or at sunrise or sunset, rather than in darkness or very low light conditions, where patients are fully adapted to darkness before measuring visual acuity. SUMMARY

[0006] We show here compounds with surprising visual improvement under low lighting conditions without a meaningful impact on pupil size. This is evidenced by improved visual acuity under low luminance lighting conditions and visual field testing under standard conditions.

[0007] The present disclosure relates generally to the use of alpha-2 adrenergic agonists to improve vision, such as to improve visual acuity (e.g., under low luminance lighting conditions) and / or to improve visual field. In this method, the alpha-2 adrenergic agonist is administered to a mammal in need thereof, or to a mammal with normal vision.

[0008] Some embodiments include a method of improving visual acuity comprising administering an alpha-2 adrenergic agonist to a mammal in need thereof.

[0009] Some embodiments include a method of improving visual acuity under low luminance lighting conditions comprising administering an alpha-2 adrenergic agonist to a mammal in need thereof, or to a mammal with normal vision.

[0010] Some embodiments include a method of improving visual field comprising administering an alpha-2 adrenergic agonist to a mammal in need thereof, or to a mammal with normal vision.

[0011] Some embodiments include a method of improving or delaying the gradual loss of indicators of visual function under normal or low luminance lighting conditions comprising administering an alpha-2 adrenergic agonist to a mammal in need thereof.

[0012] In some embodiments, the alpha-2 adrenergic agonist is a compound that has no significant effect on pupil size when administered in an amount effective to improve visual acuity or visual field.

[0013] Some embodiments include methods of improving visual acuity or visual field without decreasing pupil size comprising administering an alpha-2 adrenergic agonist to a mammal in need thereof or to a mammal with normal vision, wherein the mammal experiences an improvement in visual acuity or visual field without a decrease in pupil size. DETAILED DESCRIPTION

[0015] The present disclosure relates generally to the use of alpha-2 adrenergic agonists for improving vision, such as improving visual acuity (e.g., under low light illumination conditions), improving visual field, improving or delaying the gradual loss of other indicators of visual function (e.g., contrast sensitivity under normal or low light illumination, color vision under normal or low light illumination, and / or performance of vision-related tasks (e.g., navigating a maze or driving) under normal or low light illumination) under normal or low light illumination conditions. In this method, an alpha-2 adrenergic agonist is administered to a mammal in need thereof. The mammal can experience improved vision within a short time (e.g., within or at 2 weeks, 4 weeks, 3 months, 6 months, or 1 year from the start of treatment).

[0016] In some embodiments, the method or use includes reducing the use of low vision devices, such as wearable or handheld low vision devices, including, for example, magnifiers, bioptic telescopic glasses, magnifying glasses, prism glasses, computer software, tablet or cell phone devices, cameras, and the like, by the human patient. Reducing use includes avoiding the use of low vision devices altogether, as well as using the devices at a reduced frequency, or using devices that provide a lower level of correction (e.g., a smaller magnification).

[0017] In some embodiments, the improvement in vision (e.g., improved visual acuity (e.g., under low light illumination conditions) and / or improved visual field) is performed without a pupillary effect due to pupil constriction. In some embodiments, the improvement in vision (e.g., improvement in visual acuity (e.g., under low light illumination conditions) and / or improvement in visual field) occurs in humans without a decrease in pupil size, or without a clinically meaningful decrease in pupil size, or an average change in pupil size of about -0.5 mm to about 0 mm, or about -0.2 mm to about 0 mm.

[0018] In some embodiments, the improvement in vision (e.g., improvement or slowing of the gradual loss of other indicators of visual function under normal lighting or low light lighting conditions (e.g., contrast sensitivity under normal lighting or low light lighting, color vision under normal lighting or low light lighting, and / or performance of vision-related tasks under normal lighting or low light lighting conditions, e.g., traversing a maze or driving)) is carried out without pupillary effects resulting from pupil constriction. In some embodiments, the improvement in vision occurs in humans without a decrease in pupil size, or an average change in pupil size of about -0.5 mm to about 0 mm, or about -0.2 mm to about 0 mm.

