Methods and compositions for improving visual performance under mesopic light conditions using phentolamine

Abstract

The invention provides methods, compositions, and kits containing phentolamine for improving visual performance, such as improving visual performance under mesopic light conditions.

Description

METHODS AND COMPOSITIONS FOR IMPROVING VISUAL PERFORMANCE UNDER MESOPIC LIGHT CONDITIONS USING PHENTOLAMINECROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to United States Provisional Patent Application serial number 63 / 872,617, filed August 29, 2025; United States Provisional Patent Application serial number 63 / 812,588. filed May 27, 2025; United States Provisional Patent Application serial number 63 / 794.963. filed April 25, 2025; United States Provisional Patent Application serial number 63 / 774,557, filed March 19, 2025; United States Provisional Patent Application serial number 63 / 761,624, filed February 21, 2025; and United States Provisional Patent Application serial number 63 / 728,369, filed December 5, 2024; the contents of each of which are hereby incorporated by reference in their entirety.FIELD OF THE INVENTION

[0002] The invention provides methods, compositions, and kits containing phentolamine for improving visual performance, such as improving visual performance under mesopic light conditions.BACKGROUND

[0003] Deficient visual performance can have a significant negative impact on a patient’s quality7of life, affecting, for example, ability' to perform normal daily tasks, perform at school, and perform at work. The inability to see clearly can impact people during normal daylight conditions and during low-light conditions, such as nighttime. One type of vision problem experienced by a substantial number of patients is poor night vision. The inability7to see clearly under low light conditions can make it difficult and / or dangerous for a patient to operate a motor vehicle at nighttime. Patients that are more likely to experience night vision problems include those suffering from night myopia, those having an equatorial cortical cataract, those having had surgery to insert an intraocular lens, and / or those having underwent LASIK surgery. Exemplary' symptoms of poor night vision include glare, halos, starburst, ghosting patterns, and / or poor depth perception.

[0004] Certain therapies have been described for improving visual performance. For example, the Bernstein Center for Visual Performance offers programs that utilize visual aids, such as puzzles, stereoscopes, and eyeglasses, designed to improve visual performance. However, the need exists for methods and compositions that provide the patient with improved visual performance, particularly improved visual performance under mesopic light conditions.133915088 399256-OPI-030WO (214984)

[0005] The present invention addresses the aforementioned need for methods and compositions for achieving improved visual performance under mesopic light conditions.SUMMARY

[0006] The invention provides methods, compositions, and kits containing phentolamine for improving visual performance, such as improving visual performance under mesopic light conditions. The methods and compositions provide particular benefits to patients suffering from poor visual performance under mesopic light conditions, such as when driving an automobile at nighttime. Exemplary aspects and embodiments of the invention are described below.

[0007] One aspect of the invention provides a method of improving visual performance under mesopic light conditions, comprising administering to an eye of a subject in need thereof a therapeutically effective amount of a therapeutic agent selected from phentolamine or a pharmaceutically acceptable salt thereof, to provide improved visual performance under mesopic light conditions. In certain embodiments, the improvement in visual performance is improved visual acuity. In certain embodiments, the improvement in visual performance is improved contrast sensitivity.

[0008] Another aspect of the invention provides a method of treating decreased visual performance under mesopic light conditions, comprising administering to an eye of a subject in need thereof a therapeutically effective amount of a therapeutic agent selected from phentolamine or a pharmaceutically acceptable salt thereof, in order to treat the decreased visual performance under mesopic light conditions. In certain embodiments, the visual performance is visual acuity.

[0009] Another aspect of the invention provides a method of treating significant chronic night driving impairment in keratorefractive patients with photic phenomena, comprising administering to an eye of a subject in need thereof a therapeutically effective amount of a therapeutic agent selected from phentolamine or a pharmaceutically acceptable salt thereof, to treat the significant chronic night driving impairment in keratorefractive patients with photic phenomena.BRIEF DESCRIPTION OF FIGURES

[0010] Figure 1 depicts exemplar}7eye redness as measured according to (1) the CCLRU Redness Grading Scale, and (2) the NYX-001 Redness Grading Scale.233915088 399256-OPI-030WO (214984)

[0011] Figure 2 is a graph showing the change in mLCVA from baseline over a sixty day period of the study in the study eye in subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution, as further described in Example 3.

[0012] Figure 3 is a graph showing scores from the patient reported outcomes from the vision and night driving questionnaire at Day fifteen for subjects that received placebo and for subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution, where the abbreviation “POS” refers to subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution, as further described in Example 3.

[0013] Figure 4 is a graph showing scores from the patient reported outcomes from the vision and night driving questionnaire for the specific question of ‘'difficulty with glare from headlights” at baseline, Day eight, Day fifteen, and Week 6 of the study, for subjects that received placebo and for subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution, where the abbreviation “POS” refers to subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution, as further described in Example 3.

[0014] Figure 5 is a graph showing scores from the patient reported outcomes from the vision and night driving questionnaire for the specific question of “difficulty7seeing road in poor weather” at baseline, Day eight, Day fifteen, and Week 6 of the study, for subjects that received placebo and for subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution, where the abbreviation “POS” refers to subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution, as further described in Example 3.

[0015] Figure 6 is a graph showing mean pupil diameter of the subjects’ eye under mesopic light conditions, for subjects that received placebo and for subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution, where the abbreviation “POS” refers to subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution, as further described in Example 3.

[0016] Figure 7 is a graph showing change in mLCVA over time relative to baseline mLCVA, for subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution, where the abbreviation “POS” refers to subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution, as further described in Example 3.

[0017] Figure 8 is a table showing the percentage of subject w ith improvement or loss in mLCVA from baseline by visit. The abbreviation “POS” refers to subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution, as further described in Example 3.333915088 399256-OPI-030WO (214984)

[0018] Figure 9 is a graph of mean pupil diameter at baseline. Day eight, and Day fifteen of the study, for subjects that received placebo and for subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution, where the abbreviation “POS” refers to subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution, as further described in Example 1.

[0019] Figure 10 is a graph showing percentage of subjects having a mean pupil diameter within a certain range as a function of study day treatment group, for subjects that received placebo and for subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution, where the abbreviation “POS” refers to subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution, as further described in Example 1.

[0020] Figure 11 illustrates wavefront aberrometer image and data capture representation of a single subject that received 1.0% (w / v) phentolamine mesylate ophthalmic solution, as further described in Example 1.

[0021] Figure 12 is a graph showing mean severity rating of severity of photic complaints (0 to 3 scale) on Day 15 as a function of treatment group, for subjects that received placebo and for subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution, where the abbreviation “POS” refers to subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution, as further described in Example 1.

[0022] Figure 13 is a graph showing the mean mLCVA in the study eye at baseline, Day 8, and Day 15 of the study in subjects in the modified intention-to-treat (mITT) population who received either placebo or 1 .0% (w / v) phentolamine mesylate ophthalmic solution, where the abbreviation “POS” refers to subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution, as further described in Example 3.

[0023] Figure 14 is a graph showing the mean mHCVA at baseline, Day 8, and Day 15 of the study in subjects in the modified intention-to-treat (mITT) population who received either placebo or 1.0% (w / v) phentolamine mesylate ophthalmic solution, where the abbreviation “POS” refers to subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution, as further described in Example 3.DETAILED DESCRIPTION OF THE INVENTION

[0024] The invention provides methods, compositions, and kits containing phentolamine for improving visual performance, such as improving visual performance under mesopic light conditions. The methods and compositions provide particular benefits to patients suffering433915088 399256-OPI-030WO (214984)from poor visual performance under mesopic light conditions, such as when driving an automobile at nighttime. Various aspects of the invention are set forth below in sections; however, aspects of the invention described in one particular section are not to be limited to any particular section.Definitions

[0025] To facilitate an understanding of the present invention, a number of terms and phrases are defined below.

[0026] The terms “a,” ‘“an’ and ‘“the” as used herein mean “one or more” and include the plural unless the context is inappropriate.

[0001] The term “about” means within 10% of the stated value. In certain embodiments, the value may be within 8%, 6%, 5%, 4%, 2%, or 1% of the stated value.

[0027] As used herein, the terms “subject” and “patient” are used interchangeably and refer to organisms to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and most preferably includes humans.

[0028] As used herein, the term “effective amount” refers to the amount of a compound sufficient to effect beneficial or desired results. Unless specified otherwise, an effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. As used herein, the term “treating” includes any effect, e.g, lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.

[0029] As used herein, the term “pharmaceutical composition” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for therapeutic use in vivo or ex vivo.

[0030] As used herein, the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil / water or water / oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see Martin in Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA

[1975] ,533915088 399256-OPI-030WO (214984)

[0031] As used herein, the term “pharmaceutically acceptable salt7’ refers to any pharmaceutically acceptable salt (e g., acid or base) of a compound of the present invention which, upon administration to a subject, is capable of providing a compound of this invention. As is known to those of skill in the art, “salts'’ of the compounds of the present invention may be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic acid, and the like. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.

[0032] Examples of bases include, but are not limited to, alkali metals (e.g, sodium) hydroxides, alkaline earth metals (e.g., magnesium), hydroxides, ammonia, and compounds of formula NWZ, wherein W is Ci-4 alky l, and the like.

[0033] Examples of salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2 -hydroxy ethanesulfonate, lactate, maleate, methanesulfonate (mesylate), 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include anions of the compounds of the present invention compounded with a suitable cation such as Na+, NH4+, and NW4+(wherein W is a Ci-4 alkyl group), and the like.

[0034] For therapeutic use, salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0035] The term “alkanoate” is art-recognized and refers to alkyl-C(O)O'.

[0036] The term “alkyl” is art-recognized, and includes saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyd substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In certain embodiments, a straight chain or branched chain alky l has about 30 or fewer carbon atoms in633915088 399256-OPI-030WO (214984)its backbone (e.g., C1-C30 for straight chain, C3-C30 for branched chain), and alternatively, about 20 or fewer. Likewise, cycloalkyls have from about 3 to about 10 carbon atoms in their ring structure, and alternatively about 5, 6, or 7 carbons in the ring structure.

[0037] Throughout the description, where compositions and kits are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions and kits of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.

[0038] As a general matter, compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.I. Therapeutic Methods

[0039] The invention provides methods for improving visual performance, such as improving visual performance under mesopic light conditions. The methods and compositions provide particular benefits to patients suffering from poor visual performance under mesopic light conditions, such as when driving an automobile at nighttime. Various aspects and embodiments of the therapeutic methods are described in the sections below. The sections are arranged for convenience, and information in one section is not to be limited to that section, but may be applied to methods in other sections.A. Methods for Improving Visual Performance

[0040] One aspect of the invention provides a method of improving visual performance under mesopic light conditions, comprising administering to an eye of a subject in need thereof a therapeutically effective amount of a therapeutic agent selected from phentolamine or a pharmaceutically acceptable salt thereof, to provide improved visual performance under mesopic light conditions. In certain embodiments, the improvement in visual performance is improved visual acuity. In certain embodiments, the improvement in visual performance is improved contrast sensitivity. In certain embodiments, the therapeutically effective amount is sufficient to provide improved visual performance under mesopic light conditions for at least twenty -four hours.

[0041] Another aspect of the invention provides a method of reducing an aberrant focus of scattered light rays in a patient’s eye under mesopic light conditions, comprising administering733915088 399256-OPI-030WO (214984)to an eye of a subject in need thereof an effective amount of a therapeutic agent selected from phentolamine or a pharmaceutically acceptable salt thereof to reduce aberrant focus of scattered light rays in a patient’s eye under mesopic light conditions. In certain embodiments, the effective amount is sufficient to reduce aberrant focus of scattered light rays in a patient’s eye under mesopic light conditions for at least twenty -four hours.B. Methods for Treating Decreased Visual Performance

[0042] Another aspect of the invention provides a method of treating decreased visual performance under mesopic light conditions, compnsing administering to an eye of a subject in need thereof a therapeutically effective amount of a therapeutic agent selected from phentolamine or a pharmaceutically acceptable salt thereof in order to treat the decreased visual performance under mesopic light conditions. In certain embodiments, the therapeutically effective amount is sufficient to treat decreased visual performance for at least twenty-four hours. In certain embodiments, the visual performance is visual acuity.C. Methods for Treating Chronic Night Driving Impairment

[0043] Another aspect of the invention provides a method of treating chronic night driving impairment, comprising administering to an eye of a subject in need thereof a therapeutically effective amount of a therapeutic agent selected from phentolamine or a pharmaceutically acceptable salt thereof, to treat chronic night driving impairment. In certain embodiments, the chronic night driving impairment is significant chronic night driving impairment. In certain embodiments, the subject has previously received keratorefractive surgery. In certain embodiments, the subject exhibits photic phenomena and has previously received keratorefractive surgery.

[0044] Another aspect of the invention provides a method of treating significant chronic night driving impairment in keratorefractive patients with photic phenomena, comprising administering to an eye of a subject in need thereof a therapeutically effective amount of a therapeutic agent selected from phentolamine or a pharmaceutically acceptable salt thereof to treat the significant chronic night driving impairment in keratorefractive patients with photic phenomena.D. Methods for Treating Night Driving Visual Disturbance

[0045] Another aspect of the invention provides a method of treating night driving visual disturbance, comprising administering to an eye of a subject in need thereof a therapeutically833915088 399256-OPI-030WO (214984)effective amount of a therapeutic agent selected from phentolamine or a pharmaceutically acceptable salt thereof, to treat the night driving visual disturbance. In certain embodiments, the subject has previously received keratorefractive surgery. In certain embodiments, the subject exhibits photic phenomena and has previously received keratorefractive surgery. In certain embodiments, the subject suffers from an optical defect in their eye resulting in impaired visual performance under mesopic light conditions.

[0046] Another aspect of the invention provides a method of treating night driving visual disturbance and decreased visual acuity under mesopic light conditions, comprising administering to an eye of a subject in need thereof a therapeutically effective amount of a therapeutic agent selected from phentolamine or a pharmaceutically acceptable salt thereof, to treat the night driving visual disturbance and decreased visual acuity under mesopic light conditions. In certain embodiments, the subject has previously received keratorefractive surgery. In certain embodiments, the subject exhibits photic phenomena and has previously received keratorefractive surgery. In certain embodiments, the subject suffers from an optical defect in their eye resulting in impaired visual performance under mesopic light conditions.E. General Considerations for Therapeutic Methods

[0047] General considerations that may be applied to further characterize therapeutic methods described herein (e.g., the methods described in Parts A, B. C, and D above) are provided below and include, for example, the identity' of the subject, frequency and / or time of administration of the therapeutic agent, eye redness score, and other features.Subject

[0048] In certain embodiments, the method may be further characterized according to the identity' of the subject. For example, in certain embodiments, the subject has previously received keratorefractive surgery. In certain embodiments, the subject has received laser keratorefractive surgery. In certain embodiments, the subject has received LASIK surgery. In certain embodiments, the subject has received photorefractive keratectomy. In certain embodiments, the subject has at least one intraocular lens. In certain embodiments, the subject has at least one multifocal intraocular lens. In certain embodiments, the subject has comeal scars. In certain embodiments, the subject previously had comeal scars. In certain embodiments, the subject has keratoconus. In certain embodiments, the subject suffers from chronic night driving impairment. In certain embodiments, the subject suffers from photic phenomena after having received keratorefractive surgery .933915088 399256-OPI-030WO (214984)

[0049] In certain embodiments, the subject prior to receiving the therapeutic agent has a debilitating loss of best-spectacle corrected mesopic vision. In certain embodiments, the subject prior to receiving the therapeutic agent has increased risk of motor vehicle accident due to impaired vision.

[0050] In certain embodiments, the subj ect prior to receiving the therapeutic agent has a mesopic pupil diameter > 4 mm. In certain embodiments, the subject prior to receiving the therapeutic agent has a mesopic pupil diameter > 5 mm. In certain embodiments, the subject prior to receiving the therapeutic agent has a mesopic pupil diameter at least 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, or 5.9 mm. In certain embodiments, the subject prior to receiving the therapeutic agent has a mesopic pupil diameter > 6 mm. In certain embodiments, the subject prior to receiving the therapeutic agent has a mesopic pupil diameter in the range of from 5.5 mm to 6.5 mm. In certain embodiments, the subject prior to receiving the therapeutic agent has a mesopic pupil diameter in the range of from 5 mm to 7 mm. In certain embodiments, the subject prior to receiving the therapeutic agent has a mesopic pupil diameter in the range of from 5 mm to 8 mm. In certain embodiments, the subject prior to receiving the therapeutic agent has a mesopic pupil diameter in the range of from 5 mm to 9 mm. In certain embodiments, the subject prior to receiving the therapeutic agent has a mesopic pupil diameter in the range of from 5 mm to 10 mm. In certain embodiments, the subject prior to receiving the therapeutic agent has a mesopic pupil diameter in the range of from 6 mm to 7 mm. In certain embodiments, the subject prior to receiving the therapeutic agent has a mesopic pupil diameter in the range of from 6 mm to 8 mm. In certain embodiments, the subject prior to receiving the therapeutic agent has a mesopic pupil diameter in the range of from 6 mm to 9 mm. In certain embodiments, the subject prior to receiving the therapeutic agent has a mesopic pupil diameter in the range of from 6 mm to 10 mm.

[0051] In certain embodiments, the subject prior to receiving the therapeutic agent has a mesopic low contrast visual acuity score of < 20 / 63. In certain embodiments, the subject prior to receiving the therapeutic agent has a mesopic low contrast visual acuity score of less than 30 letters. In certain embodiments, the subject prior to receiving the therapeutic agent has a mesopic low contrast visual acuity score of less than 25 letters. In certain embodiments, the subject prior to receiving the therapeutic agent has a mesopic low contrast visual acuity score of less than 20 letters. In certain embodiments, the subject prior to receiving the therapeutic agent has a mesopic low contrast visual acuity score in the range of from 10 letters to 30 letters. In certain embodiments, the subject prior to receiving the therapeutic agent has a mesopic low contrast visual acuity score in the range of from 10 letters to 25 letters. In certain1033915088 399256-OPI-030WO (214984)embodiments, the subject prior to receiving the therapeutic agent has a mesopic low contrast visual acuity score in the range of from 15 letters to 20 letters. In certain embodiments, the subject prior to receiving the therapeutic agent has a mesopic high contrast visual acuity' score of less than 50 letters. In certain embodiments, the subject prior to receiving the therapeutic agent has a mesopic high contrast visual acuity score in the range of from 25 letters to 50 letters. In certain embodiments, the subject prior to receiving the therapeutic agent has a mesopic high contrast visual acuity7score in the range of from 30 letters to 50 letters. In certain embodiments, the subject prior to receiving the therapeutic agent has a mesopic high contrast visual acuity score in the range of from 40 letters to 50 letters.

[0052] In certain embodiments, the subject prior to receiving the therapeutic agent presents with > 10 letter improvement in mesopic low contrast visual acuity during illumination of the contralateral eye.

[0053] In certain embodiments, the subject prior to receiving the therapeutic agent presents with the night vision disturbance of halos distorting their vision. In certain embodiments, the subject prior to receiving the therapeutic agent presents with the night vision disturbance of starburst. In certain embodiments, the subject prior to receiving the therapeutic agent presents with the night vision disturbance of glare.

[0054] In certain embodiments, the subject has had no recent ocular procedure performed on their eye. In certain embodiments, the subject does not have an ocular disease. In certain embodiments, the subject does not have ocular inflammation.

[0055] In certain embodiments, the subject is a human. In certain embodiments, the subject is an adult human. In certain embodiments, the subject is a geriatric human.Frequency7and / or Time of Administration of Therapeutic Agent

[0056] In certain embodiments, the method may be further characterized according to the frequency and / or time of administration of the therapeutic agent. For example, in certain embodiments, the therapeutic agent is administered one time per day. In certain embodiments, the therapeutic agent is administered one or two times per day. In certain embodiments, the therapeutic agent is administered once nightly. In certain embodiments, the therapeutic agent is administered one time per day (preferably at bedtime).

[0057] In certain embodiments, the therapeutic agent is administered at or near bedtime of the subject. In certain embodiments, the therapeutic agent is administered within 1 hour of bedtime of the subject. In certain embodiments, the therapeutic agent is administered within1133915088 399256-OPI-030WO (214984)about 2 hours, 1.5 hours, 1 hour, 45 minutes, 30 minutes, or 15 minutes of the subject’s bedtime.

[0058] In certain embodiments, the therapeutic agent is administered one time per day, which is at or near bedtime of the subject.Eye Redness

[0059] In certain embodiments, the method may be further characterized according to the extent of eye redness experienced by the subject. For example, in certain embodiments, the subject experiences an increase in eye redness of no more than one grade measured using the CCLRU Redness Grading Scale during the subject's waking hours compared to the subject's level of eye redness without receiving the therapeutic agent. In certain embodiments, the subject experiences an increase in eye redness of no more than two grades measured using the CCLRU Redness Grading Scale during the subject's waking hours compared to the subject’s level of eye redness without receiving the therapeutic agent.Repeat Administration

[0060] In certain embodiments, the method may be further characterized according to the number of consecutive days of administration of the therapeutic agent. For example, in certain embodiments, the therapeutic agent is administered to the subject for at least five consecutive days. In certain embodiments, the therapeutic agent is administered to the subject for at least seven consecutive days. In certain embodiments, the therapeutic agent is administered to the subject for at least fifteen consecutive days.

