Alpha-2 adrenergic agonists for improving vision

Abstract

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

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 483,843, filed February 8, 2023, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Alpha-2 adrenergic agonists are a class of compounds that have been used to treat many conditions, including hypertension, attention deficit disorder, and certain pain conditions, and more recently as adjuncts to sedation in anesthesia. In ophthalmology, alpha-2 agonists have primarily been used to reduce intraocular pressure (IOP) in patients with glaucoma.

[0003] In the eye, α2-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 α2-agonists to lower IOP, these compounds have also been investigated as neuroprotective agents to reduce vision loss in patients with glaucoma. It is important to note that many α2-agonists reduce pupil size (miosis), which can produce a pinhole effect to improve depth of field, improve near vision, and reduce visual disturbances caused by irregularities in the ocular surface. Indeed, many of these miotic compounds are being investigated as a means to treat presbyopia, a condition in which the ability to focus at close distances is reduced, and as a means to treat blurred vision after eye surgery by reducing pupil size (Kesler et al.) (Edwards et al.). However, by reducing pupil size, these treatments may also reduce the amount of light entering the eye, potentially reducing distance vision and limiting the visual field. The U.S. Food and Drug Administration (FDA) warns that miotics, drugs that reduce pupil size, may cause temporary blurred vision or night vision in patients, and states that patients should be advised to exercise caution during night driving and other hazardous activities when lighting is inadequate (FDA prescribing information for Vuity® pilocarpine hydrochloride ophthalmic solution 1.25%). Patients with many eye diseases, including age-related macular degeneration and glaucoma, have severe impairments in vision, especially in dim light conditions. (See accompanying references.) Any therapy that significantly reduces pupil size reduces the amount of light entering the eye and may exacerbate this deficit.

[0004] While several medications are approved to lower IOP in patients with glaucoma, no treatments exist to maintain or improve visual function in these patients. Research has demonstrated that low-light visual acuity is an earlier clinical marker of changes in central retinal function than standard visual acuity measurements, and that macular damage in mild to moderate glaucoma is associated with decreased visual function under low-light conditions (Blumberg et al. 2019). Furthermore, visual complaints in patients with glaucoma are more prevalent in conditions where suboptimal luminance is present, particularly in low-light conditions (Bierings et al. 2018). These low-light visual acuity measurements better represent the actual lighting conditions experienced by individuals on cloudy days or at sunrise or sunset, rather than measurements of vision in the dark or in extreme low-light conditions, where patients are allowed to fully adapt to darkness before undergoing vision testing. Summary of the Invention

[0005] Herein, we demonstrate compounds that have surprising improvements in vision, including under low light conditions, without significantly affecting pupil size. This has been demonstrated for improved visual acuity under low light conditions and visual field testing under standard conditions.

[0006] The present disclosure generally relates to the use of alpha-2 adrenergic agonists to improve vision, e.g., improve visual acuity, such as under low-light conditions, and / or improve visual field. In the methods, the alpha-2 adrenergic agonist is administered to a mammal in need thereof, or alternatively to a mammal with normal vision.

[0007] Some embodiments include a method of improving vision comprising administering an alpha 2 adrenergic agonist to a mammal in need thereof.

[0008] Some embodiments include a method of improving vision under low lighting conditions, comprising administering an alpha-2 adrenergic agonist to a mammal in need thereof, or alternatively to a mammal with normal vision.

[0009] Some embodiments include a method of improving visual field, comprising administering an alpha-2 adrenergic agonist to a mammal in need thereof, or alternatively to a mammal with normal vision.

[0010] Some embodiments include a method for improving or slowing the progressive loss of an indicator of visual function under normal or low-intensity lighting conditions, comprising administering an alpha-2 adrenergic agonist to a mammal in need thereof.

[0011] In some embodiments, the alpha 2 adrenergic agonist is a compound that does not have a significant effect on pupil size when administered in an amount effective to improve visual acuity or visual field.

[0012] Some embodiments include a method of improving visual acuity or visual field without pupil size reduction, comprising administering an alpha-2 adrenergic agonist to a mammal in need thereof, or alternatively to a mammal with normal vision, wherein the mammal experiences improved visual acuity or visual field without pupil size reduction. DETAILED DESCRIPTION OF THE INVENTION

[0013] Detailed Description The present disclosure generally relates to the use of alpha adrenergic agonists to improve vision, for example, to improve visual acuity under low-intensity lighting conditions, to improve visual field, and to improve or delay the progressive loss of other indicators of visual function under normal or low-intensity lighting conditions, such as contrast sensitivity under normal or low-intensity lighting, color vision under normal or low-intensity lighting, and / or performance of vision-related tasks such as maze navigation or navigation under normal or low-intensity lighting. In this method, an alpha adrenergic agonist is administered to a mammal in need thereof. The improvement in vision can be experienced by the mammal within a short period of time, for example, within 2 weeks, 4 weeks, 3 months, 6 months, or 1 year, from the start of treatment.