[0019] Visual acuity decline can be determined by a decrease in Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity or by being below normal ETDRS visual acuity.

[0020] The ETDRS visual acuity of a patient having improved visual acuity after treatment can have an improvement of > 5 letters, > 10 letters, > 15 letters, or more letters compared to the ETDRS visual acuity of the patient prior to treatment. An improvement of > 15 letters in ETDRS visual acuity is equivalent to an increase of 3 lines on a standard eye chart.

[0021] The patient can be a non-human mammal or a human. In some embodiments, the mammal is a human. In some embodiments, the patient is a human. In some embodiments, the patient is a non-human mammal, e.g., a dog, cat, mouse, rat, rabbit, monkey, horse, pig, etc.

[0022] In some embodiments, the human patient is 0-18 years old, 18-30 years old, 30-50 years old, 50-65 years old, or 65-100 years old. In some embodiments, the human patient is female. In some embodiments, the human patient is male.

[0023] The mammal (e.g., human) can be experiencing a retinal disorder, glaucoma, or another ocular disorder, e.g., an ophthalmic condition associated with a decrease in visual acuity. A retinal disorder can be associated with a decrease in visual acuity if the patient with the retinal disorder also has a decreased visual acuity. In some embodiments, the decreased visual acuity can be caused by the retinal disorder or ocular disorder. In some embodiments, the mammal (e.g., human) can be experiencing a retinal disorder or ocular disorder and a decreased visual acuity, and the decreased visual acuity is not associated with the retinal disorder or ocular disorder.

[0024] Low light visual acuity refers to visual acuity determined using a standard Early Treatment Diabetic Retinopathy Study (ETDRS) chart with a 2.0 log unit neutral density filter placed in front of the eye.

[0025] The mammal (e.g., human) can be experiencing a retinal disorder or other ocular disorder, e.g., a retinal disorder associated with reduced low-light visual acuity. A retinal disorder is associated with reduced low-light visual acuity if the patient with the retinal disorder can also have reduced low-light visual acuity. In some embodiments, the reduced low-light visual acuity can be caused by the retinal disorder or ocular disorder. In some embodiments, the mammal (e.g., human) can be experiencing a retinal disorder or ocular disorder and reduced low-light visual acuity, and the reduced low-light visual acuity is not associated with the retinal disorder or ocular disorder.

[0026] The mammal (e.g., human) can be experiencing a retinal disorder or other ocular disorder, e.g., a retinal disorder associated with reduced visual field. A retinal disorder is associated with reduced visual field if the patient with the retinal disorder can also have reduced visual field. In some embodiments, the reduced visual field can be caused by the retinal disorder or ocular disorder. In some embodiments, the mammal (e.g., human) can be experiencing a retinal disorder or ocular disorder and reduced visual field, and the reduced visual field is not associated with the retinal disorder or ocular disorder.

[0027] In some embodiments, the mammal (e.g., human) has glaucoma. In some embodiments, the mammal (e.g., human) has ocular hypertension. In some embodiments, the mammal (e.g., human) has age-related macular degeneration. In some embodiments, the mammal (e.g., human) has a retinal disorder or ocular disorder associated with reduced visual acuity that is not glaucoma, ocular hypertension, or age-related macular degeneration.

[0028] In some embodiments, the mammal (e.g., human) has a retinal disorder or ocular disorder associated with reduced visual acuity that is not glaucoma, ocular hypertension, or age-related macular degeneration.

[0029] In some embodiments, the mammal (e.g., human) has a retinal disorder or ocular disorder associated with reduced low-light visual acuity that is not glaucoma, ocular hypertension, or age-related macular degeneration.