[0061] In certain embodiments, the therapeutic agent is administered to the subject daily for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17. 18, 19, 20, 21, 22, 23, 24, 25, 26, 27. 28. 29. 30. 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43. 44. 45. 46. 47, or 48 weeks. In certain embodiments, the therapeutic agent is administered to the subject daily for at least 6 weeks. In certain embodiments, the therapeutic agent is administered to the subject once per day for at least 3 out of every 7 days for period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15. 16. 17. 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31. 32. 33. 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or 48 weeks. In certain embodiments, the therapeutic agent is administered to the subject once per day for at least 4 out of every 7 days for period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30. 31. 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46. 47. or 48 weeks. In certain embodiments, the therapeutic agent is administered to the subject once per day for at least 5 out1233915088 399256-OPI-030WO (214984)of every 7 days for period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11. 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or 48 weeks. In certain embodiments, the therapeutic agent is administered to the subject once per day for at least 6 out of every 7 days for period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20. 21. 22. 23. 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, or 48 weeks. In certain embodiments, the therapeutic agent is administered to the subject once per day for at least 3 out of every77 days for each 7 day period. In certain embodiments, the therapeutic agent is administered to the subject once per day for at least 4 out of every 7 days for each 7 day period. In certain embodiments, the therapeutic agent is administered to the subject once per day for at least 5 out of every 7 days for each 7 day period. In certain embodiments, the therapeutic agent is administered to the subject once per day for at least 3 out of every76 days for each 7 day period.Effects of the Therapeutic Agent

[0062] In certain embodiments, the method may be further characterized according to the effects of the therapeutic agent. For example, in certain embodiments, the subject experiences a reduction in pupil diameter under mesopic conditions that is at least 5% compared to the pupil diameter of the subject under the same mesopic conditions but not having received said therapeutic agent. In certain embodiments, the subject experiences a reduction in pupil diameter under mesopic conditions that is at least 10% compared to the pupil diameter of the subject under the same mesopic conditions but not having received said therapeutic agent. In certain embodiments, the subject experiences a reduction in pupil diameter under mesopic conditions that is at least 20% compared to the pupil diameter of the subject under the same mesopic conditions but not having received said therapeutic agent. In certain embodiments, the subject experiences a reduction in pupil diameter under mesopic conditions that is at least 5, 6, 7, 8, 9. 10. 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25. 26. 27. 28, 29, or 30 percent compared to the pupil diameter of the subject under the same mesopic conditions but not having received said therapeutic agent.

[0063] In certain embodiments, the subject experiences a reduction in pupil diameter of at least 0.5 mm when measured under mesopic conditions relative to the diameter of the subject’s pupil under the same mesopic conditions but not having received said therapeutic agent. In certain embodiments, the subject experiences a reduction in pupil diameter of at least 1 mm when measured under mesopic conditions relative to the diameter of the subject’s pupil under the same mesopic conditions but not having received said therapeutic agent. In certain1333915088 399256-OPI-030WO (214984)embodiments, the subject experiences a reduction in pupil diameter of at least 1.1, 1.2, or 1.3 mm when measured under mesopic conditions relative to the diameter of the subject’s pupil under the same mesopic conditions but not having received said therapeutic agent. In certain embodiments, the subject experiences a reduction in pupil diameter of at least 1.4 mm when measured under mesopic conditions relative to the diameter of the subject’s pupil under the same mesopic conditions but not having received said therapeutic agent. In certain embodiments, the subject experiences a reduction in pupil diameter of at least 1.5 mm when measured under mesopic conditions relative to the diameter of the subject's pupil under the same mesopic conditions but not having received said therapeutic agent. In certain embodiments, the subject experiences a reduction in pupil diameter of at least 1.6 mm when measured under mesopic conditions relative to the diameter of the subject’s pupil under the same mesopic conditions but not having received said therapeutic agent. In certain embodiments, the subject experiences a reduction in pupil diameter of at least 1.7 mm when measured under mesopic conditions relative to the diameter of the subject’s pupil under the same mesopic conditions but not having received said therapeutic agent. In certain embodiments, the subject experiences a reduction in pupil diameter of at least 2 mm when measured under mesopic conditions relative to the diameter of the subject's pupil under the same mesopic conditions but not having received said therapeutic agent. In certain embodiments, the subject experiences a reduction in pupil diameter of at least 3 mm when measured under mesopic conditions relative to the diameter of the subject’s pupil under the same mesopic conditions but not having received said therapeutic agent.

[0064] In certain embodiments, the subject experiences a reduction in pupil diameter ranging from about 0.5 mm to about 3 mm when measured under mesopic conditions relative to the diameter of the subject’s pupil under the same mesopic conditions but not having received said therapeutic agent. In certain embodiments, the subject experiences a reduction in pupil diameter ranging from about 0.6 mm to about 3 mm when measured under mesopic conditions relative to the diameter of the subject's pupil under the same mesopic conditions but not having received said therapeutic agent. In certain embodiments, the subject experiences a reduction in pupil diameter ranging from about 1 mm to about 3 mm when measured under mesopic conditions relative to the diameter of the subject’s pupil under the same mesopic conditions but not having received said therapeutic agent. In certain embodiments, the subject experiences a reduction in pupil diameter ranging from about 2 mm to about 3 mm when measured under mesopic conditions relative to the diameter of the subject’s pupil under the same mesopic conditions but not having received said therapeutic agent. In certain embodiments, the subject1433915088 399256-OPI-030WO (214984)expen ences a reduction in pupil diameter ranging from about 0.6 mm to about 1.2 mm when measured under mesopic conditions relative to the diameter of the subject’s pupil under the same mesopic conditions but not having received said therapeutic agent. In certain embodiments, the subject experiences a reduction in pupil diameter ranging from about 0.6 mm to about 1.7 mm when measured under mesopic conditions relative to the diameter of the subject’s pupil under the same mesopic conditions but not having received said therapeutic agent. In certain embodiments, the subject experiences a reduction in pupil diameter ranging from about 0.6 mm to about 1.5 mm when measured under mesopic conditions relative to the diameter of the subject’s pupil under the same mesopic conditions but not having received said therapeutic agent. In certain embodiments, the subject experiences a reduction in pupil diameter ranging from about 1.0 mm to about 1.5 mm when measured under mesopic conditions relative to the diameter of the subject’s pupil under the same mesopic conditions but not having received said therapeutic agent. In certain embodiments, the subject experiences a reduction in pupil diameter ranging from about 1.1 mm to about 1.5 mm when measured under mesopic conditions relative to the diameter of the subject’s pupil under the same mesopic conditions but not having received said therapeutic agent. In certain embodiments, the subject experiences a reduction in pupil diameter ranging from about 1.2 mm to about 1.5 mm when measured under mesopic conditions relative to the diameter of the subject’s pupil under the same mesopic conditions but not having received said therapeutic agent. In certain embodiments, the subject experiences a reduction in pupil diameter ranging from about 1.3 mm to about 1.5 mm when measured under mesopic conditions relative to the diameter of the subject's pupil under the same mesopic conditions but not having received said therapeutic agent. In certain embodiments, the subject experiences a reduction in pupil diameter ranging from about 1.3 mm to about 1.6 mm when measured under mesopic conditions relative to the diameter of the subject’s pupil under the same mesopic conditions but not having received said therapeutic agent. In certain embodiments, the subject experiences a reduction in pupil diameter ranging from about 1.3 mm to about 1.7 mm when measured under mesopic conditions relative to the diameter of the subject’s pupil under the same mesopic conditions but not having received said therapeutic agent. In certain embodiments, the subject experiences a reduction in pupil diameter ranging from about 1.3 mm to about 1.8 mm when measured under mesopic conditions relative to the diameter of the subject's pupil under the same mesopic conditions but not having received said therapeutic agent. In certain embodiments, the subject experiences a reduction in pupil diameter ranging from about 1.3 mm to about 1.9 mm when1533915088 399256-OPI-030WO (214984)measured under mesopic conditions relative to the diameter of the subject’s pupil under the same mesopic conditions but not having received said therapeutic agent.

[0065] The effect of the therapeutic agent upon repeat administration (e.g.. daily administration) can be characterized. For example, in certain embodiments, an effect described herein (e.g., a reduction in pupil diameter, improvement in visual performance (e.g., improvement in visual acuity and / or improvement in a patient reported outcome measure, such as questions in a subject questionnaire evaluating visual performance under mesopic conditions)) can be characterized according to ability to achieve the effect over a duration of time, such as for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24. 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40. 41, 42, 43, 44, 45, 46, 47, or 48 weeks. In certain embodiments, the ability to achieve the effect is characterized over a duration ranging from 1 to 6 weeks, 2 to 6 weeks, 1 to 48 weeks, 2 to 48 weeks, or 6 to 48 weeks.

[0066] In certain embodiments, the method results in an improvement in visual acuity characterized by at least a one-line improvement in the subject’s vision measured using a Snellen chart. In certain embodiments, the method results in an improvement in visual acuity characterized by at least a two-line improvement in the subject’s vision measured using a Snellen chart. In certain embodiments, the method results in an improvement in visual acuity characterized by at least a three-line improvement in the subject’s vision measured using a Snellen chart. In certain embodiments, the method results in an improvement in visual acuity characterized by at least a one-line improvement in the subject’s vision. In certain embodiments, the method results in an improvement in visual acuity characterized by at least a two-line improvement in the subject’s vision. In certain embodiments, the method results in an improvement in visual acuity7characterized by at least a three-line improvement in the subject’s vision.

[0067] The improvement in visual acuity can be measured under photopic conditions, mesopic conditions, and / or scotopic conditions. Further, the visual acuity measurement can be taken under conditions that test low-contrast visual acuity or under conditions that test high- contrast visual acuity. In certain embodiments, the visual acuity is measured under mesopic conditions. In certain embodiments, the improvement in visual acuity is an improvement in low-contrast visual acuity. In certain embodiments, the improvement in visual acuity is an improvement in high-contrast visual acuity. In certain embodiments, the improvement in visual1633915088 399256-OPI-030WO (214984)acuity is an improvement in mesopic low-contrast visual acuity. In certain embodiments, the improvement in visual acuity is an improvement in mesopic high-contrast visual acuity.

[0068] In certain embodiments, the improvement in visual acuity is an improvement of at least 5 letters in a visual acuity score, as measured using a Snellen chart. In certain embodiments, the improvement in visual acuity is an improvement of at least 10 letters in a visual acuity score, as measured using a Snellen chart. In certain embodiments, the improvement in visual acuity is an improvement of at least 15 letters in a visual acuity score, as measured using a Snellen chart. The improvement in visual acuity may be relative to the subject’s visual acuity before the start of therapy using the therapeutic agent. The improvement in visual acuity may be measured at selected time points, such as at a certain number of hours or days after the start of therapy using the therapeutic agent. In certain embodiments, the improvement in visual acuity is at 0.5, 1 , 3, or 5 hours after the first administration of the therapeutic agent to the subject. In certain embodiments, the improvement in visual acuity is at 1, 3, 5, 8, or 15 days after the first administration of the therapeutic agent to the subject. In certain embodiments, the improvement in visual acuity is at 1, 2. 3, 4, 5, 6, 7, 8, 9. 10. 11. 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or 48 weeks after the first administration of the therapeutic agent to the subject.

[0069] An improvement in visual acuity can also be characterized according to the percentage of subjects that achieve a particular magnitude of improvement in visual acuity within a population of subjects that have received the therapeutic agent. For example, in certain embodiments, at least 10% of a population of said subjects achieve the stated improvement in visual acuity. To illustrate, in certain embodiments, at least 10% of a population of subjects that received the therapeutic agent achieve an improvement of at least 5 letters in a visual acuity score, as measured using a Snellen chart. In certain embodiments, at least 12% of the population of said subjects achieve the stated improvement in visual acuity. In certain embodiments, at least 15% of the population of said subjects achieve the stated improvement in visual acuity. In certain embodiments, at least 16% of the population of said subjects achieve the stated improvement in visual acuity. In certain embodiments, at least 50% of the population of said subjects achieve the stated improvement in visual acuity. In certain embodiments, at least 55% of the population of said subjects achieve the stated improvement in visual acuity. In certain embodiments, at least 60% of the population of said subjects achieve the stated improvement in visual acuity. In certain embodiments, at least 10, 11, 12, 13, 14, 15, 16, 17. 18. 19. 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33. 34. 35. 36, 37, 38, 39, 40,1733915088 399256-OPI-030WO (214984)41, 42, 43. 44. 45. 46. 47. 48. 49, 50, 51, 52, 53, 54, 55, 56, 57, 58. 59. 60. 61. 62. 63, 64, 65, 66, 67, 68, 69, or 70 percent of the population of said subjects achieve the stated improvement in visual acuity.

[0070] In certain embodiments, at 1 hour after the first administration of the therapeutic agent to the subject, the subject's visual performance has improved by at least 5 letters in a mesopic low-contrast visual acuity score, as measured using a Snellen chart, compared to the subject’s mesopic low-contrast visual acuity score prior to receiving the therapeutic agent. In certain embodiments, at 1 hour after the first administration of the therapeutic agent to the subject, the subject’s visual performance has improved by at least 8 letters in a mesopic low- contrast visual acuity score, as measured using a Snellen chart, compared to the subject's mesopic low-contrast visual acuity score prior to receiving the therapeutic agent. In certain embodiments, at 1 hour after the first administration of the therapeutic agent to the subject, the subject’s visual performance has improved by at least 10 letters in a mesopic low-contrast visual acuity score, as measured using a Snellen chart, compared to the subject’s mesopic low- contrast visual acuity score prior to receiving the therapeutic agent. In certain embodiments, at 1 hour after the first administration of the therapeutic agent to the subject, the subject’s visual performance has improved by an amount in the range of from 5 to 11 letters in a mesopic low- contrast visual acuity score, as measured using a Snellen chart, compared to the subject’s mesopic low-contrast visual acuity score prior to receiving the therapeutic agent. In certain embodiments, at 1 hour after the first administration of the therapeutic agent to the subject, the subject’s visual performance has improved by an amount in the range of from 8 to 1 1 letters in a mesopic low-contrast visual acuity score, as measured using a Snellen chart, compared to the subject’s mesopic low-contrast visual acuity score prior to receiving the therapeutic agent.

[0071] In certain embodiments, upon daily administration of the therapeutic agent to the subject for at least 3 days, the method results in an improvement in visual acuity characterized by at least a two-line improvement in the subject’s mesopic low-contract visual acuity measured using a Snellen chart. In certain embodiments, upon daily administration of the therapeutic agent to a population of said subjects for at least 3 days, the method results in an improvement in visual acuity characterized by at least a two-line improvement in the subjects’ mesopic low-contract visual acuity for at least 50% of the population of said subjects, as measured using a Snellen chart. In certain embodiments, upon daily administration of the therapeutic agent to a population of said subjects for at least 3 days, the method results in an improvement in visual acuity characterized by at least a two-line improvement in the subjects’ mesopic low-contract visual acuity for at least 55% of the population of said subjects, as1833915088 399256-OPI-030WO (214984)measured using a Snellen chart. In certain embodiments, upon daily administration of the therapeutic agent to a population of said subjects for at least 3 days, the method results in an improvement in visual acuity characterized by at least a two-line improvement in the subjects’ mesopic low-contract visual acuity for at least 58% of the population of said subjects, as measured using a Snellen chart.

[0072] In certain embodiments, upon daily administration of the therapeutic agent to a population of said subjects for at least 8 days, the subject’s visual performance has improved by at least 5 letters in a mesopic low-contrast visual acuity' score, as measured using a Snellen chart, compared to the subject’s mesopic low-contrast visual acuity score prior to receiving the therapeutic agent. In certain embodiments, upon daily administration of the therapeutic agent to a population of said subjects for at least 8 days, the subject’s visual performance has improved by at least 8 letters in a mesopic low-contrast visual acuity score, as measured using a Snellen chart, compared to the subject’s mesopic low-contrast visual acuity score prior to receiving the therapeutic agent. In certain embodiments, upon daily administration of the therapeutic agent to a population of said subjects for at least 8 days, the subject’s visual performance has improved an amount in the range of from 8 to 1 1 letters in a mesopic low- contrast visual acuity score, as measured using a Snellen chart, compared to the subject’s mesopic low-contrast visual acuity score prior to receiving the therapeutic agent. In certain embodiments, upon daily administration of the therapeutic agent to the subject for at least 8 days, the method results in an improvement in visual acuity characterized by at least a two-line improvement in the subject’s mesopic low-contract visual acuity measured using a Snellen chart. In certain embodiments, upon daily administration of the therapeutic agent to the subj ect for at least 8 days, the method results in an improvement in visual acuity characterized by at least a three-line improvement in the subject’s mesopic low-contract visual acuity measured using a Snellen chart. In certain embodiments, upon daily administration of the therapeutic agent to a population of said subjects for at least 8 days, the method results in an improvement in visual acuity characterized by at least a three-line improvement in the subjects’ mesopic low- contract visual acuity for at least 12% of the population of said subjects, as measured using a Snellen chart. In certain embodiments, upon daily administration of the therapeutic agent to a population of said subjects for at least 8 days, the method results in an improvement in visual acuity characterized by at least a three-line improvement in the subjects’ mesopic low-contract visual acuity for at least 15% of the population of said subjects, as measured using a Snellen chart. In certain embodiments, upon daily administration of the therapeutic agent to a population of said subjects for at least 8 days, the method results in an improvement in visual1933915088 399256-OPI-030WO (214984)acuity characterized by at least a three-line improvement in the subjects’ mesopic low-contract visual acuity for at least 16% of the population of said subjects, as measured using a Snellen chart. In certain embodiments, upon daily administration of the therapeutic agent to a population of said subjects for at least 8 days, the method results in an improvement in visual acuity characterized by at least a two-line improvement in the subjects' mesopic low-contract visual acuity for at least 50% of the population of said subjects, as measured using a Snellen chart. In certain embodiments, upon daily administration of the therapeutic agent to a population of said subjects for at least 8 days, the method results in an improvement in visual acuity characterized by at least a two-line improvement in the subjects' vision for at least 55% of the population of said subjects, as measured using a Snellen chart. In certain embodiments, upon daily administration of the therapeutic agent to a population of said subjects for at least 8 days, the method results in an improvement in visual acuity characterized by at least a two-line improvement in the subjects’ mesopic low-contract visual acuity for at least 60% of the population of said subjects, as measured using a Snellen chart.

[0073] In certain embodiments, upon daily administration of the therapeutic agent to a population of said subjects for at least 15 days, the subject’s visual performance has improved by at least 5 letters in a mesopic low-contrast visual acuity score, as measured using a Snellen chart, compared to the subject’s mesopic low-contrast visual acuity score prior to receiving the therapeutic agent. In certain embodiments, upon daily administration of the therapeutic agent to a population of said subjects for at least 15 days, the subject’s visual performance has improved by at least 8 letters in a mesopic low-contrast visual acuity score, as measured using a Snellen chart, compared to the subject’s mesopic low-contrast visual acuity score prior to receiving the therapeutic agent. In certain embodiments, upon daily administration of the therapeutic agent to a population of said subjects for at least 15 days, the subject's visual performance has improved by an amount in the range of from 8 to 11 letters in a mesopic low- contrast visual acuity score, as measured using a Snellen chart, compared to the subject’s mesopic low-contrast visual acuity score prior to receiving the therapeutic agent. In certain embodiments, upon daily administration of the therapeutic agent to the subject for at least 15 days, the method results in an improvement in visual acuity characterized by at least a two-line improvement in the subject’s mesopic low-contract visual acuity measured using a Snellen chart. In certain embodiments, upon daily administration of the therapeutic agent to the subj ect for at least 15 days, the method results in an improvement in visual acuity characterized by at least a three-line improvement in the subject’s mesopic low-contract visual acuity measured using a Snellen chart. In certain embodiments, upon daily administration of the therapeutic2033915088 399256-OPI-030WO (214984)agent to a population of said subjects for at least 15 days, the method results in an improvement in visual acuity characterized by at least a three-line improvement in the subjects’ mesopic low- contract visual acuity for at least 12% of the population of said subjects, as measured using a Snellen chart. In certain embodiments, upon daily administration of the therapeutic agent to a population of said subjects for at least 15 days, the method results in an improvement in visual acuity characterized by at least a three-line improvement in the subjects’ mesopic low-contract visual acuity for at least 15% of the population of said subjects, as measured using a Snellen chart. In certain embodiments, upon daily administration of the therapeutic agent to a population of said subjects for at least 15 days, the method results in an improvement in visual acuity characterized by at least a three-line improvement in the subjects’ mesopic low-contract visual acuity' for at least 17% of the population of said subjects, as measured using a Snellen chart.