[0014] In some embodiments, the method or use comprises reducing the use by the human patient of a low vision device, such as a wearable or portable low vision device, including, for example, a magnifying glass, binoculars (biopic telescopic glasses), magnifier, prism glasses, computer software, a tablet or phone, a camera, etc. Reducing use includes avoiding the use of the low vision device altogether, as well as using the device less frequently or using a device that provides a lesser level of correction, for example with less magnification.

[0015] In some embodiments, this improvement in vision, e.g., improved visual acuity, such as under low lighting conditions, and / or improved visual field, occurs in the absence of pupillary effects due to pupil constriction. In some embodiments, this improvement in vision, e.g., improved visual acuity, such as under low lighting conditions, and / or improved visual field, occurs in humans without a reduction in pupil size, or without a clinically significant reduction in pupil size, or with an average change in pupil size of about -0.5 mm to about 0 mm, or about -0.2 mm to about 0 mm.

[0016] In some embodiments, this improvement in vision, e.g., improving or slowing the progressive loss of other indices of visual function under normal or low-intensity lighting conditions, such as contrast sensitivity under normal or low-intensity lighting, color vision under normal or low-intensity lighting, and / or performance of vision-related tasks such as maze navigation or navigation under normal or low-intensity lighting, occurs in the absence of pupillary effects due to pupil constriction. In some embodiments, this improvement in vision occurs in humans without a reduction in pupil size, or with an average change in pupil size of about -0.5 mm to about 0 mm, or about -0.2 mm to about 0 mm.

[0017] Poor visual acuity may be determined by poor visual acuity in the Early Treatment of Diabetic Retinopathy Study (ETDRS) or by having ETDRS visual acuity that is below normal.

[0018] Patients whose vision improves after treatment may have an improvement of 5 or more letters, 10 or more letters, or 15 or more letters in ETDRS visual acuity compared to the patient's ETDRS visual acuity before treatment. An increase of 15 or more letters in ETDRS visual acuity corresponds to an increase of 3 lines on a standard eye chart.

[0019] The patient may 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, such as a dog, cat, mouse, rat, rabbit, monkey, horse, pig, etc.

[0020] 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.

[0021] A mammal, such as a human, may experience a retinal condition, glaucoma, or other eye disease, such as an eye condition accompanied by vision loss. The retinal condition is accompanied by vision loss, as patients with retinal conditions may also have vision loss. In some embodiments, the vision loss may be caused by a retinal condition or eye disorder. In some embodiments, a mammal, such as a human, may experience both a retinal condition or eye disorder and vision loss, and the vision loss is unrelated to the retinal condition or eye disorder.

[0022] 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.

[0023] A mammal, such as a human, may experience a retinal symptom or other ocular disorder, such as a retinal symptom accompanied by decreased low-light vision. A patient with a retinal symptom may also have decreased low-light vision, and the retinal symptom is accompanied by decreased low-light vision. In some embodiments, the decreased low-light vision may be caused by a retinal symptom or ocular disorder. In some embodiments, a mammal, such as a human, may experience both a retinal symptom or ocular disorder and decreased low-light vision, and the decreased low-light vision is unrelated to the retinal symptom or ocular disorder.

[0024] A mammal, such as a human, may experience a retinal symptom or other eye disease, such as a retinal symptom accompanied by a narrowing of the visual field. If a patient with a retinal symptom also has a narrowing of the visual field, the retinal symptom is accompanied by a narrowing of the visual field. In some embodiments, the narrowing of the visual field may be caused by a retinal symptom or an eye disorder. In some embodiments, a mammal, such as a human, may experience both a retinal symptom or an eye disorder and a narrowing of the visual field, and this narrowing of the visual field is unrelated to the retinal symptom or an eye disorder.

[0025] In some embodiments, the mammal, e.g., a human, has glaucoma. In some embodiments, the mammal, e.g., a human, has ocular hypertension. In some embodiments, the mammal, e.g., a human, has age-related macular degeneration. In some embodiments, the mammal, e.g., a human, has a retinal or ocular condition associated with decreased vision that is not glaucoma, ocular hypertension, or age-related macular degeneration.