[0030] In some embodiments, the mammal (e.g., human) has a retinal disorder or ocular disorder associated with reduced visual field, and the retinal disorder or ocular disorder associated with reduced visual field is not glaucoma, ocular hypertension, or age-related macular degeneration, e.g., diabetic retinopathy; other forms of macular degeneration, e.g., geographic atrophy; retinal degeneration, including inherited retinal diseases, such as retinitis pigmentosa, radiation retinopathy; retinal diseases caused by toxic drugs, light, or other insults; retinopathy of prematurity; ischemic retinal diseases, including central retinal vein occlusion, branch retinal vein occlusion, central retinal artery occlusion; sickle cell retinopathy; myopia and myopia-related retinal degeneration; uveitis or other inflammatory retinal diseases; vision loss associated with ocular surgery, vision loss associated with Alzheimer’s disease or other neurological diseases, including stroke or cerebral ischemia, vision loss caused by ocular surgery; etc.

[0031] In some embodiments, the a-2 adrenergic agonist is effective to treat a retinal disorder or ocular disorder in addition to (or as an alternative to) improving visual acuity or visual field. In some embodiments, the a-2 adrenergic agonist is effective to treat glaucoma. In some embodiments, the a-2 adrenergic agonist is effective to treat ocular hypertension. In some embodiments, the a-2 adrenergic agonist is effective to treat age-related macular degeneration. In some embodiments, the a-2 adrenergic agonist is effective to treat a retinal disorder or ocular disorder associated with reduced visual acuity, which is not glaucoma, ocular hypertension, or age-related macular degeneration, e.g., diabetic retinopathy; other forms of macular degeneration, e.g., geographic atrophy; retinal degeneration, including inherited retinal diseases, such as retinitis pigmentosa, radiation retinopathy; retinal diseases caused by toxic drugs, light, or other insults; retinopathy of prematurity; ischemic retinal diseases, including central retinal vein occlusion, branch retinal vein occlusion, central retinal artery occlusion; sickle cell retinopathy; myopia and myopia-related retinal degeneration; uveitis or other inflammatory retinal diseases; vision loss associated with ocular surgery, vision loss associated with Alzheimer’s disease or other neurological diseases, including stroke or cerebral ischemia, vision loss caused by ocular surgery; etc.

[0032] In some embodiments, the a-2 adrenergic agonist is effective to delay progression of myopia without changes in pupil size.

[0033] Alternatively, the a-2 adrenergic agonist can be administered to a mammal (e.g., human) with normal vision to provide better vision (e.g., visual acuity) than normal or better vision than the mammal had prior to treatment.

[0034] The term "treating" or "treatment" broadly includes any type of therapeutic activity, including diagnosing, curing, mitigating, or preventing a disease in a human or other animal, or otherwise affecting the structure or any function of a human or other animal's body in any way.

[0035] Any suitable alpha-2 adrenergic agonist can be used, for example:

[0036] (R1= CH3)

[0037] 5-methyl-N-(4,5-dihydro-1H-imidazol-2-yl)quinoxalin-6-amine;

[0038]

[0039] 7-(imidazol-4-ylmethyl)-5,6,7,8-tetrahydroquinoline;

[0040]

[0041] (S)-(+)-7-(imidazol-4-ylmethyl)-5,6,7,8-tetrahydroquinoline;

[0042]

[0043] N-(4-bromo-1H-benzo[d]imidazol-5-yl)imidazolidine-2-imine;

[0044]

[0045] 4-bromo-N-(3,4-dihydro-2H-pyrrol-5-yl)-1H-benzo[d]imidazol-5-amine;

[0046]

[0047] N-(4-chloro-1,5-naphthyridin-3-yl)imidazolidine-2-imine;

[0048]

[0049] 2-(4-amino-2,6-dichloroanilino)-2-imidazoline;

[0050]

[0051] (S)-4-[1-(2,3-dimethylphenyl)ethyl]-3H-imidazole;

[0052]

[0053] (R,S)-4-[1-(2,3-dimethylphenyl)ethyl]-3H-imidazole;