[0074] In certain embodiments, upon daily administration of the therapeutic agent to a subject for at least 60 days, the subject’s visual performance has improved by at least 5 letters in a mesopic low-contrast visual acuity score, as measured using a Snellen chart, compared to the subject’s mesopic low-contrast visual acuity score prior to receiving the therapeutic agent. In certain embodiments, upon daily administration of the therapeutic agent to a subject for at least 60 days, the subject’s visual performance has improved by at least 8 letters in a mesopic low-contrast visual acuity score, as measured using a Snellen chart, compared to the subject’s mesopic low-contrast visual acuity score prior to receiving the therapeutic agent. In certain embodiments, upon daily administration of the therapeutic agent to a subject for at least 60 days, the subject’s visual performance has improved by an amount in the range of from 8 to 11 letters in a mesopic low-contrast visual acuity score, as measured using a Snellen chart, compared to the subject's mesopic low-contrast visual acuity score prior to receiving the therapeutic agent. In certain embodiments, upon daily administration of the therapeutic agent to the subject for at least 60 days, the method results in an improvement in visual acuity characterized by at least a two-line improvement in the subject’s mesopic low-contract visual acuity measured using a Snellen chart. In certain embodiments, upon daily administration of the therapeutic agent to the subject for at least 60 days, the method results in an improvement in visual acuity' characterized by at least a three-line improvement in the subject’s mesopic low- contract visual acuity measured using a Snellen chart. In certain embodiments, upon daily administration of the therapeutic agent to a population of said subjects for at least 60 days, the method results in an improvement in visual acuity characterized by at least a three-line improvement in the subjects’ mesopic low-contract visual acuity for at least 12% of the2133915088 399256-OPI-030WO (214984)population of said subjects, as measured using a Snellen chart. In certain embodiments, upon daily administration of the therapeutic agent to a population of said subjects for at least 60 days, the method results in an improvement in visual acuity characterized by at least a three- line improvement in the subjects’ mesopic low-contract visual acuity for at least 15% of the population of said subjects, as measured using a Snellen chart. In certain embodiments, upon daily administration of the therapeutic agent to a population of said subjects for at least 60 days, the method results in an improvement in visual acuity characterized by at least a three- line improvement in the subjects’ mesopic low-contract visual acuity for at least 17% of the population of said subjects, as measured using a Snellen chart.

[0075] In certain embodiments, upon daily administration of the therapeutic agent to the subject for at least six weeks, the method results in an improvement in visual acuity characterized by at least a two-line improvement in the subject’s mesopic low-contract visual acuity measured using a Snellen chart. In certain embodiments, upon daily administration of the therapeutic agent to the subject for at least six weeks, the method results in an improvement in visual acuity characterized by at least a three-line improvement in the subject’s mesopic low- contract visual acuity measured using a Snellen chart. In certain embodiments, upon daily administration of the therapeutic agent to a population of said subjects for at least six weeks, the method results in an improvement in visual acuity characterized by at least a three-line improvement in the subjects’ mesopic low-contract visual acuity for at least 12% of the population of said subjects, as measured using a Snellen chart. In certain embodiments, upon daily administration of the therapeutic agent to a population of said subjects for at least six weeks, the method results in an improvement in visual acuity7characterized by at least a three- line improvement in the subjects’ mesopic low-contract visual acuity for at least 15% of the population of said subjects, as measured using a Snellen chart. In certain embodiments, upon daily administration of the therapeutic agent to a population of said subjects for at least six weeks, the method results in an improvement in visual acuity7characterized by at least a three- line improvement in the subjects’ mesopic low-contract visual acuity for at least 17% of the population of said subjects, as measured using a Snellen chart.

[0076] In certain embodiments, upon daily administration of the therapeutic agent to the subject for at least twelve weeks, the method results in an improvement in visual acuity characterized by at least a two-line improvement in the subject’s mesopic low-contract visual acuity measured using a Snellen chart. In certain embodiments, upon daily administration of the therapeutic agent to the subject for at least twelve weeks, the method results in an2233915088 399256-OPI-030WO (214984)improvement in visual acuity characterized by at least a three-line improvement in the subject’s mesopic low-contract visual acuity measured using a Snellen chart.

[0077] In certain embodiments, upon daily administration of the therapeutic agent to the subject for at least twenty-four weeks, the method results in an improvement in visual acuity characterized by at least a two-line improvement in the subject’s mesopic low-contract visual acuity measured using a Snellen chart. In certain embodiments, upon daily administration of the therapeutic agent to the subject for at least twenty-four weeks, the method results in an improvement in visual acuity characterized by at least a three-line improvement in the subject’s mesopic low-contract visual acuity measured using a Snellen chart.

[0078] In certain embodiments, upon daily administration of the therapeutic agent to the subject for at least forty-eight weeks, the method results in an improvement in visual acuity characterized by at least a two-line improvement in the subject's mesopic low-contract visual acuity measured using a Snellen chart. In certain embodiments, upon daily administration of the therapeutic agent to the subject for at least forty-eight weeks, the method results in an improvement in visual acuity characterized by at least a three-line improvement in the subject’s mesopic low-contract visual acuity measured using a Snellen chart.

[0079] In certain embodiments, upon daily administration of the therapeutic agent to the subject for at least 15 days, the subject does not experience tachyphylaxis of the therapeutic agent. In certain embodiments, upon daily administration of the therapeutic agent to the subject for at least 30 days, the subject does not experience tachyphylaxis of the therapeutic agent. In certain embodiments, upon daily administration of the therapeutic agent to the subject for at least 60 days, the subject does not experience tachyphylaxis of the therapeutic agent. In certain embodiments, upon daily administration of the therapeutic agent to the subject for at least 6 weeks, the subject does not experience tachyphylaxis of the therapeutic agent. In certain embodiments, upon daily administration of the therapeutic agent to the subject for at least 12 weeks, the subject does not experience tachyphylaxis of the therapeutic agent. In certain embodiments, upon daily administration of the therapeutic agent to the subject for at least 24 weeks, the subject does not experience tachyphylaxis of the therapeutic agent. In certain embodiments, upon daily administration of the therapeutic agent to the subject for at least 48 weeks, the subject does not experience tachyphylaxis of the therapeutic agent.

[0080] In certain embodiments, the subject experiences an improvement in patient reported outcome evaluating visual performance. In certain embodiments, the improvement in patient reported outcome is at least a 5% improvement in patient reported outcome. In certain2333915088 399256-OPI-030WO (214984)embodiments, the improvement in patient reported outcome is at least a 10% improvement in patient reported outcome. In certain embodiments, the improvement in patient reported outcome is at least a 15% improvement in patient reported outcome.

[0081] In certain embodiments, the patient reported outcome is from a vision and night driving questionnaire (VND-Q). In certain embodiments, the patient reported outcome is from a vision and night driving questionnaire (VND-Q) that characterizes subject response to one or more of the following (i) seeing dark coloured cars when driving at night, (li) seeing pedestrians or animals on the roadside when driving at night, (iii) reading street signs when driving at night, (iv) seeing the road because of oncoming headlights when driving at night, (v) seeing because of glare when driving at dawn or dusk, (vi) adjusting after passing headlights from oncoming cars when driving at night, (vii) judging the distance to your turnoff or exit while driving at night, (viii) judging the distance between you and another moving cars when driving at night, or (ix) seeing the road in rain or poor weather when driving at night.

[0082] In certain embodiments, the subject experiences an improvement in seeing dark coloured cars when driving at night. In certain embodiments, the subject experiences an improvement in seeing pedestrians or animals on the roadside when driving at night. In certain embodiments, the subject experiences an improvement in reading street signs when driving at night. In certain embodiments, the subject experiences an improvement in seeing the road because of oncoming headlights w hen driving at night. In certain embodiments, the subject experiences an improvement in seeing because of glare w hen driving at dawn or dusk. In certain embodiments, the subject experiences an improvement in adjusting after passing headlights from oncoming cars when driving at night. In certain embodiments, the subject experiences an improvement in judging the distance to your turnoff or exit while driving at night. In certain embodiments, the subject experiences an improvement in judging the distance between you and another moving cars when driving at night. In certain embodiments, the subject expen ences an improvement in seeing the road in rain or poor weather when driving at night.Minimum Pupil Diameter

[0083] In certain embodiments, the method may be further characterized according to the minimum pupil diameter experienced by the subject under mesopic conditions. For example, in certain embodiments, the method is further characterized in that the method does not cause the diameter of the subject’s pupil under mesopic conditions to be less than 2.4 mm. In certain embodiments, the method is further characterized in that the method does not cause the2433915088 399256-OPI-030WO (214984)diameter of the subject’s pupil under mesopic conditions to be less than 2.5 mm. In certain embodiments, the method is further characterized in that the method does not cause the diameter of the subject’s pupil under mesopic conditions to be less than 2.7 mm. In certain embodiments, the method is further characterized in that the method does not cause the diameter of the subject’s pupil under mesopic conditions to be less than 3 mm. In certain embodiments, the method is further characterized in that the method does not cause the diameter of the subject’s pupil under mesopic conditions to be less than 3.5 mm. In certain embodiments, the method is further characterized in that the method does not cause the diameter of the subject’s pupil under mesopic conditions to be less than 4 mm. In certain embodiments, the method is further characterized in that the method does not cause the diameter of the subject’s pupil under mesopic conditions to be less than 4.5 mm.

[0084] The minimum pupil diameter under mesopic conditions can be important to ensure that the pupil is large enough to permit sufficient light to enter the eye so the subject has adequate vision under mesopic conditions.Amount of Therapeutic Agent

[0085] In certain embodiments, the method may be further characterized according to the amount of therapeutic agent administered to the patient. For example, in certain embodiments, the therapeutic agent is administered topically to the eye of the subject in an amount of from about 0.2 to about 1.0 mg. In certain embodiments, the therapeutic agent is administered topically to the eye of the subject in an amount of from about 0.3 to about 0.4 mg. In certain embodiments, the therapeutic agent is administered topically to the eye of the subject in an amount of from about 0.3 to about 0.5 mg. In certain embodiments, the therapeutic agent is administered topically to the eye of the subject in an amount of about 0.3 mg. In certain embodiments, the therapeutic agent is administered topically to the eye of the subject in an amount of about 0.4 mg. In certain embodiments, the therapeutic agent is administered topically to the eye of the subject in an amount of about 0.5 mg. In certain embodiments, the therapeutic agent is administered topically to the eye of the subject in an amount of from about 0.3 to about 0.7 mg. In certain embodiments, the therapeutic agent is administered topically to the eye of the subject in an amount of from about 0.3 to about 0.6 mg. In certain embodiments, the therapeutic agent is administered topically to the eye of the subject in an amount of from about 0.5 to about 1.0 mg. In certain embodiments, the therapeutic agent is administered topically to the eye of the subject in an amount of from about 0.9 to about 1.1 mg. In certain2533915088 399256-OPI-030WO (214984)embodiments, the therapeutic agent is administered topically to the eye of the subject in an amount of about 1.0 mg.

[0086] In certain embodiments, the therapeutic agent is administered topically to the eye of the subject in the form of an eye drop containing the therapeutic agent at a concentration of about 1% w / w. In certain embodiments, the therapeutic agent is administered topically to the eye of the subject in the form of an eye drop containing the therapeutic agent at a concentration of about 1% w / v. In certain embodiments, the therapeutic agent is administered topically to the eye of the subject in the form of one eye drop containing the therapeutic agent at a concentration of about 1% w / w. In certain embodiments, the therapeutic agent is administered topically to the eye of the subject in the form of one eye drop containing the therapeutic agent at a concentration of about 1% w / v.Identity of the Therapeutic Agent

[0087] In certain embodiments, the method may be further characterized according to the identity of the therapeutic agent. For example, in certain embodiments, the therapeutic agent is a pharmaceutically acceptable salt of phentolamine. In certain embodiments, the therapeutic agent is phentolamine mesylate.Treating Night Driving Visual Disturbance

[0088] In connection with methods set forth in Sections A, B, and C, the following further embodiments are provided. In certain embodiments, the method further comprises treating night driving visual disturbance. In certain embodiments, the method further comprises treating night driving visual disturbance in a patient suffering from poor visual performance under mesopic light conditions. In certain embodiments, the method further comprises treating night driving visual disturbance in a patient that has previously received keratorefractive surgery-.Additional Considerations

[0089] The phentolamine or a pharmaceutically acceptable salt thereof is desirably administered to the eye of the patient in the form of an ophthalmic solution, which is delivered to the eye in the form of an eye drop. A standard eye drop typically contains from about 0.03 mL to about 0.05 mL of solution. In certain embodiments, the eye drop contains about 0.03 mL of solution. In certain embodiments, the eye drop contains about 0.04 mL of solution. In certain embodiments, the eye drop contains about 0.05 mL of solution.2633915088 399256-OPI-030WO (214984)

[0090] Certain patient populations may respond particularly well to the therapeutic methods. One way to characterize patients is according to eye color, such as those having a substantial amount of pigment in their iris. As such, one population of patients is those in which the patient’s iris is brown. Another way to characterize patient populations is according to race, such as African American, Hispanic, or Asian patients.

[0091] It is reiterated here that all embodiments described throughout the patent application (including, for example. Sections A, B, C, D, and E) may be combined in various permutations and all such permutations are contemplated.IL Ophthalmic Solutions Containing Phentolamine

[0092] The therapeutic methods involve administering phentolamine or a pharmaceutically acceptable salt thereof to the patient. The phentolamine or a pharmaceutically acceptable salt thereof is desirably in the form of an ophthalmic solution. The ophthalmic solution is formulated to be suitable for administration to the eye of a patient, and desirably provides immediate release of phentolamine. that is, the ophthalmic solution is not a sustained release formulation that delivers phentolamine over an extended duration, such as hours, days or weeks. In a preferred embodiment, the therapeutic agent is a pharmaceutically acceptable salt of phentolamine. In a more preferred embodiment, the therapeutic agent is phentolamine mesylate.

[0093] The ophthalmic solution desirably comprises an aqueous pharmaceutically acceptable carrier and phentolamine or a pharmaceutically acceptable salt thereof. The ophthalmic solution may contain excipients(s) that are suitable for administration to the eye. Various pharmaceutically acceptable salts are described in the literature. The preferred salt form of phentolamine is phentolamine mesylate. Accordingly, the methods may use an ophthalmic solution that comprises an aqueous pharmaceutically acceptable carrier and phentolamine mesylate.

[0094] Accordingly, in certain embodiments, the methods use an ophthalmic solution comprising an aqueous pharmaceutically acceptable carrier and phentolamine or a pharmaceutically acceptable salt thereof. In certain other embodiments, the ophthalmic solution comprises an aqueous pharmaceutically acceptable carrier and phentolamine mesylate. In certain other embodiments, the ophthalmic solution comprises water, a polyol, and phentolamine or a pharmaceutically acceptable salt thereof. In certain other embodiments, the ophthalmic solution comprises water, mannitol, and phentolamine mesylate. In certain other embodiments, ophthalmic solution comprises water, a poly ol, an alkali metal carboxylate, and2733915088 399256-OPI-030WO (214984)phentolamine or a pharmaceutically acceptable salt thereof. In certain other embodiments, the ophthalmic solution comprises water, mannitol, sodium acetate, and phentolamine mesylate.Aqueous Ophthalmic Solution Free of a Chelating Agent

[0095] In certain embodiments, the therapeutic agent utilized in the methods is presented in the form of an aqueous ophthalmic solution free of a chelating agent, wherein said solution comprises (a) phentolamine or a pharmaceutically acceptable salt thereof; (b) at least one polyol compound, such as a polyol compound having a molecular weight less than 250 g / mol: (c) at least one buffer; and (d) water; wherein the solution does not contain a chelating agent. The amounts of ingredients in the aqueous ophthalmic solutions may be selected in order to achieve particular performance properties, such as stability to storage, minimize irritation to the eye of a patient, and enhance penetration of phentolamine into the eye of a patient.

[0096] One exemplary preferred solution is an aqueous ophthalmic solution free of a chelating agent comprising: (a) about 0. 1% (w / v) to about 4% (w / v) of phentolamine or a pharmaceutically acceptable salt thereof; (b) about 1% (w / v) to about 6% (w / v) of at least one polyol compound having a molecular weight less than 250 g / mol; (c) about 0.1 mM to about 10 mM of at least one buffer; and (d) water; wherein the solution has a pH in the range of 4.0 to 7.5 and does not contain a chelating agent.

[0097] In certain embodiments, the therapeutic agent is presented in the form of a 1.0% (w / v) phentolamine mesylate ophthalmic solution containing 1% (w / v) phentolamine mesylate, 4% (w / v) mannitol, 3 mM sodium acetate, and water.

[0098] Exemplar)’ components and features of the aqueous ophthalmic solutions are described in more detail below.Phentolamine & Pharmaceutically Acceptable Salts

[0099] The aqueous ophthalmic solution comprises phentolamine or a pharmaceutically acceptable salt of phentolamine. Exemplary pharmaceutically acceptable salts include, for example, the hydrochloric acid salt and mesylate salt. Accordingly, in certain embodiments, the solution comprises phentolamine (i.e., as the free base). In certain other embodiments, the solution comprises phentolamine hydrochloride. In certain yet other embodiments, the solution comprises phentolamine mesylate.

[0100] The amount of phentolamine or a pharmaceutically acceptable salt thereof in the aqueous ophthalmic solution may be adjusted in order to achieve desired performance properties. For example, where is it desired to provide a larger amount of phentolamine (or2833915088 399256-OPI-030WO (214984)pharmaceutically acceptable salt thereof) to the patient in a single administration of the aqueous ophthalmic solution, the concentration of phentolamine (or pharmaceutically acceptable salt thereof) is increased in the aqueous ophthalmic solution. Single administration of aqueous ophthalmic solutions having a higher concentration of phentolamine (or pharmaceutically acceptable salt thereof) may provide the patient with improved visual performance for a longer duration of time because more phentolamine (or pharmaceutically acceptable salt thereof) is administered to the patient.

[0101] Accordingly, in certain embodiments, the aqueous ophthalmic solution comprises from about 0.1% (w / v) to about 2% (w / v) of phentolamine or a pharmaceutically acceptable salt thereof. In certain embodiments, the aqueous ophthalmic solution comprises from about 0.25% (w / v) to about 2% (w / v) of phentolamine or a pharmaceutically acceptable salt thereof. In certain other embodiments, the aqueous ophthalmic solution comprises from about 0.5% (w / v) to about 2% (w / v) of phentolamine or a pharmaceutically acceptable salt thereof. In certain other embodiments, the aqueous ophthalmic solution comprises from about 0.25% (w / v) to about 1% (w / v) of phentolamine or a pharmaceutically acceptable salt thereof. In certain other embodiments, the aqueous ophthalmic solution comprises about 1% (w / v) of phentolamine or a pharmaceutically acceptable salt thereof. In certain other embodiments, the aqueous ophthalmic solution comprises from about 0.1% (w / v) to about 4% (w / v) of phentolamine mesylate. In certain other embodiments, the aqueous ophthalmic solution comprises from about 0.1% (w / v) to about 2% (w / v) of phentolamine mesylate. In certain other embodiments, the aqueous ophthalmic solution comprises from about 0.25% (w / v) to about 2% (w / v) of phentolamine mesylate. In certain other embodiments, the aqueous ophthalmic solution comprises from about 0.5% (w / v) to about 2% (w / v) of phentolamine mesylate. In certain other embodiments, the aqueous ophthalmic solution comprises from about 0.25% (w / v) to about 1% (w / v) of phentolamine mesylate. In certain other embodiments, the aqueous ophthalmic solution comprises about 1% (w / v) of phentolamine mesylate. In certain other embodiments, the aqueous ophthalmic solution comprises about 0.25% (w / v) or about 0.5% (w / v) of phentolamine mesylate.Polyol Compounds

[0102] The aqueous ophthalmic solution comprises one or more polyol compounds. The polyol compound is an organic compound having at least two hydroxyl groups (e.g.. from 2 to about 6 hydroxyl groups). The polyol compound is beneficial to the aqueous ophthalmic solution because, for example, it can increase the stability of the aqueous ophthalmic solution2933915088 399256-OPI-030WO (214984)to storage and / or modify the tonicity of the aqueous ophthalmic solution. Exemplary polyol compounds include, for example, mannitol, glycerol, propylene glycol, ethylene glycol, sorbitol, and xylitol.

[0103] The aqueous ophthalmic solution may contain a single polyol compound or a mixture of one or more polyol compounds. In other words, the aqueous ophthalmic solution comprises at least one polyol compound. In certain embodiments, the aqueous ophthalmic solution comprises at least one polyol compound that is mannitol, glycerol, propylene glycol, ethylene glycol, sorbitol, or xylitol. In certain other embodiments, the at least one polyol compound is mannitol. In certain other embodiments, the at least one polyol compound is glycerol. In certain other embodiments, the at least one polyol compound is propylene glycol. In certain other embodiments, the at least one polyol compound is mannitol, and the solution further comprises glycerol. In certain other embodiments, the at least one polyol compound is mannitol, and the solution further comprises propylene glycol. In certain other embodiments, the at least one polyol compound is glycerol, and the solution further comprises propylene glycol. In certain other embodiments, the mannitol described in embodiments above is D- mannitol.