[0026] In some embodiments, the mammal, e.g., a human, has a retinal or ocular condition accompanied by decreased vision, wherein the retinal or ocular condition accompanied by decreased vision is not glaucoma, ocular hypertension, or age-related macular degeneration.

[0027] In some embodiments, the mammal, e.g., a human, has a retinal or ocular condition accompanied by decreased low-light vision, and the retinal or ocular condition accompanied by decreased low-light vision is not glaucoma, ocular hypertension, or age-related macular degeneration.

[0028] In some embodiments, the mammal, e.g., a human, has a retinal or ocular condition accompanied by a reduction in visual field, wherein the retinal or ocular condition accompanied by a reduction in visual field is not glaucoma, ocular hypertension, or age-related macular degeneration, but is, for example, 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 drug administration, 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 eye surgery, vision loss associated with Alzheimer's disease or other neurological diseases including stroke or cerebral ischemia, vision loss due to eye surgery, etc.

[0029] In some embodiments, in addition to (or instead of) improving visual acuity or visual field, alpha 2 adrenergic agonists may be effective in treating retinal or ocular conditions. In some embodiments, alpha 2 adrenergic agonists may be effective in treating glaucoma. In some embodiments, alpha 2 adrenergic agonists may be effective in treating ocular hypertension. In some embodiments, alpha 2 adrenergic agonists may be effective in treating age-related macular degeneration. In some embodiments, alpha 2 adrenergic agonists may be effective in treating retinal conditions or ocular diseases associated with vision loss that are not glaucoma, ocular hypertension, or age-related macular degeneration, such as diabetic retinopathy; other forms of macular degeneration, such as geographic atrophy; retinal degenerations including inherited retinal diseases such as retinitis pigmentosa and radiation retinopathy; retinal conditions caused by toxic drug administration, light, or other insults; retinopathy of prematurity; ischemic retinal diseases including central retinal vein occlusion, branch retinal vein occlusion, and central retinal artery occlusion; sickle cell retinopathy; myopia and myopia-related retinal degeneration; uveitis or other inflammatory retinal diseases; vision loss associated with ophthalmic surgery, vision loss associated with Alzheimer's disease or other neurological diseases including stroke or cerebral ischemia, vision loss due to ophthalmic surgery, and the like.

[0030] In some embodiments, alpha 2 adrenergic agonists may be effective in slowing the progression of myopia in the absence of pupil changes.

[0031] Alternatively, an alpha 2 adrenergic agonist may be administered to a mammal, such as a human, with normal vision to provide vision, such as better than normal vision, or better than the mammal's normal vision prior to treatment.

[0032] The term "treat" or "treatment" broadly includes any type of medical procedure, including the diagnosis, cure, mitigation, or prevention of disease in humans or other animals, or any procedure affecting the structure or any function of the human or other animal body.

[0033] Any suitable alpha 2 adrenergic agonist can be used, for example:

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[0046] [ka] can be used.

[0047] 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.

[0048] [ka]

[0049] 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 (which can also be a prodrug).

[0050] [ka]

[0051] Unless otherwise indicated, reference herein to a compound, such as an alpha-2 adrenergic agonist, by structure, name, or other means includes pharmaceutically acceptable salts; alternative solid forms, such as polymorphs, solvates, hydrates, etc.; tautomers; deuterium-modified compounds, e.g., deuterium-modified dextromethorphan; or any chemical species that can be rapidly converted to a compound described herein under the conditions in which the compound is used as described herein.

[0052] Pharmaceutically acceptable salts include salts that are acceptable for administration to animals or humans. Suitable examples of alpha2 adrenergic agonist pharmaceutically acceptable salts include salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.; or salts of organic acids such as 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.

[0053] The alpha adrenergic agonist may be administered by any suitable route, for example, topical ophthalmic administration (e.g., in the form of eye drops), injection or implant, for example, a solution, suspension, gel, sustained-release injection, biodegradable or non-biodegradable implant, etc. Injection may be at any suitable site, including intraocular, subconjunctival, subretinal, suprachoroidal, intracameral, sub-Tenon's injection, etc. Administration may also be by systemic routes, for example, oral or intravenous administration.

[0054] The alpha-2 adrenergic agonist can be administered alone as the sole active pharmaceutical agent used in treatment, or can be administered in combination with one or more other active pharmaceutical agents. Similarly, a dosage form or pharmaceutical composition, such as an eye drop or a sustained-release implant injection, 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.

[0055] In some embodiments, eye drops containing an alpha adrenergic agonist can be administered to the affected eye of a mammal, such as a human. When administered as eye drops, by another topical ophthalmic route, or orally, the alpha 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, can be administered once daily, twice daily, three times daily, or more frequently. Administration can continue daily (once, twice, three times, or more) for at least 1 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.