[0054]

[0055] (R,S)-(3-(1H-imidazol-4-yl)ethyl-2-methylphenyl)methanol

[0056] and esters thereof;

[0057]

[0058] [3-[(1S)-1-(1H-imidazol-5-yl)ethyl]-2-methylphenyl]methyl-2,2-dimethylpropanoate (Compound 1 in Example 1)

[0059]

[0060] 4-bromo-5-(2-imidazolin-2-ylamino)benzoimidazole; and

[0061]

[0062] (R)-7-(imidazol-4-ylmethyl)-5,6,7,8-tetrahydroquinoline

[0063] In some embodiments, the alpha-2 adrenergic agonist is (S)-(3-(1H- imidazol-4-yl)ethyl-2-methylphenyl)methanol, or a pharmaceutically acceptable salt or ester thereof.

[0064]

[0065] (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol

[0066] In some embodiments, the alpha-2 adrenergic agonist is [3-[(1S)-1-(1H- imidazol-5-yl)ethyl]-2-methylphenyl]methyl-2,2-dimethylpropanoate, which is an ester of (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol (and can also be a prodrug).

[0067]

[0068] [3-[(1S)-1-(1H-imidazol-5-yl)ethyl]-2-methylphenyl]methyl-2,2-dimethylpropanoate (Compound 1 in Example 1)

[0069] Any reference to a compound (e.g., an alpha-2 adrenergic agonist) herein by structure, name, or any other means includes a pharmaceutically acceptable salt unless otherwise noted; an alternative solid form, such as a polymorph, solvate, hydrate, etc.; a tautomer; a deuterium-modified compound, such as a deuterium-modified dextromethorphan; or any chemical species that can rapidly convert to a compound described herein under the conditions in which the compound is used as described herein.

[0070] Pharmaceutically acceptable salts include salts that are acceptable for administration to animals or humans. Examples of suitable pharmaceutically acceptable salts of an alpha-2 adrenergic agonist include salts of inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.); or salts of organic acids (e.g., citric acid, acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, etc.).

[0071] An alpha-2 adrenergic agonist can be administered by any suitable route of administration, such as by topical ophthalmic administration (e.g., in the form of eye drops), injection, or implant (e.g., a solution, suspension, gel, sustained release formulation injection, biodegradable or non-biodegradable implant). An injection can be into any suitable location, including intraocular injection, subconjunctival injection, subretinal injection, suprachoroidal injection, intracameral injection, sub-Tenon’s capsule injection, etc. Administration can also be by a systemic route, such as oral or intravenous administration.

[0072] An alpha-2 adrenergic agonist can be administered alone (as the only active pharmaceutical agent used in a therapy), or it can be administered in combination with one or more other active pharmaceutical agents. Similarly, a dosage form or pharmaceutical composition (e.g., an eye drop or sustained release implant) can contain an alpha-2 adrenergic agonist as the only active pharmaceutical agent in the dosage form or pharmaceutical composition, or the dosage form or pharmaceutical composition can contain an alpha-2 adrenergic agonist and one or more additional active pharmaceutical agents.

[0073] In some embodiments, an eye drop containing an alpha-2 adrenergic agonist can be administered to an affected eye of a mammal (e.g., a human). For eye drops (another topical ophthalmic route) or oral administration, the alpha-2 adrenergic drug (e.g., [3-[(1S)-1-(1H-imidazol-5-yl)ethyl]-2-methylphenyl]methyl-2,2-dimethylpropanoate, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol, or another compound described herein) can be administered once daily, twice daily, three times daily, or more frequently. Administration can be daily (once, twice, three times, or more), for at least one day, at least 7 days, at least 2 weeks, at least 4 weeks, at least 2 months, at least 3 months, at least 6 months, at least 12 months, at least 2 years, at least 5 years, at least 10 years, about 1-4 weeks, about 1-6 months, about 6-12 months, about 1-3 years, about 3-5 years, up to 10 years, up to 20 years, up to 40 years, up to 80 years, up to 100 years, or more.