[0104] The amount of the at least one polyol compound in the aqueous ophthalmic solution may be selected in order to achieve desired performance properties for the solution. The polyol compound may, for example, increase the stability of the solution to storage and / or modify the tonicity of the solution to make it more suitable for administration to the eye of a patient. In certain embodiments, the aqueous ophthalmic solution comprises from about 2% (w / v) to about 5% (w / v) of the at least one polyol compound. In certain other embodiments, the aqueous ophthalmic solution comprises from about 3.5% (w / v) to about 4.5% (w / v) of the at least one polyol compound. In certain other embodiments, the aqueous ophthalmic solution comprises about 4% (w / v) of the at least one polyol compound. In certain other embodiments, the aqueous ophthalmic solution comprises from about 2% (w / v) to about 3% (w / v) mannitol, and about 0.5% (w / v) to about 1.5% (w / v) glycerin. In certain other embodiments, the mannitol described in embodiments above is D-mannitol.

[0105] In certain embodiments, the amount of polyol may be selected based on the amount of phentolamine (or pharmaceutically acceptable salt thereof), such that there is an inverse relationship between the amount of phentolamine (or pharmaceutically acceptable salt thereof) and the polyol in order to achieve isotonicity with the eye. For example, in embodiments where the aqueous ophthalmic solution contains about 2% (w / v) phentolamine, mannitol is3033915088 399256-OPI-030WO (214984)present in the solution at a concentration of about 3% (w / v). In embodiments where the aqueous ophthalmic solution contains about 1% (w / v) phentolamine, mannitol is present in the solution at a concentration of about 4% (w / v). To further illustrate this principle, in embodiments where the aqueous ophthalmic solution contains about 0.5% (w / v) phentolamine, mannitol may be present in the solution at a concentration of about 4.5% (w / v). In certain embodiments, the mannitol described in embodiments above is D-mannitol.

[0106] It is appreciated that the aqueous ophthalmic solution can contain additional ingredients described herein, such as various polymer materials. One such embodiment is an aqueous ophthalmic solution comprising, for example, at least one polyol compound that is propylene glycol, and further comprising polypropylene glycol, such as polypropylene glycol having a weight average molecular weight in the range of about 5,000 g / mol to about 100,000 g / mol.Buffer

[0107] The aqueous ophthalmic solution comprises at least one buffer. The buffer imparts to the solution a buffering capacity, that is, the capacity to neutralize, within limits, either acids or bases (alkali) with relatively little or no change in the original pH. The buffer may be an acid, a base, or a combination of an acid and a base. The buffer may be organic, inorganic, or a combination of organic and inorganic components. It should be understood that the buffer at least partially dissociates in aqueous solution to form a mixture of, e.g., an acid and conjugate base or a base and conjugate acid. For example, the buffer may be a combination of a carboxylic acid and its carboxylate salt. In another embodiment, the buffer may be a combination of an acid and a base, where the acid and the base are not conjugates. For example, the acid may be boric acid and the base may be tris(hydroxymethyl)aminomethane (TRIS).

[0108] Exemplary buffers include organic acids (e.g., acetic acid, sorbic acid, and oxalic acid), a borate salt, a hydrogen carbonate salt, a carbonate salt, a gluconate salt, a lactate salt, a phosphate salt, a propionate salt, a perborate salt, tris-(hydroxymethyl)aminomethane (TRIS), bis(2-hydroxyethyl)-imino-tris-(hydroxymethyl)aminoalcohol (bis-tris), N-[2-hydroxy-l,l- bis(hydroxymethyl)ethyl]glycine (tricene), N-[2-hydroxy-l,l-bis(hydroxymethyl)ethyl]glycine, 3-(N-morpholino)propanesulfonic acid, N-(carbamoylmethyl)taurine (ACES), an amino acid, salts thereof, and combinations thereof. It should be understood that the salt form of a buffer may comprise any suitable counterion. For example, the salt form of an acid may comprise an alkali or alkaline earth metal counterion.3133915088 399256-OPI-030WO (214984)

[0109] The buffer can be characterized according to its strength, i.e., the buffering capacity. The buffering capacity can be tested, for example, by determining the millimoles (mM) of strong acid or base (or respectively, hydrogen or hydroxide ions) required to change the pH of a buffer solution by one unit when added to one liter (a standard unit) of the buffer solution. The buffering capacity generally depends on the type and concentration of the buffer components and can be greater in particular pH ranges. For example, a buffer may have an optimal buffering capacity in a pH range near the pl<aof the buffer, e.g., within about 1 pH unit or within about 2 pH units of the pKa the buffer. In certain embodiments, the buffer is a w eak buffer, such as an alkali metal carboxylate (e.g., sodium acetate).

[0110] In certain embodiments, the buffer is a weak acid buffer having one or more of the following characteristics: (a) a pKa of from about 4.0 to about 6.0; more preferably, from about 4.5 to about 5.5; and (b) a lipophilicity value Log P of from about -0.50 to about 1 .5; more preferably, from about -0.25 to about 1.35.

[0111] The amount of buffer can be adjusted in order to achieve desired performance properties for the aqueous ophthalmic solution. For example, in certain embodiments, the buffer may be present at a concentration of less than about 10 rnM, less than about 7 mM, less than about 5 mM, less than about 3 mM, or less than about 2 mM. In some embodiments, the buffer may be present at a concentration of from about 1 mM to about 10 mM, from about 1 mM to about 7 mM, from about 1 mM to about 5 mM, from about 1 mM to about 3 mM, from about 1 mM to about 2 mM, from about 2 mM to about 5 mM, or from about 2 mM to about 3 mM. In yet other embodiments, the buffer is present at a concentration of about 3 mM.

[0112] The amount and identity of the buffer may be selected in order to achieve certain performance properties for the aqueous ophthalmic solution. For example, the amount of buffer may impact the quantity of acid that may be neutralized before there is substantial change in the pH of the aqueous ophthalmic solution. Also, the amount of buffer may impact the tonicity of the aqueous ophthalmic solution. Desirably, the quantity and identity of the buffer should be selected in order to minimize any irritation that may be caused by administration of the aqueous ophthalmic solution to the eye of a patient. Accordingly, in certain embodiments, the buffer is present at a concentration in the range of about 2 mM to about 4 mM. In yet other embodiments, the buffer is present at a concentration of about 3 mM. In certain embodiments, the buffer comprises an alkali metal alkylcarboxylate. In certain other embodiments, the buffer comprises an alkali metal acetate. In yet other embodiments, the buffer comprises sodium acetate.3233915088 399256-OPI-030WO (214984)Solution pH

[0113] The aqueous ophthalmic solution may be characterized according to the pH of the solution. Desirably, the aqueous ophthalmic solution has a pH in the range of 4.0 to 7.5. In certain embodiments, the aqueous ophthalmic solution has a pH in the range of 4.5 to 7.5. In certain embodiments, the solution has a pH in the range of 4.5 to 6.0. In certain other embodiments, the solution has a pH in the range of 4.5 to 5.5. In yet other embodiments, the solution has a pH in the range of 4.7 to 5. 1.Additional Materials for Aqueous Ophthalmic Solutions

[0114] The aqueous ophthalmic solutions may contain additional materials in order to make the composition more suitable for administration to the eye of a patient. Exemplary additional materials are described below and include, for example, a tonicity modifier, preservative, antioxidant, viscosity modifying agent, stabilizing agent, comeal permeation enhancing agent, and surfactants.A. Tonicity Modifier

[0115] The aqueous ophthalmic solution may optionally comprise one or more tonicity modifiers. The tonicity modifier may be ionic or non-ionic. In certain embodiments, the tonicity modifier may be a salt, a carbohydrate, or a polyol. Exemplary tonicity modifiers include alkali metal or alkaline earth metal halides (such as LiBr, Lid, Lil, KBr, KCL KI, NaBr, NaCl, Nal, CaCL, and MgCL), boric acid, dextran (e.g., Dextran 70), cyclodextrin, dextrose, mannitol, glycerin, urea, sorbitol, propylene glycol, or a combination thereof.

[0116] It is appreciated that the tonicity modifier may be added to the aqueous ophthalmic solution in an amount sufficient to provide a desired osmolality. In certain embodiments, the tonicity modifier is present in the aqueous ophthalmic solution in an amount sufficient so that the aqueous ophthalmic solution has an osmolality ranging from about 50 to about 1000 mOsm / kg, from about 100 to about 400 mOsm / kg, from about 200 to about 400 mOsm / kg, or from about 280 to about 380 mOsm / kg. In certain embodiments, a tonicity modifier may be present in an amount ranging from about 0.01% (w / v) to about 7% (w / v), about 0.01% (w / v) to about 5% (w / v), about 0.01% (w / v) to about 1% (w / v), about 0.1% (w / v) to about 1% (w / v), about 0.05% (w / v) to about 5% (w / v), about 0.05% (w / v) to about 0.5% (w / v), about 1% (w / v) to about 3% (w / v), or about 2% (w / v) to about 4% (w / v), of the aqueous ophthalmic solution.3333915088 399256-OPI-030WO (214984)B. Preservative

[0117] The aqueous ophthalmic solution may optionally comprise one or more preservatives in order to, for example, reduce or prevent microbial contamination. Exemplary preservatives include quaternary ammonium salts such as polyquatemium-1, cetrimide, benzalkonium chloride, or benzoxonium chloride; alky I -mercury salts of thiosalicylic acid such as thiomersal, phenylmercuric nitrate, phenylmercuric acetate, or phenylmercuric borate; parabens such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol, phenyl ethanol, cyclohexanol, 3-pentanol, or resorcinol; a peroxide; chlorine dioxide or PURITE; guanidine derivatives such as chlorohexidine gluconate or polyaminopropyl biguanide; and combinations thereof.

[0118] The amount of preservative can be adjusted in order to achieve desired performance properties for the aqueous ophthalmic solution. In certain embodiments, the preservative is present in an amount less than about 5% (w / v), 3% (w / v), 1% (w / v), or 0.1% (w / v) of the aqueous ophthalmic solution. In certain other embodiments, the preservative is present in an amount ranging from about 0.01% (w / v) to about 5% (w / v), about 0.01% (w / v) to about 1% (w / v), about 0.1% (w / v) to about 1% (w / v), about 0.05% (w / v) to about 5% (w / v), or about 0.05% (w / v) to about 0.5% (w / v). of the aqueous ophthalmic solution.C. Antioxidant

[0119] The aqueous ophthalmic solution may optionally comprise one or more antioxidants. Exemplary antioxidants for use in the aqueous ophthalmic solutions described herein include water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium bisulfite, sodium sulfite, and the like; and oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxy toluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like.

[0120] The amount of antioxidant can be adjusted in order to achieve desired performance properties for the aqueous ophthalmic solution. In certain embodiments, the antioxidant is present in an amount less than about 5% (w / v), 3% (w / v), 1% (w / v), or 0.1% (w / v) of the aqueous ophthalmic solution. In certain other embodiments, the antioxidant is present in an amount ranging from about 0.01% (w / v) to about 5% (w / v), about 0.01% (w / v) to about 1% (w / v), about 0.1% (w / v) to about 1% (w / v). about 0.05% (w / v) to about 5% (w / v). or about 0.05% (w / v) to about 0.5% (w7v), of the aqueous ophthalmic solution.3433915088 399256-OPI-030WO (214984)Exemplary Aqueous Ophthalmic Solutions

[0121] The aqueous ophthalmic solutions having been generally described above will now be more specifically described by reference to the following more specific examples. The following more specific examples are only exemplary and are not intended to limit the scope of the invention in any way.

[0122] One such exemplary' solution is an aqueous ophthalmic solution free of a chelating agent comprising: (a) about 0.1% (w / v) to about 2% (w / v) of phentolamine mesylate; (b) about 1% (w / v) to about 6% (w / v) of at least one polyol compound selected from the group consisting of mannitol, glycerol, and propylene glycol; (c) about 1 mM to about 6 mM of an alkali metal acetate; and (d) water; wherein the solution has a pH in the range of 4 to 6 and does not contain a chelating agent.

[0123] The aqueous ophthalmic solution may be more specifically defined according to the following embodiments. For example, in certain embodiments, the aqueous ophthalmic solution comprises from about 0.25% (w / v) to about 1% (w / v) of phentolamine mesylate. In certain embodiments, the aqueous ophthalmic solution comprises from about 1% (w / v) to about 4% (w / v) mannitol. In certain other embodiments, the aqueous ophthalmic solution comprises 4% (w / v) mannitol. In certain embodiments, the alkali metal acetate is sodium acetate. In certain other embodiments, the aqueous ophthalmic solution comprises 3 mM sodium acetate. In still other embodiments, the aqueous ophthalmic solution consists of (i) about 0.25% (w / v) to about 1% (w / v) of phentolamine mesylate; (ii) about 1% (w / v) to about 6% (w / v) of one or more polyol compounds selected from the group consisting of mannitol, glycerol, and propylene glycol; (iii) about 1 mM to about 6 mM of an alkali metal acetate; (iv) acetic acid; and (v) water; wherein the solution has a pH in the range of 4 to 6.

[0124] Another such exemplary solution is an aqueous ophthalmic solution free of a chelating agent comprising: (a) about 0.5% (w / v) to about 2% (w / v) of phentolamine mesylate; (b) about 1% (w / v) to about 6% (w / v) of at least one polyol compound selected from the group consisting of is mannitol, glycerol, and propylene glycol; (c) about 1 mM to about 6 mM of an alkali metal acetate; and (d) water; wherein the solution has a pH in the range of 4.5 to 5.5 and does not contain a chelating agent.

[0125] The aqueous ophthalmic solution may be more specifically defined according to the following embodiments. For example, in certain embodiments, the aqueous ophthalmic solution comprises from about 1% (w / v) to about 4% (w / v) mannitol. In certain other embodiments, the aqueous ophthalmic solution comprises 4% (w / v) mannitol. In certain3533915088 399256-OPI-030WO (214984)embodiments, the alkali metal acetate is sodium acetate. In certain other embodiments, the aqueous ophthalmic solution comprises 3 mM sodium acetate. In still other embodiments, the aqueous ophthalmic solution consists of (i) about 0.5% (w / v) to about 2% (w / v) of phentolamine mesylate; (ii) about 1% (w / v) to about 6% (w / v) of one or more polyol compounds selected from the group consisting of mannitol, glycerol, and propylene glycol;(iii) about 1 mM to about 6 mM of an alkali metal acetate; (iv) acetic acid; and (v) water; wherein the solution has a pH in the range of 4.5 to 5.5.

[0126] Another such exemplary solution is an aqueous ophthalmic solution free of a chelating agent comprising: (a) about 0.25% (w / v) to about 2% (w / v) of phentolamine mesylate; (b) about 1% (w / v) to about 6% (w / v) of at least one polyol compound selected from the group consisting of mannitol, glycerol, and propylene glycol; (c) about 1 mM to about 6 mM of an alkali metal acetate; and (d) water; wherein the solution has a pH in the range of 4.5 to 5.5 and does not contain a chelating agent.

[0127] The aqueous ophthalmic solution may be more specifically defined according to the following embodiments. For example, in certain embodiments, the aqueous ophthalmic solution comprises from about 0.25% (w / v) to about 1% (w / v) of phentolamine mesylate. In certain other embodiments, the aqueous ophthalmic solution comprises from about 1% (w / v) to about 4% (w / v) mannitol. In certain other embodiments, the aqueous ophthalmic solution comprises 4% (w / v) mannitol. In certain embodiments, the alkali metal acetate is sodium acetate. In certain other embodiments, the aqueous ophthalmic solution comprises 3 mM sodium acetate. In still other embodiments, the aqueous ophthalmic solution consists of (i) about 0.5% (w / v) to about 1% (w / v) of phentolamine mesylate; (ii) about 1% (w / v) to about 6% (w / v) of one or more polyol compounds selected from the group consisting of mannitol, glycerol, and propylene glycol; (iii) about 1 mM to about 6 mM of an alkali metal acetate;(iv) acetic acid; and (v) water; wherein the solution has a pH in the range of 4.5 to 5.5.

[0128] Another exemplary aqueous ophthalmic solution comprises phentolamine mesylate (e.g., at 1% w / v), mannitol (e.g., at 4% w / v), sodium acetate (e.g., at 3 mM). and water, wherein the solution has a pH in the range of about 4 to about 6. In certain embodiments, the solution has a pH in the range of 4.5 to 5. 1. In certain embodiments, the aqueous ophthalmic solution consists essentially of phentolamine mesylate (e.g., at 1% w / v), mannitol (e.g., at 4% w / v), sodium acetate (e.g., at 3 mM), and water, wherein the solution has a pH in the range of 4 to 6. In certain embodiments, the aqueous ophthalmic solution comprises phentolamine mesylate at 1% w / v, mannitol 4% w / v, sodium acetate at 3 mM, and water, wherein the3633915088 399256-OPI-030WO (214984)solution has a pH in the range of 4.5 to 5. 1. In certain other embodiments, the aqueous ophthalmic solution consists of phentolamine mesylate (e g., at 1% w / v), mannitol (e g., at 4% w / v), sodium acetate (e.g., at 3 mM), and water, wherein the solution has a pH in the range of 4.5 to 5. 1. In certain embodiments, the aqueous ophthalmic solution consists essentially of phentolamine mesylate at 1% w / v, mannitol 4% w / v. sodium acetate at 3 mM. and water, wherein the solution has a pH in the range of 4.5 to 5.1 .

[0129] Yet another exemplary solution is an aqueous ophthalmic solution free of a chelating agent that comprises: (a) about 0.1% (w / v) to about 2% (w / v) of phentolamine mesylate; (b) about 1% (w / v) to about 6% (w / v) of at least one polyol compound selected from the group consisting of mannitol, glycerol, and propylene glycol; (c) about 1 mM to about 6 mM of an alkali metal acetate; and (d) water; wherein the solution has a pH in the range of 4 to 6 and does not contain a chelating agent.

[0130] Yet another exemplary solution is an aqueous ophthalmic solution free of a chelating agent that comprises: (a) about 0.25% (w / v) to about 2% (w / v) of phentolamine mesylate; (b) about 3% (w / v) to about 5% (w / v) of mannitol; (c) about 2 mM to about 4 mM of sodium acetate; and (d) water; wherein the solution has a pH in the range of 4.6 to 5.2 and does not contain a chelating agent.

[0131] Yet another exemplary solution is an aqueous ophthalmic solution free of a chelating agent that comprises: (a) about 0. 1% (w / v) to about 2% (w / v) of phentolamine mesylate; (b) about 3% (w / v) to about 5% (w / v) of mannitol; (c) about 2 mM to about 4 mM of sodium acetate; and (d) water; wherein the solution has a pH in the range of 4.6 to 5.2 and does not contain a chelating agent. In certain embodiments, the aqueous ophthalmic solution free of a chelating agent that comprises about 0.25% (w / v) to about 1% (w / v) of phentolamine mesylate.

[0132] Yet another exemplary solution is an aqueous ophthalmic solution free of a chelating agent, comprising: (a) about 0.25% (w / v) to about 2% (w / v) of phentolamine mesylate; (b) about 3% (w / v) to about 5% (w / v) of mannitol; (c) about 2 mM to about 4 mM of sodium acetate; and (d) water; wherein the solution has a pH in the range of 4.5 to 5.2 and does not contain a chelating agent.

[0133] Yet another exemplary solution is an aqueous ophthalmic solution free of a chelating agent that comprises: (a) about 0.5% (w / v) to about 2% (w / v) of phentolamine mesylate; (b) about 3% (w / v) to about 5% (w / v) of mannitol; (c) about 2 mM to about 4 mM of3733915088 399256-OPI-030WO (214984)sodium acetate; and (d) water; wherein the solution has a pH in the range of 4.6 to 5.2 and does not contain a chelating agent.

[0134] Yet another exemplary solution is an aqueous ophthalmic solution free of a chelating agent that comprises: (a) about 0.5% (w / v) to about 1% (w / v) of phentolamine mesylate; (b) about 3% (w / v) to about 5% (w / v) of mannitol; (c) about 1 mM to about 4 mM of sodium acetate; and (d) water; wherein the solution has a pH in the range of 4.6 to 5.2 and does not contain a chelating agent.

[0135] Yet another exemplary solution is an aqueous ophthalmic solution free of a chelating agent, comprising: (a) about 0.1% (w / v) to about 1% (w / v) of phentolamine mesylate; (b) about 4% mannitol; (c) about 3 mM sodium acetate; and (d) water; wherein the solution has a pH in the range of 4.6 to 5.2 and does not contain a chelating agent. In certain embodiments, another exemplary solution is an aqueous ophthalmic solution free of a chelating agent that comprises about 0.25% (w / v) to about 1% (w / v) of phentolamine mesylate.