[0056] In some embodiments, an injectable dosage form or implantable injection of an alpha 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, can be administered once every 1 to 4 years, 1 to 3 times per year, 3 to 6 times per year, 6 to 12 times per year, etc.

[0057] In some embodiments, an alpha adrenergic agonist, such as [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 other compounds described herein, is administered as a topical ophthalmic solution 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 0.2-0.5% (w / v), or about 0.5-1% (w / v) of the alpha adrenergic agonist.

[0058] For topical ophthalmic administration, such as eye drops, the composition may include components or excipients such as buffers, tonicity agents, preservatives, cosolvents, viscosity enhancers, etc. in an aqueous or water solution (e.g., deionized water).

[0059] Suitable buffering agents include, for example, phosphate, bicarbonate, citrate, borate, etc. The topical ophthalmic composition can have any suitable pH, for example, about 5 to 9, about 6 to 8, about 6.5 to 7, or about 7 to 7.5.

[0060] Suitable tonicity agents may include, for example, salts such as sodium chloride, potassium chloride, and the like; sugars such as glucose, dextrose, glycerin, and the like.

[0061] Preservatives can help prevent microbial contamination during use. Suitable preservatives include stabilized oxychloro complex (sold under the trade name Purite™), stabilized chlorine dioxide, benzalkonium chloride, thimerosal, chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol, edetate disodium, sorbic acid, and the like. The concentration of a suitable preservative can be about 0.001 to 1% by weight, or about 0.01 to 0.5% by weight.

[0062] The solubility of the components of the present composition can be enhanced by the addition of a surfactant or other suitable co-solvent in the composition. Such surfactants or co-solvents include polysorbates 20, 60, and 80, Pluronic® F-68, F-84, and P-103, cyclodextrin, solutol, or other agents known to those skilled in the art. In some embodiments, the surfactant or co-solvent is present in an amount of about 0.01% to 2% by weight.

[0063] A viscosity higher than that of a single aqueous solution may be desirable to enhance intraocular absorption of the active compound, reduce variability in dispensing of the formulation, reduce physical separation of suspension or emulsion components of the formulation, and / or for other improvements in ophthalmic formulations. Such viscosity-enhancing agents include, for example, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, or other agents known to those skilled in the art. In some embodiments, the viscosity-enhancing agent is present at about 0.01% to 2% by weight.

[0064] Table 1 shows suitable eye drop formulations.

[0065] [Table 1]

[0066] The alpha 2 adrenergic agonists may be embedded or injected into sustained release implants, such as biodegradable or biodegradable implants, including those made from polymeric materials, such as polymers derived from and / or including organic esters and organic ethers, which when degraded result in physiologically acceptable degradation products, including monomers; polymers derived from anhydrides, amides, orthoesters, etc., alone or in combination with other monomers. Polymers of hydroxyaliphatic carboxylic acids, either homopolymers 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 may be 0-20%, 20-40%, 40-60%, 60-80%, or more than 80% by weight of the implantable injectable formulation.

[0067] In some embodiments, the implant is a polyglycolic acid (PLGA) copolymer having about 0-100% polylactic acid, 15-85% polylactic acid, or about 35-65% polylactic acid. Some implants use copolymers having about 50% polylactic acid.

[0068] [Example 1] Whitecap Biosciences recently completed a Phase 1 / 2 study evaluating the safety and IOP-lowering efficacy of Compound 1 ophthalmic solution in patients with primary open-angle glaucoma or ocular hypertension. The first part 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 efficacy of a single drop of ophthalmic solution containing [3-[(1S)-1-(1H-imidazol-5-yl)ethyl]-2-methylphenyl]methyl-2,2-dimethylpropanoate (Compound 1) at concentrations between 0.05% and 0.4%. The second part of this study was a double-blind, randomized, multicenter, active-controlled, parallel study to evaluate the safety and intraocular pressure-lowering efficacy of 0.15% Compound 1 and 0.4% Compound 1 eye drops compared with 0.5% timolol eye drops in patients with glaucoma or ocular hypertension. In addition to evaluating the effect of Compound 1 on IOP reduction, this study also evaluated the drug's effect on visual function.

[0069] intraocular pressure In the first part of this study, after a single dose to the study eye, the mean change from baseline (mean ± SD) in IOP on Day 1 ranged from -0.9 ± 0.9 to -3.4 ± 2.2 mmHg for the 0.05% Compound 1 group, -2.1 ± 1.9 to -8.3 ± 4.1 mmHg for the 0.15% Compound 1 group, and -1.9 ± 2.4 to -8.2 ± 1.9 mmHg for the 0.4% Compound 1 group. Peak effect occurred within 30 minutes to 4 hours across treatment groups.