[0074] In some embodiments, an alpha-2 adrenergic drug of an injectable dosage form or implant (e.g., [3-[(1S)-1-(1H-imidazol-5-yl)ethyl]-2-methylphenyl]methyl-2,2-dimethylpropanoate, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol, or another compound described herein) can be administered once every 1-4 years, 1-3 times per year, 3-6 times per year, 6-12 times per year, etc.

[0075] In some embodiments, an alpha-2 adrenergic agonist (e.g., [3-[(1S)-1-(1H-imidazol-5-yl)ethyl]-2-methylphenyl]methyl-2,2-dimethylpropanoate, (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol, or another compound described herein) is administered in a topical ophthalmic fluid containing about 0.01-1% (w / v), about 0.01-0.04% (w / v), about 0.04-0.06% (w / v), about 0.06-0.1% (w / v), about 0.1-0.2% (w / v), about, about 0.2-0.5% (w / v), or about 0.5-1% (w / v) of the alpha-2 adrenergic agonist.

[0076] For topical ophthalmic administration, e.g., in eye drops, the composition can include ingredients or excipients in an aqueous or water solution (e.g., deionized water), such as a buffer, a tonicity agent, a preservative, a cosolvent, a viscosity builder, etc.

[0077] Suitable buffers include, for example, phosphates, bicarbonates, citrates, borates, and the like. Topical ophthalmic compositions can have any suitable pH, for example, about 5-9, about 6-8, about 6.5-7, or about 7-7.5.

[0078] Suitable tonicity agents can include, for example, salts, such as sodium chloride, potassium chloride, and the like; sugars, such as dextrose, dextrose, glycerin, and the like.

[0079] Preservatives can help prevent microbial contamination during use. Suitable preservatives include stabilized oxychloro complexes (sold under the trademark Purite™), stabilized chlorine dioxide, benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenethyl alcohol, disodium edetate, sorbic acid, and the like. Suitable concentrations of preservatives can be about 0.001-1% by weight, or about 0.01-0.5% by weight.

[0080] The solubility of components of the compositions of the present application can be enhanced by surfactants or other suitable cosolvents in the composition. Such surfactants or cosolvents include polysorbate 20, 60, and 80, Pluronic® F-68, F-84, and P-103, cyclodextrins, Solutol, or other agents known to those skilled in the art. In some embodiments, the surfactant or cosolvent is present in an amount of about 0.01% to 2% by weight.

[0081] Increasing the viscosity above that of simple aqueous solutions can be desirable to increase ocular absorption of active compounds, reduce variability in dispensing the formulation, reduce physical separation of components of a suspension or emulsion formulation, and / or otherwise improve ophthalmic formulations. Such viscosity building agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, or other agents known to those skilled in the art. In some embodiments, the viscosity building agent is present in an amount of about 0.01% to 2% by weight.

[0082] Table 1 describes suitable eye drop formulations.

[0083] Table 1

[0084]

[0085] An alpha-2 adrenergic agonist can be implanted or injected into a sustained release implant (e.g., a biodegradable or bioerodible implant) including implants made from polymeric materials such as polymers derived from and / or including organic esters and organic ethers that upon degradation produce physiologically acceptable degradation products including monomers; polymeric materials derived from and / or including anhydrides, amides, orthoesters, and the like (either by themselves or in combination with other monomers); addition or condensation polymers; polymers of hydroxyaliphatic carboxylic acids (homo- or copolymers), and polysaccharides such as polymers of D-lactic acid, L-lactic acid, racemic lactic acid, glycolic acid, polycaprolactone, and combinations thereof. The alpha-2 adrenergic agonist can be 0-20%, 20-40%, 40-60%, 60-80%, or greater than 80% of the weight of the implant.