[0136] Yet another exemplary solution is an aqueous ophthalmic solution free of a chelating agent, comprising: (a) about 0.5% (w / v) to about 1% (w / v) of phentolamine mesylate; (b) about 4% mannitol; (c) about 3 mM sodium acetate; and (d) water; wherein the solution has a pH in the range of 4.6 to 5.2 and does not contain a chelating agent.EXAMPLES

[0137] The invention now being generally described, will be more readily understood by reference to the following examples, which are included merely for purposes of illustrating certain aspects and embodiments of the present invention, and are not intended to limit the invention.EXAMPLE 1

[0138] A clinical study was performed in which phentolamine mesylate was administered to eyes of human subjects suffering from decreased visual performance under mesopic light conditions. Experimental procedures and results are described below.Part I - Experimental Procedures

[0139] One-hundred and forty-five human subjects suffering from decreased visual performance under mesopic light conditions were enrolled in the study. Subjects in the study satisfied the inclusion criteria set forth below. Subjects were randomized 1 : 1 to receive placebo or one eye drop of 1.0% (w / v) phentolamine mesylate ophthalmic solution once daily at or near bedtime for 14 days. The 1.0% (w / v) phentolamine mesylate ophthalmic contained:3833915088 399256-OPI-030WO (214984)1% (w / v) phentolamine mesylate, 4% (w / v) mannitol, 3 mM sodium acetate, and water. The placebo was a solution containing 4% (w / v) mannitol, 3 mM sodium acetate, and water. Subjects were evaluated for mesopic low contrast visual acuity on day 8 and 15 of the study.

[0140] Of the 145 subjects enrolled in the study, 25 subjects had previously undergone keratorefractive surgery.

[0141] Subjects in the study satisfied the following inclusion criteria: (1) male or female > 18 years of age; (2) subject-reported dim-light vision disturbance (likely subjects with a history of multifocal IOLS, post-laser-assisted in situ keratomileusis [LASIK]. comeal scars, and keratoconus), (3) ability to comply with all protocol-mandated procedures independently, (4) otherwise healthy and a well-controlled subject, (5) able and willing to give written consent to participate in this study, (6) able to self-administer study medication, (7) pupil diameter > 5 mm under mesopic conditions (prior to illumination) in at least one eye, (8) mesopic low contrast visual acuity score of < 30 ETDRS letters (20 / 63 Snellen or worse) in monocular mesopic low-contrast best-corrected distance visual acuity (rnLCVA) at baseline in at least one eye, and (9) >10-letter improvement in rnLCVA in response to consensual pupillary' constriction by illumination of the fellow eye using a Brightness Acuity Tester (BAT).

[0142] Subjects enrolled in the study did not have any of the following exclusion criteria: (1) prior history of dry eye diagnosis, taking prescription drops for dry eye, or taking artificial tear drops occasionally for dry eye; (2) prior history of fluctuating vision; (3) clinically significant ocular disease as deemed by the Investigator that might interfere with the study; (4) known hypersensitivity to any topical alpha-adrenoceptor antagonists; (5) known allergy or contraindication to any component of the vehicle formulation; (6) history of cauterization of the punctum or punctal plug (silicone or collagen) insertion or removal; (7) ocular trauma, ocular surgery (e.g., IOLs) or laser procedure (e.g., LASIK, photorefractive keratectomy [PRK]) within 6 months prior to screening; (8) use of any topical prescription or over-the-counter (OTC) ophthalmic medications of any kind within 7 days of screening; (9) recent or current evidence of ocular infection or inflammation in either eye (where subjects must be symptom free for at least 7 days); (10) history of diabetic retinopathy, diabetic macular edema, or dry or wet macular degeneration; (11) history of any traumatic (surgical or nonsurgical) or nontraumatic condition affecting the pupil or iris; (12) unwilling or unable to discontinue use of contact lenses at screening until study completion, except for keratoconus subjects who maywear contacts up to 24 hours prior to their scheduled visits; (13) known hypersensitivity or contraindication to alpha- and / or beta-adrenoceptor antagonists; (14) clinically significant3933915088 399256-OPI-030WO (214984)systemic disease that might interfere with the study; (15) initiation of treatment with or any changes to the current dosage, drug, or regimen of any systemic adrenergic or cholinergic drugs within 7 days prior to screening or during the study; (16) participation in any investigational study within 30 days prior to screening and during the conduct of the study; (17) females of childbearing potential who are pregnant, nursing, planning a pregnancy, or not using a medically acceptable form of birth control; (18) resting heart rate outside the specified range (50-110 beats per minute); and (19) hypertension with resting diastolic blood pressure > 105 mmHg or systolic blood pressure > 160 mmHg.

[0143] Demographic characteristics for 143 subjects randomized in the study are shown in the following table.4033915088 399256-OPI-030WO (214984)A - 55 letters = 20 / 20 Snellen acuityB - 70 letters = 20 / 20 Snellen acuity pLCVA = photopic low-contrast visual acuity

[0144] The primary efficacy endpoint was percentage of subjects with > 15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (>3 lines) of improvement in the study eye compared to baseline in monocular mesopic low contrast visual acuity at Day 8.Additional outcome measures of the study are:(a) Percent of subjects with > 5, > 10, and > 15 ETDRS letters (> 1, > 2, and > 3 lines, respectively) improvement compared to baseline in mesopic low contrast visual acuity at Day 8 (excluding the primary endpoint);(b) Percent of subjects with > 5, > 10, and > 15 ETDRS letters (> 1, > 2, and > 3 lines, respectively) improvement compared to baseline in Photopic Low Contrast Visual Acuity and mesopic high contrast visual acuity at Day 8 and Day 15;(c) Change from baseline in study eye mesopic pupil diameter; and(d) Percent change from baseline in study eye mesopic pupil diameter.Part II - Results

[0145] In the cohort of 143 subjects that completed the 14 day course of treatment using either placebo or 1.0% (w / v) phentolamine mesylate ophthalmic solution, a 3-line improvement in mesopic low contrast visual acuity was observed at Day 15 for 21% (14 / 68) of subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution, whereas 3-line improvement in mesopic low contrast visual acuity was observed at Day 15 for only 3% (2 / 73) of subjects that received placebo. At Day 8, a gain of 15 or more ETDRS letters of mesopic low contrast distance visual acuity was observed for 13% of subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution, whereas a gain of 15 or more ETDRS letters of mesopic low contrast distance visual acuity was observed for only 3% of subjects that received placebo. Patient-reported outcomes were significantly more favorable in the following categories for subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution compared to4133915088 399256-OPI-030WO (214984)subjects that received placebo: (a) severity of dim light disturbance, (b) glare, (c) halos, and (d) starbursts. Additionally, subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution had a clinically meaningful 10 letter (2 -line) improvement in mesopic low contrast visual acuity at Day 8 and at Day 15 compared to placebo.

[0146] Treatment with 1.0% (w / v) phentolamine mesylate ophthalmic solution also significantly increased the percentage of subjects gaining > 10 letters of mLCVA at Day 8 compared to placebo (41% for subjects receiving 1.0% (w / v) phentolamine mesylate ophthalmic solution vs. 22% for subjects receiving placebo; p<0.05) and at Day 15 (44% for subjects receiving 1.0% (w / v) phentolamine mesylate ophthalmic solution vs. 23% for subject receiving placebo; p<0.05). Subjects treated with 1.0% (w / v) phentolamine mesylate ophthalmic solution also had a significantly greater increase in mean mLCVA from baseline compared with the placebo group at Day 8 (2.5 letters; p<0.0l) and at Day 15 (3.0 letters; ?<0.001). No significant difference between the subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution versus placebo was observed in the percentage of subjects with > 15 or > 10 letters improvement from baseline in mHCVA at either Day 8 or Day 15.

[0147] Efficacy analyses were conducted on the modified intent-to-treat (mITT) population, defined as all randomized participants who received at least one dose of study medication and had at least one post-baseline efficacy assessment. The per-protocol (PP) population included those without major protocol deviations. Only 2 subjects, both in the POS group, were excluded from the PP population. One withdrew voluntarily due to time constraints not allowing the subject to complete the study, and one discontinued due to mild adverse events (allergic dermatitis of eyelid). Safety analyses included all participants who received at least one dose of study drug.

[0148] Improvement in mean low-contrast visual acuity in study eyes under photopic conditions due to phentolamine mesylate ophthalmic solution was also observed. In study eyes of the per protocol (PP) Population, mean (SD) pLCVA at baseline was 34. 1 (8.42) letters in the group that received phentolamine mesylate ophthalmic solution and 33.8 (10.25) letters in the group that received placebo. At Day 8, the LS mean (SE) change from baseline in study eyes was 5.1 (0.58) letters for the group that received phentolamine mesylate ophthalmic solution and 2.2 (0.56) letters for the group that received placebo, (LS mean difference [95% CI], 3.0 [1 .37, 4.52] letters; p=0.0003). A significantly greater mean change in pLCVA in the group that received phentolamine mesylate ophthalmic solution compared with the group that4233915088 399256-OPI-030WO (214984)received placebo was also observed at Day 15 (LS mean difference [95% Cl], 4.3 [2.58, 5.92] letters; ><0.0001).

[0149] Eyes treated with phentolamine mesylate ophthalmic solution had a significant, though moderate, reduction in pupil diameter. In study eyes mean (SD) mesopic pupil diameter at baseline was 6. 1 (0.76) mm in the group to receive phentolamine mesylate ophthalmic solution and 6. 1 (0.78) mm in the group to receive placebo. At Day 8, the LS mean (SE) change from baseline among study eyes was -1.1 (0.08) mm for group that received phentolamine mesylate ophthalmic solution and -0. 1 (0.08) mm for the group that received placebo, representing a statistically significant reduction in mesopic pupil diameter in the group that received phentolamine mesylate ophthalmic solution (LS mean difference [95% CI], -1.0 [- 1.16, -0.74] mm; ><0.0001). A significant reduction in mesopic pupil diameter in the group that received phentolamine mesylate ophthalmic solution compared with the group that received placebo was also observed at Day 15 (LS mean difference [95% CI], -1.0 [-1.15, - 0.77] mm; / ?<0.()()() l ). Treatment with phentolamine mesylate ophthalmic solution significantly increased the percentage of subjects with pupil diameter in mesopic conditions <6mm, <5mm, and <4mm compared to placebo. These pupil diameter results are presented graphically in Figures 9 and 10.

[0150] Wavefront aberrometry was obtained on a subset of subjects in this study. A representative subject shows a reduction in higher-order aberrations with a reduction in pupil diameter from 5.08 mm to 3.98 mm after 14 days of phentolamine mesylate ophthalmic solution treatment (see Figure 11). Notably, mLCVA increased from 19 letters at baseline to 30 letters at Day 15, accompanied by a subjective decrease in glare.

[0151] In a population defined by 68 subjects enrolled in the study that received 1.0% (w / v) phentolamine mesylate ophthalmic solution and 73 subjects enrolled in the study that received placebo, the following results demonstrate the exemplars ■ significant benefits of the 1.0% (w / v) phentolamine mesylate ophthalmic solution relative to placebo:(A)At day 15: 22% of subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution reported at least a two-grade reduction in the severity of glare at night compared to only 4% of subjects that received placebo reporting at least a two- grade reduction in the severity of glare at night.(B) At day 15: 21% of subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution reported at least a two-grade reduction in the severity of halos at night4333915088 399256-OPI-030WO (214984)compared to only 3% of subjects that received placebo reporting at least a two-grade reduction in the severity of halos at night.(C) At day 15: 25% of subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution reported at least a two-grade reduction in the severity of starbursts at night compared to 0% of subjects that received placebo reporting at least a two-grade reduction in the severity of starbursts at night.(D) Subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution reported significantly reduced severity of dim light vision disturbance (DLD) at day 8 and day 15 relative to subjects that received placebo. At day 15, subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution had a mean severity of DLD score of 3.3, whereas subjects that received placebo had a mean severity of DLD score of 4.3, indicating that the severity of DLD in the placebo group was greater than the severity of DLD in the group that received 1.0% (w / v) phentolamine mesylate ophthalmic solution. At day 8, subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution had a mean severity of DLD score of 4.3, whereas subjects that received placebo had a mean severity of DLD score of 4.6, indicating that the severity of DLD in the placebo group was greater than the severity of DLD in the group that received 1.0% (w / v) phentolamine mesylate ophthalmic solution. At baseline (i.e., time 0 days), subjects in the 1.0% (w / v) phentolamine mesylate ophthalmic solution group had a mean severity of DLD score of 5.0, whereas subjects that received placebo had a mean severity of DLD score of 4.8.(E) At day 15: 47% of subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution reported at least a two-grade reduction in the overall severity of dim light disturbance in their vision compared to only 15% of subjects that received placebo reporting at least a tw o-grade reduction in the overall severity of dim light disturbance in their vision

[0152] Results showing mean severity rating of severity of photic complaints (0 to 3 scale) on Day 15 as a function of treatment group are presented in Figure 12. The results demonstrate that subjects treated with phentolamine mesylate ophthalmic solution rated glare, halos, and starburst (0-3 scale) significantly lower compared with subjects in the placebo group at Day 15.

[0153] Subjects treated with phentolamine mesylate ophthalmic solution also rated overall severity of dim light disturbances (DLD) (on a scale of 1-7) significantly lower compared w ith subjects in the placebo group at Day 8 (4.3 for subjects treated with phentolamine mesylate4433915088 399256-OPI-030WO (214984)ophthalmic solution vs 4.6 for subjects treated with placebo, respectively; p< 0.01) and at Day 15 (3.3 for subjects treated with phentolamine mesylate ophthalmic solution vs 4.3 for subjects treated with placebo, respectively; O.OOO l ).

[0154] Additionally, results from the clinical study showed that the percentage of subjects with severe night vision difficulties (level 5-7) was reduced by 45% in subjects treated with 1.0% (w / v) phentolamine mesylate ophthalmic solution. More specifically, starting from baseline where 70% of subjects (in the group to receive 1.0% (w / v) phentolamine mesylate ophthalmic solution) reported severe night vision difficulties (level 5-7), the percentage of subjects reporting severe night vision difficulties (level 5-7) was only 25% at day 15 in the group treated with 1.0% (w / v) phentolamine mesylate ophthalmic solution. By contrast for the group of subjects receiving placebo, the percentage of subjects with severe night vision difficulties (level 5-7) was reduced by only 1 % in subjects that received placebo at day 15. That is, in the placebo group, starting from baseline where 58% of subjects (in the group to receive placebo) reported severe night vision difficulties (level 5-7), the percentage of subjects reporting severe night vision difficulties (level 5-7) was 42% at day 15 in the group that received placebo. This demonstrates that treating subjects with 1.0% (w / v) phentolamine mesylate ophthalmic solution reduces the occurrence of severe night vision difficulties.

[0155] Use of the phentolamine mesylate ophthalmic solution demonstrated a favorable safety and tolerability profile in this study. Over 14 days of daily treatment with the phentolamine mesylate ophthalmic solution only 32% of subjects reported any treatment emergent adverse events (TEAEs) compared to 16% of placebo treated subjects. The most common treatment-related TEAEs were instillation site pain (13%), dysgeusia (11%), conjunctival hyperemia (9%), and instillation site erythema (9%). These events were predominantly mild and transient. There were no serious adverse events reported, or any TEAEs leading to withdrawal from the study. Notably, there were no adverse events of floaters, retinal tears, or retinal detachments. No systemic effects of phentolamine mesylate ophthalmic solution on systolic or diastolic blood pressure or heart rate were observed in this study. There was no increase in intraocular pressure with the use of phentolamine mesylate ophthalmic solution. No subject treated with phentolamine mesylate ophthalmic solution lost >l-line of mLCVA in the study eye.

[0156] In the cohort of 25 subjects that had previously undergone keratorefractive surgery and completed the 14 day course of treatment using either placebo or 1.0% (w / v) phentolamine mesylate ophthalmic solution, a 3-line improvement in mesopic low contrast visual acuity was4533915088 399256-OPI-030WO (214984)observed at Day 15 for 21% (3 / 14) of subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution, whereas a 3-line improvement in mesopic low contrast visual acuity was not observed at Day 15 for any of the subjects (0 / 11) that received placebo. In the cohort of 25 subjects that had previously undergone keratorefractive surgery' and completed the 14 day course of treatment using either placebo or 1.0% (w / v) phentolamine mesylate ophthalmic solution, a 3-line improvement in mesopic low contrast visual acuity was observed at Day 8 for 29% (4 / 14) of subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution, whereas a 3-line improvement in mesopic low contrast visual acuity was observed at Day 8 for 9% (1 / 11) of subjects that received placebo. Additionally, subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution had a reduced number of photopic complaints.

[0157] In the cohort of subjects participating in the study that had previously undergone keratorefractive surgery, the mean improvement in mesopic low contrast visual acuity score at Day 15 was 10.1 letters in subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution, whereas the mean improvement in mesopic low contrast visual acuity' score at Day 15 was only 5.1 letters in subjects that received placebo. There was a statistically significant reduction in occurrence of halos (p=0.02) and starburst (p=0.03) in subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution, compared to the occurrence of such vision disturbances in subjects that received placebo during the study. Moreover, in the cohort of 25 subjects that had previously undergone keratorefractive surgery’ and completed the 14 day course of treatment using either placebo or 1.0% (w / v) phentolamine mesylate ophthalmic solution, the following results demonstrate the exemplary' significant benefits of the 1.0% (w / v) phentolamine mesylate ophthalmic solution relative to placebo:(A) At day 15: 31% of subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution reported at least a two-grade reduction in the severity' of glare at night compared to only 9% of subjects that received placebo reporting at least a two-grade reduction in the severity of glare at night.(B) At day 15: 38% of subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution reported at least a two-grade reduction in the severity of halos at night compared to 0% of subjects that received placebo reporting at least a two-grade reduction in the severity of halos at night.(C) At day 15: 38% of subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution reported at least a two-grade reduction in the severity' of starbursts at night4633915088 399256-OPI-030WO (214984)compared to 0% of subjects that received placebo reporting at least a two-grade reduction in the severity of starbursts at night.(D) At day 15: 69% of subjects that received 1.0% (w / v) phentol amine mesylate ophthalmic solution reported at least a two-grade reduction in the overall severity of dim light disturbance in their vision compared to only 18% of subjects that received placebo reporting at least a two-grade reduction in the overall severity of dim light disturbance in their vision.

[0158] In the cohort of subjects participating in the study that had previously undergone keratorefractive surgery, the binocular change from baseline mesopic low contrast visual acuity (letters read) at Day 15 was 8.91 letters in subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution, whereas for subjects that received placebo the binocular change from baseline mesopic low contrast visual acuity (letters read) at Day 15 was 3.61 letters. With regards to pupil diameter under mesopic conditions, for the cohort of subjects participating in the study that had previously undergone keratorefractive surgery, mean pupil diameter under mesopic conditions was 4.87 mm at day 15 in subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution, whereas mean pupil diameter under mesopic conditions was 6. 15 mm in subjects that received placebo.EXAMPLE 2

[0159] A clinical study will be performed in which phentolamine mesylate will be administered to eyes of human subjects who have previously undergone keratorefractive surgery and suffer from decreased visual performance under mesopic light conditions. Experimental procedures are described below.Part I - Experimental Procedures

[0160] Human subjects who have previously undergone keratorefractive surgery and suffer from decreased visual performance under mesopic light conditions are to be enrolled in the study, which may be two hundred human subjects who have previously undergone keratorefractive surgery and suffer from decreased visual performance under mesopic light conditions. Subjects in the study satisfy the inclusion criteria set forth below. The study shall proceed in two stages: a first stage lasting approximately 6 weeks, and an optional second stage lasting up to 42 additional weeks. Subjects are stratified by iris color (light vs. dark irides) and randomized 1 : 1 to receive one eye drop of placebo or one eye drop of 1.0% (w / v) phentolamine mesylate ophthalmic solution once daily at or near bedtime for the length of the4733915088 399256-OPI-030WO (214984)study. The 1.0% (w / v) phentolamine mesylate ophthalmic contains: 1% (w / v) phentolamine mesylate, 4% (w / v) mannitol, 3 mM sodium acetate, and water. The placebo is a solution containing 4% (w / v) mannitol, 3 mM sodium acetate, and water. Subjects are evaluated for visual acuity (including mesopic low contrast visual acuity (mLCVA) and mesopic high contrast visual acuity (mHCVA)). pupil diameter, and responses to a vision and night driving questionnaire (VND-Q) containing 9 items. The evaluations are conducted at screening: on days 3, 8, 15, and 6 weeks of the first stage of the study; and in the second stage of the study on weeks 12, 18, 24, 30, 36, 42, and 48 (counting from day 1 of the first stage).