[0070] The second part of the study achieved its primary endpoint of statistically significant IOP reduction within groups at 2 hours on Day 14 when administered twice daily. Mean change from baseline analysis of study eyes demonstrated statistically significant IOP-lowering effects at all post-baseline time points for both Compound 1 treatment groups (p<0.007), and for timolol (p<0.004). At the primary endpoint (Day 14, 2 hours), the mean change from baseline in IOP for subjects receiving 0.15% Compound 1 was -4.9 ± 1.8 mmHg (p<0.001), for subjects receiving 0.4% Compound 1 was -5.1 ± 2.5 mmHg (p<0.001), and for subjects receiving timolol was -6.0 ± 3.0 mmHg (p<0.001).

[0071] Additional analyses examining the effect of Compound 1 on visual function included low-light visual acuity and visual field. A dose-related improvement in low-light visual acuity was observed in patients receiving Compound 1. The percentage of subjects achieving a 15-letter or greater increase in Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity measured under low light in the test eye during at least one study visit was 8.7% in subjects receiving 0.15% Compound 1, 16.7% in subjects receiving 0.4% Compound 1, and 0% in subjects receiving 0.5% timolol. The improvement in visual function in the treated non-test eyes confirmed the findings from the test eyes. The percentage of subjects who achieved a 15 or more letter increase in ETDRS visual acuity measured under low light in the non-study eye during at least one study visit was 17.4% in subjects receiving 0.15% Compound 1, 25.0% in subjects receiving 0.4% Compound 1, and 8.3% in subjects receiving 0.5% Timolol.

[0072] Improved visual field results were also demonstrated in both the test eyes and the treated non-test eyes in patients receiving Compound 1 compared with those receiving timolol. The change in mean visual field deviation (dB) from baseline at Day 14 in the test eyes (where a positive change indicates visual field improvement) was 0.2 ± 1.2 in subjects receiving 0.15% Compound 1, -0.5 ± 2.3 in subjects receiving 0.4% Compound 1, and -1.2 ± 2.3 in subjects receiving timolol. For non-test eyes, the change in mean deviation (dB) was 0.4 ± 1.5 in subjects receiving 0.15% Compound 1, -0.2 ± 1.4 in subjects receiving 0.4% Compound 1, and -2.0 ± 3.4 in subjects receiving timolol. The percentage of patients with an improvement of 1 dB or greater is shown in Table 1.

[0073] [Table 2]

[0074] Pupil size The effect of Compound 1 on pupil size was assessed at the baseline visit and on Day 14. Results from Hour 0 to Hour 2 revealed no change in the majority of subjects. Neither dose of Compound 1 significantly reduced pupil size. In the test eyes, the mean change in pupil size from baseline to Hour 0 on Day 14 at the end of the study (when visual function was assessed) was 0.0 mm in subjects receiving 0.15% Compound 1, −0.1 mm in subjects receiving 0.4% Compound 1, and −0.1 mm in subjects receiving timolol. In the treated non-test eyes, the mean change in pupil size from baseline to Hour 0 on Day 14 at the end of the study (when visual function was assessed) was 0.0 mm in subjects receiving 0.15% Compound 1, −0.1 mm in subjects receiving 0.4% Compound 1, and −0.1 mm in subjects receiving timolol.

[0075] safety Both doses of Compound 1 were safe and well tolerated. The majority of subjects reported that study medication was "comfortable" or "very comfortable."

Claims

1. A method for improving vision, comprising administering an alpha-2 adrenergic agonist to a mammal in need thereof.

2. 1. A method for improving vision under low lighting conditions, comprising administering an alpha-2 adrenergic agonist to a mammal in need thereof.

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

4. 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 for improving or slowing the progressive loss of an indicator of visual function under normal or low-intensity lighting conditions without constriction of pupil size, comprising administering an alpha-2 adrenergic agonist to a mammal in need thereof, wherein the mammal experiences an improvement or slowing of the progressive loss of an indicator of visual function under normal or low-intensity lighting conditions without constriction of pupil size.

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

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

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

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

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

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

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

13. 12. 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 to 13, wherein the mammal is a human.

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

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

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

18. 15. The method of claim 14, wherein the human has a retinal condition accompanied by decreased low-light vision.

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

20. 20. The method of any one of claims 1-19, wherein the improvement in visual function, visual acuity, or visual field occurs within two weeks of receiving the first dose of the alpha-2 adrenergic agonist.

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