[0086] In some embodiments, the implant is a polyglycolic acid (PLGA) copolymer with about 0-100% polylactic acid, 15-85% polylactic acid, or about 35-65% polylactic acid. In some implants, a copolymer with about 50% polylactic acid is used.

[0087] Example 1

[0088] Whitecap Biosciences recently completed a 1 / 2 phase study to evaluate the safety and IOP lowering effect of Compound 1 ophthalmic solutions in patients with primary open angle glaucoma or ocular hypertension. Part 1 was an open-label dose escalation study. The objective of Part 1 of this study (WB007-001) was to evaluate the safety, tolerability, and IOP lowering effect of a single drop of ophthalmic solutions containing [3-[(1S)-1-(1H-Imidazol-5-yl)ethyl]-2-methylphenyl]methyl-2,2-dimethylpropanoate (Compound 1) at concentrations ranging from 0.05% to 0.4%. Part 2 of this study was a double-masked, randomized, multicenter active-controlled, parallel study to evaluate the safety and IOP lowering effect of ophthalmic solutions containing 0.15% Compound 1 and 0.4% Compound 1 compared to 0.5% timolol ophthalmic solution in patients with glaucoma or ocular hypertension. In addition to evaluating the efficacy of Compound 1 to lower IOP, this study also evaluated the effect of this drug on visual function.

[0089] Intraocular pressure

[0090] In Part 1 of the study, the mean change from baseline in IOP (mean ± SD) for the 0.05% Compound 1 group ranged from -0.9 ± 0.9 to -3.4 ± 2.2 mm Hg, for the 0.15% Compound 1 group from -2.1 ± 1.9 to -8.3 ± 4.1 mm Hg, and for the 0.4% Compound 1 group from -1.9 ± 2.4 to -8.2 ± 1.9 mm Hg on Day 1 after a single dose to the study eye. Peak efficacy across treatment groups occurred within 30 minutes to 4 hours.

[0091] The primary endpoint of a statistically significant IOP reduction within the group was achieved at 2 hours on Day 14 when dosed twice daily in Part 2 of the study. Analysis of mean change from baseline in the study eye indicated that both Compound 1 treatment groups had a statistically significant IOP lowering effect at all post-baseline time points (p < 0.007) and for timolol at all post-baseline time points (p < 0.004). For the primary endpoint (2 hours on Day 14, the time of peak effect for timolol), the mean change from baseline in IOP was -4.9 ± 1.8 mm Hg (p < 0.001) for subjects receiving 0.15% Compound 1, -5.1 ± 2.5 mm Hg (p < 0.001) for subjects receiving 0.4% Compound 1, and -6.0 ± 3.0 mm Hg (p < 0.001) for subjects receiving timolol.

[0092] Additional analyses to examine the effect of Compound 1 on visual function included low- luminance visual acuity and visual field. In patients treated with Compound 1, a dose- dependent improvement in low-luminance visual acuity was observed. The percentage of subjects who achieved an increase of 15 letters or more in Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity measured in the study eye at low luminance at at least one study visit was 8.7% for subjects receiving 0.15% Compound 1, 16.7% for subjects receiving 0.4% Compound 1, and 0% for subjects receiving 0.5% timolol. Improvements in visual function in the treated non-study eye corroborated the findings from the study eye. The percentage of subjects who achieved an increase of 15 letters or more in ETDRS visual acuity measured in the non-study eye at low luminance at at least one study visit was 17.4% for subjects receiving 0.15% Compound 1, 25.0% for subjects receiving 0.4% Compound 1, and 8.3% for subjects receiving 0.5% timolol.

[0093] Improved visual field outcomes in patients receiving Compound 1 were also demonstrated in study eyes and in non-study eyes treated. In study eyes, the change in mean deviation (dB) from baseline at Day 14 (where a positive change represents an improvement in visual field) was 0.2 ± 1.2 for subjects receiving 0.15% Compound 1, -0.5 ± 2.3 for subjects receiving 0.4% Compound 1, and -1.2 ± 2.3 for subjects receiving timolol. For non-study eyes, the change in mean deviation (dB) was 0.4 ± 1.5 for subjects receiving 0.15% Compound 1, -0.2 ± 1.4 for subjects receiving 0.4% Compound 1, and -2.0 ± 3.4 for subjects receiving timolol. The percentage of patients with an improvement of 1 dB or greater is shown in Table 1.