[0161] Subjects in the study satisfy the following inclusion criteria: (1) male or female > 18 years of age; (2) have undergone keratorefractive surgery (e.g., laser-assisted in situ keratomileusis [LASIK], photorefractive keratectomy [PRK], small-incision lenticule extraction [SMITE], radial keratotomy [RK], etc.) and have subject-reported dim-light vision disturbance (e.g., glare, halos, and / or starbursts) first noted within two months following the refractive surgery, (3) able to comply with all protocol-mandated procedures independently, (4) able and willing to give written consent to participate in this study. (5) able to self-administer study medication. Subjects in the study also satisfied the following inclusion criteria, all in the same eye: (6) pupil diameter > 5 mm under mesopic conditions (prior to illumination) in at least one eye, and (7) mLCVA score of < 30 ETDRS letters (20 / 63 Snellen, or worse) in at least one eye, and (8) mLCVA improvement of >10 ETDRS letters in at least one eye during illumination of the contralateral eye.

[0162] Subjects enrolled in the study shall not have any of the following exclusion criteria (in either eye, where appropriate): (1) prior history of dry eye diagnosis, taking prescription drops for dry eye, or taking artificial tear drops routinely for dry eye; (2) prior history of fluctuating vision; (3) clinically significant ocular disease as deemed by the Investigator that might interfere with the study; (4) history of comeal endothelial dystrophy; (5) known hypersensitivity to any topical alpha-adrenoceptor antagonists; (6) known allergy or contraindication to any component of the vehicle formulation; (7) history of cauterization of the punctum or punctal plug (silicone or collagen) insertion or removal; (8) pseudophakic subjects with extended depth-of-focus or multifocal lOL’s; (9) ocular trauma, ocular surgery (e.g., IOLS) or laser procedure (e.g., LASIK, photorefractive keratectomy [PRK]) within 6 months prior to screening; (10) use of any topical prescription or over-the-counter (OTC) ophthalmic medications of any kind within 7 days of screening; (11) recent or current evidence of ocular infection or inflammation in either eye (where subjects must be symptom free for at least 7 days); (12) history of diabetic retinopathy, diabetic macular edema, or dry or wet macular4833915088 399256-OPI-030WO (214984)degeneration; (13) history of any traumatic (surgical or nonsurgical) or nontraumatic condition affecting the pupil or iris; (14) unwilling or unable to discontinue use of contact lenses at least 1 hour prior to screening for soft contact lenses or at least 8 hours prior to screening for hard gas-permeable contact lenses, and at least 8 hours (for both ty pes of lenses) prior to all other office visits; (15) previously undiagnosed dry eye, at the determination of the Investigator; (16) known hypersensitivity or contraindication to alpha- and / or beta-adrenoceptor antagonists; (17) clinically significant systemic disease that might interfere with the study; (18) initiation of treatment with, or any changes to, the current dosage, drug, or regimen of any systemic adrenergic or cholinergic drugs within 7 days prior to screening or during the study; (19) participation in any investigational study within 30 days prior to screening and during the conduct of the study; (20) females of childbearing potential who are pregnant, nursing, planning a pregnancy, or not using a medically acceptable form of birth control; (21) resting heart rate outside the specified range (50-110 beats per minute); and (22) hypertension with resting diastolic blood pressure > 105 mmHg or systolic blood pressure > 160 mmHg.

[0163] The primary efficacy endpoint is percentage of subjects with > 15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (>3 lines) of improvement in the study eye compared to baseline in monocular mLCVA at Day 15. (The study eye is designated as the eye with worse mLCVA at screening. If both eyes have the same mLCVA, the right eye is designated as the study eye.)

[0164] Additional outcome measures of the study include (for the study eye, the non-study eye, the best of either eye, and binocular):(a) Percent of subjects with > 10 and > 15 ETDRS letters (> 2 and > 3 lines, respectively) improvement compared to baseline in mLCVA at Days 3, 8. 15, and Week 6 (excluding the primary endpoint);(b) Mean and change from baseline (Day 1, pre-dose) mLCVA at 0.5, 1, and 3 hours post-dose on Day 1 ;(c) Percent of subjects with > 10 and > 15 ETDRS letters (> 2 and > 3 lines, respectively) improvement compared to baseline in mesopic high contrast visual acuity (mHCVA) at Days 3, 8, 15, and Week 6;(d) Mean and change from baseline mLCVA and mHCVA at Days 3, 8, 15, and Week 6;(e) Mean and change from baseline in study eye pupil diameter at Days 3, 8, 15, and Week 6; and(f) Mean and change from baseline in subject questionnaire responses at Days 3, 8, 15, and Week 6.4933915088 399256-OPI-030WO (214984)Part II - Results

[0165] At screening, 197 subjects enrolled in the study with reduced mesopic vision and photic complaints were administered a vision and night driving questionnaire (VND-Q) containing nine items. In this group, 141 of 197 (71%) participants reported “a lot of difficulty” or “severe difficulty” on at least one item in the VND-Q. Items with the highest incidence of difficulty were “seeing the road at night in poor weather” (59%), “seeing the road because of oncoming headlights” (46%), and “seeing the road because of glare at dawn or dusk” (37%). The item of “adjusting after passing headlights from oncoming cars when driving at night” also received a significant number of affirmative responses. Higher VND-Q scores are significantly associated with poor night driving performance on a closed-road circuit.EXAMPLE 3

[0166] A clinical study was performed in which phentolamine mesy late was administered to eyes of human subjects who have previously undergone keratorefractive surgery and suffer from decreased visual performance under mesopic light conditions. Experimental procedures and results are described below.Part I - Experimental Procedures

[0167] Two-hundred human subjects who have previously undergone keratorefractive surgery and suffer from decreased visual performance under mesopic light conditions were enrolled in the study. Subjects in the study satisfy the inclusion criteria set forth below. Subjects enrolled in the study were permitted to participate in two stages of the study: a first stage lasting approximately 6 weeks, and an optional second stage lasting up to 42 additional weeks. Subjects are stratified by iris color (light vs. dark irides) and randomized 1: 1 to receive one eye drop of placebo or one eye drop of 1.0% (w / v) phentolamine mesylate ophthalmic solution once daily in the evening near bedtime for the length of the study. The test article (either placebo or 1.0% (w / v) phentolamine mesylate ophthalmic solution) was administered to both eyes of subject each day of the study. The 1.0% (w / v) phentolamine mesylate ophthalmic solution contains: 1% (w / v) phentolamine mesylate, 4% (w / v) mannitol, 3 mM sodium acetate, and water, wherein the ophthalmic solution has a pH in the range of 4.5 to 5.3. The placebo is a solution containing 4% (w / v) mannitol, 3 mM sodium acetate, and water, wherein the solution has a pH in the range of 4.5 to 5.3.

[0168] The first dose of study medication will be administered at the study site by site staff at the Baseline Visit / Day 1 and mLCVA assessments will be made at 0.5, 1, and 3 hours post-5033915088 399256-OPI-030WO (214984)dose. In this study, subjects are evaluated for visual acuity (including mesopic low contrast visual acuity (mLCVA) and mesopic high contrast visual acuity (mHCVA)), pupil diameter, and responses to a vision and night driving questionnaire (VND-Q) containing 9 items. The vision and night driving questionnaire (VND-Q) containing 9 items is a validated metric reported by Kimlin JA, Black AA, DjajaN & Wood JM. in "Development and validation of a vision and night driving questionnaire,” Ophthalmic Physiol. Opt. (2016) vol. 36, pages 465- 476. Items in the vision and night driving questionnaire (VND-Q) are scored on a range of 1 to 5, where a score of 1 indicates "no difficulty ,” a score of 2 indicates “a little difficulty,” a score of 3 indicates "‘moderate difficulty’,” a score of four indicates “a lot of difficulty.” and a score of 5 indicates “extreme difficulty'.” The nine items on the vision and night driving questionnaire (VND-Q) are:1. Seeing dark coloured cars when driving at night.2. Seeing pedestrians or animals on the roadside when driving at night.3. Reading street signs when driving at night.4. Seeing the road because of oncoming headlights when driving at night.5. Seeing because of glare when driving at dawn or dusk.6. Adjusting after passing headlights from oncoming cars when driving at night.7. Judging the distance to your turnoff or exit while driving at night.8. Judging the distance between you and another moving cars when driving at night.9. Seeing the road in rain or poor weather when driving at night.Evaluations are conducted at screening; on days 3, 8, 15, and 6 weeks of the first stage of the study; and in the second stage of the study on weeks 12, 18, 24, 30, 36, 42, and 48 (counting from day 1 of the first stage). Subjects were to have five office visits in Stage 1 of the study: Day 1 (Screening / Baseline) / Visit 1, Day 3 / Visit 2, Day 8 / Visit 3, Day 15 / Visit 4 (primary' endpoint), and Week 6 (End of Stage 1 ) / Visit 5. In the optional Stage 2 of the study, subjects were to have seven office visits: visit 6 (week 12 (+ 3 days), visit 7 (week 18 (+ 3 days), visit 8 (week 24 (+ 3 days), visit 9 (week 30 (+ 3 days), visit 10 (week 36 (+ 3 days), visit 11 (week 42 (+ 3 days), and visit 12 (week 48 (+ 3 days).

[0169] Subjects in the study satisfied the following inclusion criteria: (1) male or female > 18 years of age; (2) have undergone refractive surgery (e g., laser-assisted in situ keratomileusis [LASIK], photorefractive keratectomy [PRK], small-incision lenticule extraction [SMILE], radial keratotomy [RK], etc.) and have subject-reported dim-light vision disturbance (e g.,5133915088 399256-OPI-030WO (214984)glare, halos, and / or starbursts) first noted within two months following the refractive surgery, (3) able to comply with all protocol -mandated procedures independently, (4) able and willing to give written consent to participate in this study, and (5) able to self-administer study medication. Subjects in the study also satisfied the following inclusion criteria, all in the same eye: (6) pupil diameter > 5 mm under mesopic conditions (prior to illumination) in at least one eye, and (7) mLCVA score of < 30 ETDRS letters (20 / 63 Snellen, or worse) in at least one eye, and (8) mLCVA improvement of >10 ETDRS letters in at least one eye during illumination of the contralateral eye. The mLCVA score of < 30 ETDRS letters (20 / 63 Snellen, or worse) in at least one eye may be determined using a Precision Vision Illuminator Cabinet with 5% translucent contrast chart and a mesopic fdter at 4 meters. The mLCVA improvement of >10 ETDRS letters in at least one eye during illumination of the contralateral eye may be determined using a Brightness Acuity Tester (BAT) system on the low setting using the Precision Vision Illuminator Cabinet with 5% translucent contrast chart and a mesopic filter at 4 meters.

[0170] Subjects enrolled in the study did not have any of the following exclusion criteria (in either eye, where appropriate): (1) prior unresolved dry eye diagnosis, taking prescription drops for dry eye, or taking artificial tear drops routinely for dry eye; (2) prior history of fluctuating vision; (3) clinically significant ocular disease as deemed by the Investigator that might interfere with the study; (4) history of comeal endothelial dystrophy; (5) known hypersensitivity to any topical alpha-adrenoceptor antagonists; (6) known allergy or contraindication to any component of the vehicle formulation; (7) history of cauterization of the punctum or punctal plug (silicone or collagen) insertion or removal; (8) pseudophakic subjects with extended depth-of-focus or multifocal intraocular lenses (IOLS); (9) ocular trauma, ocular surgery (e.g., IOLs) or laser procedure (e.g., LASIK, photorefractive keratectomy [PRK], SMILE, or RK) within 6 months prior to screening; (10) use of any topical prescription or over- the-counter (OTC) ophthalmic medications of any kind within 7 days of screening until study completion (with the exception of lid scrubs with over-the-counter products); (11) recent or current evidence of ocular infection or inflammation in either eye (where subjects must be symptom free for at least 7 days); (12) history' of diabetic retinopathy, diabetic macular edema, or dry or wet macular degeneration; (13) history of any7traumatic (surgical or nonsurgical) or nontraumatic condition affecting the pupil or iris; (14) unwilling or unable to discontinue use of contact lenses at least 1 hour prior to screening for soft contact lenses or at least 8 hours prior to screening for hard gas-permeable contact lenses, and at least 8 hours (for both types of lenses) prior to all other office visits; (15) previously undiagnosed dry eye, at the determination5233915088 399256-OPI-030WO (214984)of the Investigator; (16) known hypersensitivity or contraindication to alpha- and / or betaadrenoceptor antagonists; (17) clinically significant systemic disease that might interfere with the study; (18) initiation of treatment with, or any changes to, the current dosage, drug, or regimen of any systemic adrenergic or cholinergic drugs within 7 days prior to screening or during the study; (19) participation in any investigational study within 30 days prior to screening and during the conduct of the study; (20) females of childbearing potential who are pregnant, nursing, planning a pregnancy, or not using a medically acceptable form of birth control; (21) resting heart rate outside the specified range (50-110 beats per minute) at Screening; and (22) hypertension with resting diastolic blood pressure > 105 mmHg or systolic blood pressure > 160 mmHg at Screening.

[0171] The primary efficacy endpoint is percentage of subjects with > 15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (>3 lines) of improvement in the study eye compared to baseline in monocular mLCVA at Day 15. (The study eye is designated as the eye with worse mLCVA at screening. If both eyes have the same mLCVA, the right eye is designated as the study eye.)

[0172] Additional outcome measures of the study include (for the study eye, the non-study eye, the best of either eye. and binocular):(a) Percent of subjects with > 10 and > 15 ETDRS letters (> 2 and > 3 lines, respectively) improvement compared to baseline in mLCVA at Days 3, 8, 15, and Week 6 (excluding the primary endpoint);(b) Mean and change from baseline (Day 1, pre-dose) mLCVA at 0.5. 1, and 3 hours post-dose on Day 1 ;(c) Percent of subjects with > 10 and > 15 ETDRS letters (> 2 and > 3 lines, respectively) improvement compared to baseline in mesopic high contrast visual acuity (mHCVA) at Days 3, 8, 15. and Week 6;(d) Mean and change from baseline mLCVA and mHCVA at Days 3, 8, 15, and Week 6;(e) Mean and change from baseline in study eye pupil diameter at Days 3, 8, 15, and Week 6; and(f) Mean and change from baseline in subject questionnaire responses at Days 3, 8, 15, and Week 6.

[0173] Safety and tolerability were evaluated by analyzing (i) best-corrected distance visual acuity, (ii) biomicroscopy of the anterior segment, including evaluation of cornea, conjunctiva, and anterior chamber, (iii) comeal specular microscopy, if available, (iv)5333915088 399256-OPI-030WO (214984)intraocular pressure, (v) ophthalmoscopy direct or indirect fundus exam without dilation, including optic nerve, macula, vessels, and periphery, (vi) heart rate and blood pressure, and (vii) adverse events. An adverse event is any untoward medical occurrence associated with the use of a study medication in humans, whether or not considered drug related. An adverse event can therefore be any unfavorable and unintended sign (including abnormal laboratory findings), symptom, or disease temporally associated with the use of the study medication, whether or not related to the study medication.

[0174] The modified intention-to-treat population (mITT Population) includes all randomized subjects who received at least 1 dose of study medication. The mITT Population is used for the primary endpoint analysis and to analyze efficacy endpoints, with subjects included in their randomized treatment regardless of the treatment they actually received.Part II - Results

[0175] Two-hundred subjects were enrolled in the study meeting the inclusion criteria and not having any of the exclusion criteria.

[0176] At screening, 197 subjects enrolled in the study with reduced mesopic vision and photic complaints were administered a vision and night driving questionnaire (VND-Q) containing nine items. In this group, 141 of 197 (71%) participants reported “a lot of difficulty" or “severe difficulty” on at least one item in the VND-Q. Items with the highest incidence of difficulty were “seeing the road at night in poor weather” (59%), “seeing the road because of oncoming headlights” (46%), and “seeing the road because of glare at dawn or dusk” (37%). The item of “adjusting after passing headlights from oncoming cars when driving at night” also received a significant number of affirmative responses. Higher VND-Q scores are significantly associated with poor night driving performance on a closed-road circuit.

[0177] Demographic characteristics of subjects in the group that received placebo and the group that received 1.0% (w / v) phentolamine mesylate ophthalmic solution are set forth in the table below.5433915088 399256-OPI-030WO (214984)

[0178] Baseline characteristics of subjects in the group that received placebo and the group that received 1 .0% (w / v) phentolamine mesylate ophthalmic solution are set forth in the table below.A - 55 letters = 20 / 20 Snellen acuity

[0179] The study achieved the primary endpoint, which was defined as the percentage of participants achieving a >15-letter (>3-line) improvement in mesopic low contrast distance visual acuity (mLCVA). In the study, 17.3% of subjects in the group receiving 1.0% (w / v) phentolamine mesylate ophthalmic solution achieved >15-letter (>3-line) gain in mLCVA at Day 15, whereas only 9.2% of subjects in the group receiving placebo achieved >15-letter (>3- line) gain in mLCVA at Day 15 (p < 0.05).

[0180] The study also achieved multiple secondary endpoints. For example:• At Day three, 58.2% of subjects in the group receiving 1.0% (w / v) phentolamine mesylate ophthalmic solution gained >10 letters in mLCVA, whereas only 38.4% of subjects in the group receiving placebo gained >10 letters in mLCVA (p<0.05)• At Day eight, 60.2% of subjects in the group receiving 1.0% (w / v) phentolamine mesylate ophthalmic solution gained >10 letters, whereas only 35.7% of subjects in the group receiving placebo gained >10 letters (p<0.001).5533915088 399256-OPI-030WO (214984)• At Day eight 16.3% of subjects in the group receiving 1.0% (w / v) phentolamine mesylate ophthalmic solution gained >15 letters at Day eight, whereas only 8.2% of subjects in the group receiving placebo gained >15 letters at Day eight (p<0.05).

[0181] Analysis of mLCVA data collected over the duration of the study revealed that subjects in the group receiving 1.0% (w / v) phentolamine mesylate ophthalmic solution gained 8-11 letters of mLCVA at all time points from 1-hour after the first dose to Day 60 of daily dosing. Results are shown graphically in Figure 2, which shows the change in mLCVA from baseline over a sixty-day period of the study in the study eye in subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution. The difference between best mLCVA (Day 3) and the mLCVA on Day 60 was 1.85 letters. Results compared to placebo are shown graphically in Figure 13, which shows the mean mLCVA in the study eye at baseline. Day 8, and Day 15 of the study in subjects in the modified intention-to-treat (mITT) population who received either placebo or 1.0% (w / v) phentolamine mesylate ophthalmic solution, where the abbreviation “POS’" refers to subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution. The results in Figure 13 demonstrate a statistically significant improvement in mLCVA in the study eye at Day 8 and Day 15 of the study in subjects in the modified intention-to-treat (mITT) who received 1.0% (w / v) phentolamine mesylate ophthalmic solution compared to subjects who received placebo.

[0182] Analysis of results from the study indicate that no tachyphylaxis was observed in subjects receiving the 1.0% (w / v) phentolamine mesylate ophthalmic solution. In evaluating results for tachyphylaxis, no tachyphylaxis was observed with a 95% confidence interval for the change from peak response to Week 6 remaining within 5 letters. The 90% confidence interval in change from baseline in mean mLCVA between Day 3 (best response) and Week 6 in the 1.0% (w / v) phentolamine mesylate ophthalmic solution arm did not include the prespecified 5 letter loss, demonstrating no tachyphylaxis. Figure 7 provides results showing change in mLCVA over time relative to baseline mLCVA through week 6 - these results support the finding of no tachyphylaxis. Results in Figure 7 show that subjects receiving 1.0% (w / v) phentolamine mesylate ophthalmic solution gained 8-11 letter of mLCVA at all time points from one hour after the first dose to six weeks of daily dosing. The difference between the best mLCVA (which occurred at day 3) and week 6 was 1.85 letters. The 95% confidence interval of -2.73 to -0.97 does not include the prespecified criterion of -5 letters.

[0183] Analysis of mesopic high-contrast visual acuity (mHCVA) data collected during the study revealed that subjects in the group receiving 1.0% (w / v) phentolamine mesylate5633915088 399256-OPI-030WO (214984)ophthalmic solution also achieved a statistically significant improvement in mHCVA at Day 8 and Day 15 of the study compared to subjects who received placebo. Results are shown graphically in Figure 14, which show s the mean mHCVA at baseline, Day 8, and Day 15 of the study in subjects in the modified intention-to-treat (mITT) population who received either placebo or 1.0% (w / v) phentolamine mesylate ophthalmic solution, where the abbreviation “POS” refers to subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution.

[0184] Study results showed improvement in patient reported outcomes from the vision and night driving questionnaire (VND-Q). At Day 15 of the study, statistically significant improvement in patient reported outcomes from the vision and night driving questionnaire w as achieved in seven of the nine questions on the vision and night driving questionnaire (VND-Q). Results are displayed graphically in Figure 3. which shows score from the patient reported outcomes from the vision and night driving questionnaire at Day fifteen for subjects that received placebo and for subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution (where a score of 1 indicates “no difficulty,’' a score of 2 indicates “a little difficulty,” a score of 3 indicates “moderate difficulty,” a score of four indicates “a lot of difficulty,” and a score of 5 indicates “extreme difficulty.” Figure 4 provides a graph showing score from the patient reported outcomes from the vision and night driving questionnaire for the specific question of “difficulty with glare from headlights” at baseline, Day eight, Day fifteen, and Week 6 of the study, for subjects that received placebo and for subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution. Figure 5 provides a graph showing score from the patient reported outcomes from the vision and night driving questionnaire for the specific question of “difficulty seeing road in poor weather” at baseline, Day eight, Day fifteen, and Week 6 of the study, for subjects that received placebo and for subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution.

[0185] Analysis of mean pupil diameter of the subjects’ eye under mesopic light conditions w as evaluated. Results are show n in Figure 6, which is a graph showing mean pupil diameter of the subjects’ eye under mesopic light condition, for subjects that received placebo and for subjects that received 1.0% (w / v) phentolamine mesylate ophthalmic solution.

[0186] Analysis of results for safety indicate that administration of the 1.0% (w / v) phentolamine mesylate ophthalmic solution according to the study procedure was well tolerated with no drug-related serious adverse events reported. The most common treatment-emergent adverse events were mild and consistent with previous studies and included conjunctival hyperemia (35%), instillation site irritation (19%), and dysgeusia (11%). There w ere no deaths5733915088 399256-OPI-030WO (214984)during the study. One subject in each group reported a serious adverse event: there was 1 melanoma (non-ocular) in group the group that received 1.0% (w / v) phentolamine mesylate ophthalmic solution (unrelated to study drug), and there was 1 retinal detachment in the group that received placebo (unrelated to study drug). Eight subjects (8.1%) in the group treated with 1.0% (w / v) phentolamine mesylate ophthalmic solution withdrew due to an adverse event compared to 1 subject (1 %) in the placebo group that withdrew from the study. Adverse events in the group that received 1.0% (w / v) phentolamine mesylate ophthalmic solution and that withdrew' from the study included: Conjunctival hyperemia (3), conjunctivitis (2), allergic conjunctivitis (2), eye pain (1), eyelid edema (1), noninfective conjunctivitis (1). eyelid pruritic (1), and punctate keratitis (1). The adverse event of blurred vision occurred once in the group that received placebo. Fifty-nine subjects out the ninety-nine subjects (59.5%) treated with 1.0% (w / v) phentolamine mesylate ophthalmic solution reported 233 adverse events. Fifty-one subjects treated with 1.0% (w / v) phentolamine mesylate ophthalmic solution had a treatment- related adverse event. The majority of these adverse events were mild in severity and related to drug installation (discomfort, conjunctival hyperemia).

[0187] Adverse events occurring in > 5% of subjects treated with 1.0% (w / v) phentolamine mesylate ophthalmic solution included: (a) conjunctival hyperemia in 35% (86% were mild) of subjects treated with 1.0% (w / v) phentolamine mesylate ophthalmic solution vs. 4% of subjects treated with placebo, (b) installation site irritation in 19% (all mild) of subjects treated with 1.0% (w / v) phentolamine mesylate ophthalmic solution vs. 0% in subjects treated with placebo, (c) dysgeusia in 11% (all mild) of subjects treated with 1.0% (w / v) phentolamine mesylate ophthalmic solution vs 1% in subjects treated w ith placebo, and (d) 1% of subjects treated w ith 1.0% (w / v) phentolamine mesylate ophthalmic solution reported headache. A table summarizing certain adverse events is provided below.5833915088 399256-OPI-030WO (214984)

[0188] Results in Figure 8 show that no subject treated with 1.0% (w / v) phentolamine mesylate ophthalmic solution lost one or more lines of mLCVA at any timepoint measured in the study.EXAMPLE 4

[0189] A clinical study will be performed in which phentolamine mesylate will be administered to eyes of human subjects who have previously undergone keratorefractive surgery and suffer from decreased visual performance under mesopic light conditions. Experimental procedures are described below.Part I - Experimental Procedures

[0190] Human subjects who have previously undergone keratorefractive surgery and suffer from decreased visual performance under mesopic light conditions are to be enrolled in the study, which may be approximately two-hundred human subjects who have previously undergone keratorefractive surgery and suffer from decreased visual performance under mesopic light conditions. Subjects in the study satisfy the inclusion criteria set forth below. Subjects are stratified by iris color (light vs. dark irides) and randomized 1: 1 to receive one eye drop of placebo or one eye drop of 1.0% (w / v) phentolamine mesylate ophthalmic solution once daily in the evening near bedtime for the length of the study. The test article (either placebo or 1 .0% (w / v) phentolamine mesylate ophthalmic solution) was administered to both eyes of subject each day of the study. The 1.0% (w / v) phentolamine mesylate ophthalmic solution contains: 1% (w / v) phentolamine mesylate, 4% (w / v) mannitol. 3 mM sodium acetate, and water, wherein the ophthalmic solution has a pH in the range of 4.5 to 5.3. The placebo is a solution containing 4% (w / v) mannitol, 3 mM sodium acetate, and water, wherein the solution has a pH in the range of 4.5 to 5.3.

[0191] The first dose of study medication will be administered at the study site by site staff at the Baseline Visit / Day 1 and mLCVA assessments will be made at 0.5, 1, and 3 hours postdose. On each day thereafter for approximately fourteen days, subjects will self-administer 1 drop of test article (either placebo or 1.0% (w / v) phentolamine mesylate ophthalmic solution) to both eyes in the evening near bedtime. In this study, subjects may be evaluated for visual acuity (including mesopic low contrast visual acuity (mLCVA) and mesopic high contrast visual acuity (mHCVA)), pupil diameter, and / or responses to a vision and night driving questionnaire (VND-Q) containing 9 items. The vision and night driving questionnaire (VND- Q) containing 9 items is a validated metric reported by Kimlin JA, Black AA, DjajaN & Wood5933915088 399256-OPI-030WO (214984)JM. in “Development and validation of a vision and night driving questionnaire / ’ Ophthalmic Physiol. Opt. (2016) vol. 36, pages 465-476. Items in the vision and night driving questionnaire (VND-Q) are scored on a range of 1 to 5, where a score of 1 indicates “no difficulty,’’ a score of 2 indicates “a little difficulty,” a score of 3 indicates “moderate difficulty,” a score of four indicates “a lot of difficulty.” and a score of 5 indicates “extreme difficulty.” The nine items on the vision and night driving questionnaire (VND-Q) are:1. Seeing dark coloured cars when driving at night.2. Seeing pedestrians or animals on the roadside when driving at night.3. Reading street signs when driving at night.4. Seeing the road because of oncoming headlights when driving at night.5. Seeing because of glare when driving at dawn or dusk.6. Adjusting after passing headlights from oncoming cars when driving at night.7. Judging the distance to your turnoff or exit while driving at night.8. Judging the distance between you and another moving cars when driving at night.9. Seeing the road in rain or poor weather when driving at night.Evaluations are conducted at screening; on days 3, 8, and 15.

[0192] Subjects in the study shall satisfy the following inclusion criteria: (1) male or female > 18 years of age; (2) have undergone keratorefractive surgery (e.g., laser-assisted in situ keratomileusis [LASIK], photorefractive keratectomy [PRK], small-incision lenticule extraction [SMILE], radial keratotomy [RK], astigmatic keratotomy, limbal-relaxing incisions, etc. in one or both eyes) and have subject-reported night vision disturbance (e.g., glare, halos, and / or starbursts) first noted within two months following the keratorefractive surgery', (3) able to comply with all protocol-mandated procedures independently, (4) able and willing to give written consent to participate in this study, and (5) able to self-administer study medication. Subjects in the study also satisfied the following inclusion criteria, all in the same eye: (6) pupil diameter > 5 mm under mesopic conditions (prior to illumination) in at least one eye, and (7) mLCVA score of < 30 ETDRS letters (20 / 63 Snellen, or worse) in at least one eye, and (8) mLCVA improvement of >10 ETDRS letters in at least one eye during illumination of the contralateral eye. The mLCVA score of < 30 ETDRS letters (20 / 63 Snellen, or worse) in at least one eye may be determined using a Precision Vision Illuminator Cabinet with 5% translucent contrast chart and a mesopic filter at 4 meters. The mLCVA improvement of >10 ETDRS letters in at least one eye during illumination of the contralateral eye may be6033915088 399256-OPI-030WO (214984)determined using a Brightness Acuity Tester (BAT) system on the low setting using the Precision Vision Illuminator Cabinet with 5% translucent contrast chart and a mesopic filter at 4 meters.

[0193] Subjects enrolled in the study shall not have any of the following exclusion criteria (in either eye, where appropriate): (1) prior unresolved dry eye diagnosis, taking prescription drops for dry’ eye, or taking artificial tear drops routinely for dry eye: (2) prior history of fluctuating vision; (3) clinically significant ocular disease as deemed by the Investigator that might interfere with the study; (4) history’ of corneal endothelial dystrophy; (5) known hypersensitivity to any topical alpha- adrenoceptor antagonists; (6) known allergy’ or contraindication to any component of the vehicle formulation; (7) history of cauterization of the punctum or punctal plug (silicone or collagen) insertion or removal; (8) pseudophakic subjects with extended depth-of-focus or multifocal intraocular lenses (IOLS); (9) ocular trauma, ocular surgery’ (e.g., IOLs) or laser procedure (e.g., LASIK, photorefractive keratectomy [PRK], SMILE, RK, astigmatic keratotomy, or limbal-relaxing incisions) within 6 months prior to screening; (10) use of any topical prescription or over-the-counter (OTC) ophthalmic medications of any kind within 7 days of screening until study completion (with the exception of lid scrubs with over-the-counter products); (11) recent or current evidence of ocular infection or inflammation in either eye (where subjects must be symptom free for at least 7 days); (12) history of diabetic retinopathy, diabetic macular edema, or dry or wet macular degeneration; (13) history of any traumatic (surgical or nonsurgical) or nontraumatic condition affecting the pupil or iris; (14) unwilling or unable to discontinue use of contact lenses at least 1 hour prior to screening for soft contact lenses or at least 8 hours prior to screening for hard gas-permeable contact lenses, and at least 8 hours (for both ty pes of lenses) prior to all other office visits; (15) previously undiagnosed dry eye, at the determination of the Investigator; (16) known hypersensitivity or contraindication to alpha- and / or beta-adrenoceptor antagonists; (17) clinically significant systemic disease that might interfere ’ith the study; (18) initiation of treatment with, or any changes to, the current dosage, drug, or regimen of any systemic adrenergic or cholinergic drugs within 7 days prior to screening or during the study; (19) participation in any investigational study within 30 days prior to screening and during the conduct of the study; (20) participation in any prior investigational study using phentolamine ophthalmic solution; (21) females of childbearing potential who are pregnant, nursing, planning a pregnancy, or not using a medically acceptable form of birth control; (22) resting heart rate outside the specified range (50-110 beats per minute) at Screening; and (23) hypertension with6133915088 399256-OPI-030WO (214984)resting diastolic blood pressure > 105 mmHg or systolic blood pressure > 160 mmHg at Screening.

[0194] The primary efficacy endpoint is percentage of subjects with > 15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (>3 lines) of improvement in the study eye compared to baseline in monocular mLCVA at Day 15. (The study eye is designated as the eye with worse mLCVA at screening. If both eyes have the same mLCVA, the right eye is designated as the study eye.)

[0195] Additional outcome measures of the study include (for the study eye, the non-study eye, the best of either eye, and binocular):(a) Percent of subjects with > 10 and > 15 ETDRS letters (> 2 and > 3 lines, respectively) improvement compared to baseline in mLCVA at Days 8 and 15 (excluding the primary endpoint);(b) Mean and change from baseline (Day 1, pre-dose) mLCVA at 0.5, 1, and 3 hours post-dose on Day 1 ;(c) Percent of subjects with > 10 and > 15 ETDRS letters (> 2 and > 3 lines, respectively) improvement compared to baseline in mesopic high contrast visual acuity (mHCVA) at Days 8 and 15;(d) Mean and change from baseline mLCVA and mHCVA at Days 8 and 15;(e) Percentage of participants with > 10 and > 15 ETDRS letters improvement in photopic low-contrast visual acuity (pLCVA) compared to Baseline (Day 1 pre-dose) at Days 8 and 15;(f) Mean and change from Baseline (Day 1 pre-dose) in pLCVA at Days 8 and 15;(g) Mean and change from Baseline (Day 1 pre-dose) in uncorrected photopic high- contrast visual acuity (HCVA) at Day 15;(h) Mean and change from Baseline (Day 1 pre-dose) in uncorrected mHCVA at Day 15(i) Mean and change from baseline in study eye pupil diameter at Days 8 and 15; and(j ) Mean and change from baseline in subject questionnaire responses at Days 8 and 15.

[0196] Safety and tolerability' may be evaluated by analyzing (i) best-corrected distance visual acuity (such as at 12 hours post dose), (ii) biomicroscopy of the anterior segment, including evaluation of cornea, conjunctiva, and anterior chamber, (iii) percentage of participants with > 5, > 10, and > 15 letters loss mLCVA from Baseline (Day 1 pre-dose) at 12 hours post-dose, (iv) intraocular pressure, (v) ophthalmoscopy direct or indirect fundus exam without dilation, including optic nerve, macula, vessels, and periphery, (vi) heart rate and blood6233915088 399256-OPI-030WO (214984)pressure, (vii) adverse events, and (viii) percentage of participants with > 5, > 10, and > 15 letters loss best-corrected distance visual acuity from Baseline (Day 1 pre-dose) at 12 hours post-dose. An adverse event is any untoward medical occurrence associated with the use of a study medication in humans, whether or not considered drug related. An adverse event can therefore be any unfavorable and unintended sign (including abnormal laboratory findings), symptom, or disease temporally associated with the use of the study medication, whether or not related to the study medication.

[0197] The modified intention-to-treat population (mITT Population) includes all randomized subjects who received at least 1 dose of study medication. The mITT Population is used for the primary endpoint analysis and to analyze efficacy endpoints, with subjects included in their randomized treatment regardless of the treatment they actually received.INCORPORATION BY REFERENCE

[0198] The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes.EQUIVALENTS

[0199] The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.6333915088 399256-OPI-030WO (214984)

Claims

Claims:

1. A method of improving visual performance under mesopic light conditions, comprising administering to an eye of a subject in need thereof a therapeutically effective amount of a therapeutic agent selected from phentolamine or a pharmaceutically acceptable salt thereof, to provide improved visual performance under mesopic light conditions.

2. The method of claim 1, wherein the improvement in visual performance is improved visual acuity.

3. The method of claim 1, wherein the improvement in visual performance is improved contrast sensitivity.

4. The method of any one of claims 1-3. wherein the therapeutically effective amount is sufficient to provide improved visual performance under mesopic light conditions for at least twenty -four hours.

5. A method of treating decreased visual performance under mesopic light conditions, comprising administering to an eye of a subject in need thereof a therapeutically effective amount of a therapeutic agent selected from phentolamine or a pharmaceutically acceptable salt thereof, in order to treat the decreased visual performance under mesopic light conditions.

6. The method of claim 5, wherein the therapeutically effective amount is sufficient to treat decreased visual performance for at least twenty-four hours.

7. The method of claim 5 or 6, wherein the visual performance is visual acuity.

8. The method of any one of claims 1-7, wherein the subject has previously received keratorefractive surgery.

9. The method of any one of claims 1-8, wherein the subject prior to receiving the therapeutic agent has a mesopic pupil diameter > 4 mm.

10. The method of any one of claims 1 -8, wherein the subject prior to receiving the therapeutic agent has a mesopic pupil diameter > 5 mm.11 . The method of any one of claims 1-8, wherein the subject prior to receiving the therapeutic agent has a mesopic pupil diameter > 6 mm.

12. The method of any one of claims 1-11, wherein the subject prior to receiving the therapeutic agent has a mesopic low contrast visual acuity score of < 20 / 63.6433915088 399256-OPI-030WO (214984)13. The method of any one of claims 1-12, wherein the subject prior to receiving the therapeutic agent presents with > 10 letter improvement in mesopic low contrast visual acuity during illumination of the contralateral eye.

14. The method of any one of claims 1-13, wherein the subject prior to receiving the therapeutic agent presents with the night vision disturbance of halos distorting their vision.

15. The method of any one of claims 1-14, wherein the subject prior to receiving the therapeutic agent presents with the night vision disturbance of starburst.

16. The method of any one of claims 1-15, wherein the subject prior to receiving the therapeutic agent presents with the night vision disturbance of glare.

17. The method of any one of claims 1-16, wherein the subject has had no recent ocular procedure performed on their eye.

18. The method of any one of claims 1-17, wherein the subject does not have an ocular disease.

19. The method of any one of claims 1-18, wherein the therapeutic agent is administered one time per day.

20. The method of any one of claims 1-18, wherein the therapeutic agent is administered one or two times per day.

21. The method of any one of claims 1-20, wherein the therapeutic agent is administered at or near bedtime of the subject.

22. The method of any one of claims 1-20, wherein the therapeutic agent is administered within 1 hour of bedtime of the subject.

23. The method of any one of claims 1-22, wherein the subject experiences an increase in eye redness of no more than one grade measured using the CCLRU Redness Grading Scale during the subject's waking hours compared to the subject’s level of eye redness w ithout receiving the therapeutic agent.

24. The method of any one of claims 1-23, wherein the therapeutic agent is administered to the subject for at least five consecutive days.

25. The method of any one of claims 1-23, wherein the therapeutic agent is administered to the subject for at least seven consecutive days.6533915088 399256-OPI-030WO (214984)26. The method of any one of claims 1-25, wherein the subject experiences a reduction in pupil diameter under mesopic conditions that is at least 5% compared to the pupil diameter of the subject under the same mesopic conditions but not having received said therapeutic agent.

27. The method of any one of claims 1-25, wherein the subject experiences a reduction in pupil diameter under mesopic conditions that is at least 10% compared to the pupil diameter of the subject under the same mesopic conditions but not having received said therapeutic agent.

28. The method of any one of claims 1-25, wherein the subject experiences a reduction in pupil diameter under mesopic conditions that is at least 20% compared to the pupil diameter of the subject under the same mesopic conditions but not having received said therapeutic agent.

29. The method of any one of claims 1-28, wherein the subject experiences a reduction in pupil diameter of at least 0.5 mm when measured under mesopic conditions relative to the diameter of the subject’s pupil under the same mesopic conditions but not having received said therapeutic agent.

30. The method of any one of claims 1-28, wherein the subject experiences a reduction in pupil diameter of at least 1 mm when measured under mesopic conditions relative to the diameter of the subject’s pupil under the same mesopic conditions but not having received said therapeutic agent.

31. The method of any one of claims 1-28, wherein the subject experiences a reduction in pupil diameter ranging from about 0.5 mm to about 3 mm when measured under mesopic conditions relative to the diameter of the subject’s pupil under the same mesopic conditions but not having received said therapeutic agent.

32. The method of any one of claims 1-31, wherein the method results in an improvement in visual acuity characterized by at least a one-line improvement in the subject’s vision measured using a Snellen chart.

33. The method of any one of claims 1-31, wherein the method results in an improvement in visual acuity characterized by at least a two-line improvement in the subject's vision measured using a Snellen chart.

34. The method of any one of claims 1-31, wherein the method results in an improvement in visual acuity characterized by at least a three-hne improvement in the subject’s vision measured using a Snellen chart.6633915088 399256-OPI-030WO (214984)35. The method of any one of claims 1-34, further characterized in that the method does not cause the diameter of the subject’s pupil under mesopic conditions to be less than 2.4 mm.

36. The method of any one of claims 1-34, further characterized in that the method does not cause the diameter of the subject’s pupil under mesopic conditions to be less than 2.5 mm.

37. The method of any one of claims 1-34, further characterized in that the method does not cause the diameter of the subject’s pupil under mesopic conditions to be less than 2.7 mm.

38. The method of any one of claims 1-37, wherein the therapeutic agent is administered topically to the eye of the subject in an amount of from about 0.2 to about 1.0 mg.

39. The method of any one of claims 1-37, wherein the therapeutic agent is administered topically to the eye of the subject in an amount of from about 0.3 to about 0.4 mg.

40. The method of any one of claims 1-37, wherein the therapeutic agent is administered topically to the eye of the subject in an amount of from about 0.3 to about 0.5 mg.

41. The method of any one of claims 1-37, wherein the therapeutic agent is administered topically to the eye of the subject in an amount of about 0.5 mg.

42. The method of any one of claims 1-37, wherein the therapeutic agent is administered topically to the eye of the subject in an amount of from about 0.3 to about 0.7 mg.

43. The method of any one of claims 1-37, wherein the therapeutic agent is administered topically to the eye of the subject in an amount of from about 0.3 to about 0.6 mg.

44. The method of any one of claims 1-37, wherein the therapeutic agent is administered topically to the eye of the subject in an amount of from about 0.5 to about 1 .0 mg.