[0094]

[0095] Pupil size

[0096] The effect of Compound 1 on pupil size was assessed at the baseline visit and at Day 14. Pupil size results from Hour 0 to Hour 2 showed no change in most subjects. There were no meaningful reductions in pupil size for either dose of Compound 1. In study eyes, the mean change in pupil size from baseline to the end of the study at Hour 0 on Day 14 (which is the time point at which visual function was assessed) was 0.0 mm for subjects receiving 0.15% Compound 1, -0.1 mm for subjects receiving 0.4% Compound 1, and -0.1 mm for subjects receiving timolol. In non-study eyes treated, the mean change in pupil size from baseline to the end of the study at Hour 0 on Day 14 (which is the time point at which visual function was assessed) was 0.0 mm for subjects receiving 0.15% Compound 1, -0.1 mm for subjects receiving 0.4% Compound 1, and -0.1 mm for subjects receiving timolol.

[0097] Safety

[0098] Both doses of Compound 1 were safe and well tolerated. Most subjects reported that the study medication was "comfortable" or "very comfortable."

Claims

1. A method of improving visual acuity comprising administering an alpha-2 adrenergic agonist to a mammal in need thereof.

2. A method of improving visual acuity in low light conditions comprising administering an alpha-2 adrenergic agonist to a mammal in need thereof.

3. A method of improving visual field comprising administering an alpha-2 adrenergic agonist to a mammal in need thereof.

4. The method of claim 1, 2, or 3, wherein the alpha-2 adrenergic agonist is a compound that has no clinically relevant effect on pupil size when administered in an amount effective to improve visual acuity or visual field.

5. A method of improving or delaying the gradual loss of an indicator of visual function in normal lighting or low light conditions without reducing pupil size comprising administering an alpha-2 adrenergic agonist to a mammal in need thereof, wherein the mammal experiences an improvement or delay in the gradual loss of the indicator of visual function in normal lighting or low light conditions without a reduction in pupil size.

6. The method of claim 5, wherein the indicator of visual function is contrast sensitivity.

7. The method of claim 5, wherein the indicator of visual function is color vision.

8. The method of claim 5, wherein the indicator of visual function is performance on a visual-related task.

9. A method of improving visual acuity or visual field without reducing pupil size comprising administering an alpha-2 adrenergic agonist to a mammal, wherein the mammal experiences an improvement in visual acuity or visual field without a clinically meaningful reduction in pupil size.

10. The method of claim 9, wherein the mammal has normal vision.

11. The method of claim 9, wherein the human has myopia.

12. The method of any one of claims 1-10, wherein the alpha-2 adrenergic agonist is (S)-(3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methyl alcohol, or a pharmaceutically acceptable salt or ester thereof.

13. The method of claim 11, wherein the alpha-2 adrenergic agonist is [3-[(1S)-1-(1H- imidazol-5-yl)ethyl]-2-methylphenyl]methyl-2,2-dimethylpropanoate.

14. The method of any one of claims 1-13, wherein the mammal is a human.

15. The method of claim 14, wherein the human has glaucoma.

16. The method of claim 14, wherein the human has ocular hypertension.

17. The method of claim 14, wherein the human has age-related macular degeneration.

18. The method of claim 14, wherein the human has a retinal disorder associated with reduced low light visual acuity.

19. The method of claim 14, wherein the human has geographic atrophy.

20. The method of any preceding claim, wherein the improvement in visual function, visual acuity, or visual field is experienced within two weeks of receiving a first dose of the alpha-2 adrenergic agonist.

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