45. The method of any one of claims 1-37, wherein the therapeutic agent is administered topically to the eye of the subject in an amount of from about 0.9 to about 1.1 mg.

46. The method of any one of claims 1-37, wherein the therapeutic agent is administered topically to the eye of the subject in an amount of about 1.0 mg.

47. The method of any one of claims 1-46, wherein the therapeutic agent is administered topically to the eye of the subject in the form of an eye drop containing the therapeutic agent at a concentration of about 1% w / w.

48. The method of any one of claims 1-46, wherein the therapeutic agent is administered topically to the eye of the subject in the form of an eye drop containing the therapeutic agent at a concentration of about 1% w / v.6733915088 399256-OPI-030WO (214984)49. The method of any one of claims 1-37, wherein the therapeutic agent is administered topically to the eye of the subject in the form of one eye drop containing the therapeutic agent at a concentration of about 1% w / w.

50. The method of any one of claims 1-37, wherein the therapeutic agent is administered topically to the eye of the subject in the form of one eye drop containing the therapeutic agent at a concentration of about 1% w / v.

51. The method of any one of claims 1-50, wherein the therapeutic agent is a pharmaceutically acceptable salt of phentolamine.

52. The method of any one of claims 1-50, wherein the therapeutic agent is phentolamine mesylate.

53. The method of any one of claims 1-52, wherein the subject is a human.

54. The method of any one of claims 1-52, wherein the subject is an adult human.

55. The method of any one of claims 1-52, wherein the subject is a geriatric human.

56. The method of any one of claims 1-52, wherein the subject suffers from chronic night driving impairment.

57. The method of any one of claims 1-52, wherein the subject suffers from photic phenomena after having received keratorefractive surgery.

58. A method of treating significant chronic night driving impairment in keratorefractive patients with photic phenomena, comprising administering to an eye of a subject in need thereof a therapeutically effective amount of a therapeutic agent selected from phentolamine or a pharmaceutically acceptable salt thereof, to treat the significant chronic night driving impairment in keratorefractive patients with photic phenomena.

59. The method of claim 58, wherein the therapeutic agent is administered topically to the eye of the subject in an amount of from about 0.2 to about 1.0 mg.

60. The method of claim 58, wherein the therapeutic agent is administered topically to the eye of the subject in an amount of from about 0.3 to about 0.4 mg.

61. The method of claim 58, wherein the therapeutic agent is administered topically to the eye of the subject in an amount of from about 0.3 to about 0.5 mg.

62. The method of claim 58, wherein the therapeutic agent is administered topically to the eye of the subject in an amount of about 0.5 mg.6833915088 399256-OPI-030WO (214984)63. The method of claim 58, wherein the therapeutic agent is administered topically to the eye of the subject in an amount of from about 0.3 to about 0.7 mg.

64. The method of claim 58, wherein the therapeutic agent is administered topically to the eye of the subject in an amount of from about 0.3 to about 0.6 mg.

65. The method of claim 58, wherein the therapeutic agent is administered topically to the eye of the subject in an amount of from about 0.5 to about 1.0 mg.

66. The method of claim 58, wherein the therapeutic agent is administered topically to the eye of the subject in an amount of from about 0.9 to about 1.1 mg.

67. The method of claim 58, wherein the therapeutic agent is administered topically to the eye of the subject in an amount of about 1.0 mg.

68. The method of any one of claims 58-67, wherein the therapeutic agent is administered topically to the eye of the subject in the form of an eye drop containing the therapeutic agent at a concentration of about 1% w / w.

69. The method of any one of claims 58-67, wherein the therapeutic agent is administered topically to the eye of the subject in the form of an eye drop containing the therapeutic agent at a concentration of about 1% w / v.

70. The method of claim 58, wherein the therapeutic agent is administered topically to the eye of the subject in the form of one eye drop containing the therapeutic agent at a concentration of about 1% w / w.

71. The method of claim 58, wherein the therapeutic agent is administered topically to the eye of the subject in the form of one eye drop containing the therapeutic agent at a concentration of about 1% w / v.

72. The method of any one of claims 58-71, wherein the therapeutic agent is a pharmaceutically acceptable salt of phentolamine.

73. The method of any one of claims 58-71, wherein the therapeutic agent is phentolamine mesylate.

74. The method of any one of claims 58-73, wherein the subject is a human.

75. The method of any one of claims 58-73, wherein the subject is an adult human.

76. The method of any one of claims 58-73, wherein the subject is a geriatric human.6933915088 399256-OPI-030WO (214984)77. The method of any one of claims 1-76, wherein the subject prior to receiving the therapeutic agent has a debilitating loss of best-spectacle corrected mesopic vision.

78. The method of any one of claims 1-77, wherein the subject prior to receiving the therapeutic agent has increased risk of motor vehicle accident due to impaired vision.

79. The method of any one of claims 1-78, wherein the subject prior to receiving the therapeutic agent has a mesopic low contrast visual acuity score of less than 30 letters.

80. The method of any one of claims 1-78, wherein the subject prior to receiving the therapeutic agent has a mesopic low contrast visual acuity score of less than 25 letters.

81. The method of any one of claims 1-78, wherein the subject prior to receiving the therapeutic agent has a mesopic low contrast visual acuity score of less than 20 letters.

82. The method of any one of claims 1-78, wherein the subject prior to receiving the therapeutic agent has a mesopic low contrast visual acuity score in the range of from 10 letters to 30 letters.

83. The method of any one of claims 1-78, wherein the subject prior to receiving the therapeutic agent has a mesopic low contrast visual acuity score in the range of from 10 letters to 25 letters.

84. The method of any one of claims 1-78, wherein the subject prior to receiving the therapeutic agent has a mesopic low contrast visual acuity score in the range of from 15 letters to 20 letters.

85. The method of any one of claims 1-84, wherein the subject prior to receiving the therapeutic agent has a mesopic high contrast visual acuity score of less than 50 letters.

86. The method of any one of claims 1-84, wherein the subject prior to receiving the therapeutic agent has a mesopic high contrast visual acuity score in the range of from 25 letters to 50 letters.

87. The method of any one of claims 1-84, wherein the subject prior to receiving the therapeutic agent has a mesopic high contrast visual acuity score in the range of from 30 letters to 50 letters.

88. The method of any one of claims 1-84, wherein the subject prior to receiving the therapeutic agent has a mesopic high contrast visual acuity score in the range of from 40 letters to 50 letters.7033915088 399256-OPI-030WO (214984)89. The method of any one of claims 1-88, wherein at 1 hour after the first administration of the therapeutic agent to the subject, the subject’s visual performance has improved by at least 5 letters in a mesopic low-contrast visual acuity' score, as measured using a Snellen chart, compared to the subject’s mesopic low-contrast visual acuity score prior to receiving the therapeutic agent.

90. The method of any one of claims 1-88, wherein at 1 hour after the first administration of the therapeutic agent to the subject, the subject’s visual performance has improved by at least 8 letters in a mesopic low-contrast visual acuity7score, as measured using a Snellen chart, compared to the subject’s mesopic low-contrast visual acuity7score prior to receiving the therapeutic agent.

91. The method of any one of claims 1-88, wherein at 1 hour after the first administration of the therapeutic agent to the subject, the subject’s visual performance has improved by at least 10 letters in a mesopic low-contrast visual acuity score, as measured using a Snellen chart, compared to the subject’s mesopic low-contrast visual acuity7score prior to receiving the therapeutic agent.

92. The method of any one of claims 1-88, wherein at 1 hour after the first administration of the therapeutic agent to the subject, the subject's visual performance has improved by an amount in the range of from 5 to 11 letters in a mesopic low-contrast visual acuity score, as measured using a Snellen chart, compared to the subject’s mesopic low-contrast visual acuity score prior to receiving the therapeutic agent.

93. The method of any one of claims 1-88, wherein at 1 hour after the first administration of the therapeutic agent to the subject, the subject's visual performance has improved by an amount in the range of from 8 to 11 letters in a mesopic low-contrast visual acuity score, as measured using a Snellen chart, compared to the subject’s mesopic low-contrast visual acuity score prior to receiving the therapeutic agent.

94. The method of any7one of claims 1-93, wherein upon daily administration of the therapeutic agent to the subject for at least 3 days, the method results in an improvement in visual acuity7characterized by at least a two-line improvement in the subject’s mesopic low- contract visual acuity7measured using a Snellen chart.

95. The method of any one of claims 1-93, wherein upon daily administration of the therapeutic agent to a population of said subjects for at least 3 days, the method results in an improvement in visual acuity characterized by at least a two-line improvement in the7133915088 399256-OPI-030WO (214984)subjects’ mesopic low-contract visual acuity for at least 50% of the population of said subjects, as measured using a Snellen chart.

96. The method of any one of claims 1-93, wherein upon daily administration of the therapeutic agent to a population of said subjects for at least 3 days, the method results in an improvement in visual acuity7characterized by at least a two-line improvement in the subjects’ mesopic low-contract visual acuity for at least 55% of the population of said subjects, as measured using a Snellen chart.

97. The method of any7one of claims 1-93, wherein upon daily administration of the therapeutic agent to a population of said subjects for at least 3 days, the method results in an improvement in visual acuity characterized by at least a two-line improvement in the subjects' mesopic low-contract visual acuity7for at least 58% of the population of said subjects, as measured using a Snellen chart.

98. The method of any one of claims 1-97, wherein upon daily administration of the therapeutic agent to a population of said subjects for at least 8 days, the subject’s visual performance has improved by at least 5 letters in a mesopic low-contrast visual acuity score, as measured using a Snellen chart, compared to the subject’s mesopic low-contrast visual acuity score prior to receiving the therapeutic agent.

99. The method of any one of claims 1-97, wherein upon daily administration of the therapeutic agent to a population of said subjects for at least 8 days, the subject’s visual performance has improved by at least 8 letters in a mesopic low-contrast visual acuity score, as measured using a Snellen chart, compared to the subject’s mesopic low-contrast visual acuity score prior to receiving the therapeutic agent.

100. The method of any one of claims 1-97, wherein upon daily administration of the therapeutic agent to a population of said subjects for at least 8 days, the subject’s visual performance has improved an amount in the range of from 8 to 11 letters in a mesopic low- contrast visual acuity score, as measured using a Snellen chart, compared to the subject’s mesopic low-contrast visual acuity score prior to receiving the therapeutic agent.

101. The method of any one of claims 1-97, wherein upon daily administration of the therapeutic agent to the subject for at least 8 days, the method results in an improvement in visual acuity characterized by at least a two-line improvement in the subject's mesopic low- contract visual acuity measured using a Snellen chart.7233915088 399256-OPI-030WO (214984)102. The method of any one of claims 1-97, wherein upon daily administration of the therapeutic agent to the subject for at least 8 days, the method results in an improvement in visual acuity7characterized by at least a three-line improvement in the subject’s mesopic low-contract visual acuity measured using a Snellen chart.

103. The method of any one of claims 1-97, wherein upon daily administration of the therapeutic agent to a population of said subjects for at least 8 days, the method results in an improvement in visual acuity characterized by at least a three-line improvement in the subjects’ mesopic low-contract visual acuity for at least 12% of the population of said subjects, as measured using a Snellen chart.

104. The method of any one of claims 1-97, wherein upon daily administration of the therapeutic agent to a population of said subjects for at least 8 days, the method results in an improvement in visual acuity characterized by at least a three-line improvement in the subjects’ mesopic low-contract visual acuity for at least 15% of the population of said subjects, as measured using a Snellen chart.

105. The method of any one of claims 1-97, wherein upon daily administration of the therapeutic agent to a population of said subjects for at least 8 days, the method results in an improvement in visual acuity7characterized by at least a three-line improvement in the subjects’ mesopic low-contract visual acuity for at least 16% of the population of said subjects, as measured using a Snellen chart.

106. The method of any one of claims 1-97 or 103-105, wherein upon daily administration of the therapeutic agent to a population of said subjects for at least 8 days, the method results in an improvement in visual acuity7characterized by at least a two-line improvement in the subjects' mesopic low-contract visual acuity7for at least 50% of the population of said subjects, as measured using a Snellen chart.

107. The method of any one of claims 1-97 or 103-105, wherein upon daily administration of the therapeutic agent to a population of said subjects for at least 8 days, the method results in an improvement in visual acuity characterized by at least a two-line improvement in the subjects’ vision for at least 55% of the population of said subjects, as measured using a Snellen chart.

108. The method of any one of claims 1-97 or 103-105, wherein upon daily administration of the therapeutic agent to a population of said subjects for at least 8 days, the method results in an improvement in visual acuity characterized by at least a two-line improvement in the7333915088 399256-OPI-030WO (214984)subjects’ mesopic low-contract visual acuity for at least 60% of the population of said subjects, as measured using a Snellen chart.

109. The method of any one of claims 1-108, wherein upon daily administration of the therapeutic agent to a population of said subjects for at least 15 days, the subject’s visual performance has improved by at least 5 letters in a mesopic low-contrast visual acuityscore, as measured using a Snellen chart, compared to the subject’s mesopic low-contrast visual acuity score prior to receiving the therapeutic agent.

110. The method of any one of claims 1-108, wherein upon daily administration of the therapeutic agent to a population of said subjects for at least 15 days, the subject’s visual performance has improved by at least 8 letters in a mesopic low-contrast visual acuity7score, as measured using a Snellen chart, compared to the subject’s mesopic low-contrast visual acuity score prior to receiving the therapeutic agent.

111. The method of any one of claims 1-108, wherein upon daily administration of the therapeutic agent to a population of said subjects for at least 15 days, the subject's visual performance has improved by an amount in the range of from 8 to 11 letters in a mesopic low-contrast visual acuity7score, as measured using a Snellen chart, compared to the subject’s mesopic low-contrast visual acuity- score prior to receiving the therapeutic agent.

112. The method of any one of claims 1-108, wherein upon daily administration of the therapeutic agent to the subject for at least 15 days, the method results in an improvement in visual acuity characterized by at least a two-line improvement in the subject's mesopic low-contract visual acuity measured using a Snellen chart.

113. The method of any one of claims 1-108, wherein upon daily administration of the therapeutic agent to the subject for at least 15 days, the method results in an improvement in visual acuity7characterized by at least a three-line improvement in the subject's mesopic low-contract visual acuity measured using a Snellen chart.

114. The method of any one of claims 1-108, wherein upon daily administration of the therapeutic agent to a population of said subjects for at least 15 days, the method results in an improvement in visual acuity characterized by at least a three-line improvement in the subjects’ mesopic low-contract visual acuity for at least 12% of the population of said subjects, as measured using a Snellen chart.

115. The method of any one of claims 1-108, wherein upon daily administration of the therapeutic agent to a population of said subjects for at least 15 days, the method results in7433915088 399256-OPI-030WO (214984)an improvement in visual acuity characterized by at least a three-line improvement in the subjects’ mesopic low-contract visual acuity for at least 15% of the population of said subjects, as measured using a Snellen chart.

116. The method of any one of claims 1-108, wherein upon daily administration of the therapeutic agent to a population of said subjects for at least 15 days, the method results in an improvement in visual acuity characterized by at least a three-line improvement in the subjects’ mesopic low-contract visual acuity for at least 17% of the population of said subjects, as measured using a Snellen chart.

117. The method of any one of claims 1-116, wherein upon daily administration of the therapeutic agent to a population of said subjects for at least 60 days, the subject’s visual performance has improved by at least 5 letters in a mesopic low-contrast visual acuityscore, as measured using a Snellen chart, compared to the subject's mesopic low-contrast visual acuity score prior to receiving the therapeutic agent.

118. The method of any one of claims 1-116, wherein upon daily administration of the therapeutic agent to a population of said subjects for at least 60 days, the subject’s visual performance has improved by at least 8 letters in a mesopic low-contrast visual acuity score, as measured using a Snellen chart, compared to the subject’s mesopic low-contrast visual acuity score prior to receiving the therapeutic agent.

119. The method of any one of claims 1-116, wherein upon daily administration of the therapeutic agent to a population of said subjects for at least 60 days, the subject's visual performance has improved by an amount in the range of from 8 to 1 1 letters in a mesopic low-contrast visual acuity score, as measured using a Snellen chart, compared to the subject’s mesopic low-contrast visual acuity score prior to receiving the therapeutic agent.

120. The method of any one of claims 1-116, wherein upon daily administration of the therapeutic agent to the subject for at least 60 days, the method results in an improvement in visual acuity characterized by at least a two-line improvement in the subject’s mesopic low-contract visual acuity measured using a Snellen chart.

121. The method of any one of claims 1-116, wherein upon daily administration of the therapeutic agent to the subject for at least 60 days, the method results in an improvement in visual acuity characterized by at least a three-line improvement in the subject's mesopic low-contract visual acuity measured using a Snellen chart.7533915088 399256-OPI-030WO (214984)122. The method of any one of claims 1-116, wherein upon daily administration of the therapeutic agent to a population of said subjects for at least 60 days, the method results in an improvement in visual acuity' characterized by at least a three-line improvement in the subjects' mesopic low-contract visual acuity' for at least 12% of the population of said subjects, as measured using a Snellen chart.

123. The method of any one of claims 1-116, wherein upon daily administration of the therapeutic agent to a population of said subjects for at least 60 days, the method results in an improvement in visual acuity7characterized by' at least a three-line improvement in the subjects’ mesopic low-contract visual acuity' for at least 15% of the population of said subjects, as measured using a Snellen chart.

124. The method of any one of claims 1-116, wherein upon daily administration of the therapeutic agent to a population of said subjects for at least 60 days, the method results in an improvement in visual acuity characterized by at least a three-line improvement in the subjects’ mesopic low-contract visual acuity for at least 17% of the population of said subjects, as measured using a Snellen chart.

125. The method of any one of claims 1-124, wherein upon daily administration of the therapeutic agent to the subject for at least six weeks, the method results in an improvement in visual acuity' characterized by at least a two-line improvement in the subject's mesopic low-contract visual acuity measured using a Snellen chart.

126. The method of any one of claims 1-124, wherein upon daily administration of the therapeutic agent to the subject for at least six weeks, the method results in an improvement in visual acuity' characterized by at least a three-line improvement in the subject’s mesopic low-contract visual acuity measured using a Snellen chart.

127. The method of any one of claims 1-124, wherein upon daily administration of the therapeutic agent to a population of said subjects for at least six weeks, the method results in an improvement in visual acuity characterized by’ at least a three-line improvement in the subjects’ mesopic low-contract visual acuity for at least 12% of the population of said subjects, as measured using a Snellen chart.

128. The method of any one of claims 1-124, wherein upon daily administration of the therapeutic agent to a population of said subjects for at least six weeks, the method results in an improvement in visual acuity characterized by at least a three-line improvement in the7633915088 399256-OPI-030WO (214984)subjects’ mesopic low-contract visual acuity for at least 15% of the population of said subjects, as measured using a Snellen chart.

129. The method of any one of claims 1-124, wherein upon daily administration of the therapeutic agent to a population of said subjects for at least six weeks, the method results in an improvement in visual acuity' characterized by at least a three-line improvement in the subjects’ mesopic low-contract visual acuity for at least 17% of the population of said subjects, as measured using a Snellen chart.

130. The method of any one of claims 1-129, wherein upon daily administration of the therapeutic agent to the subject for at least twelve weeks, the method results in an improvement in visual acuity characterized by at least a two-line improvement in the subject’s mesopic low-contract visual acuity' measured using a Snellen chart.

131. The method of any one of claims 1-129, yvherein upon daily administration of the therapeutic agent to the subject for at least twelve weeks, the method results in an improvement in visual acuity characterized by at least a three-line improvement in the subject’s mesopic low-contract visual acuity measured using a Snellen chart.

132. The method of any one of claims 1-131, wherein upon daily administration of the therapeutic agent to the subject for at least twenty-four weeks, the method results in an improvement in visual acuity characterized by at least a two-line improvement in the subject’s mesopic low-contract visual acuity measured using a Snellen chart.

133. The method of any one of claims 1-131, wherein upon daily administration of the therapeutic agent to the subject for at least twenty-four weeks, the method results in an improvement in visual acuity characterized by at least a three-line improvement in the subject’s mesopic low-contract visual acuity measured using a Snellen chart.

134. The method of any one of claims 1-133, yvherein upon daily administration of the therapeutic agent to the subject for at least forty-eight yveeks, the method results in an improvement in visual acuity' characterized by at least a two-line improvement in the subject's mesopic low-contract visual acuity measured using a Snellen chart.

135. The method of any one of claims 1-133, yvherein upon daily administration of the therapeutic agent to the subject for at least forty-eight weeks, the method results in an improvement in visual acuity characterized by at least a three-line improvement in the subject’s mesopic low-contract visual acuity measured using a Snellen chart.7733915088 399256-OPI-030WO (214984)136. The method of any one of claims 1-135, wherein upon daily administration of the therapeutic agent to the subject for at least 15 days, the subject does not experience tachyphylaxis of the therapeutic agent.

137. The method of any one of claims 1-135, wherein upon daily administration of the therapeutic agent to the subject for at least 30 days, the subject does not experience tachyphylaxis of the therapeutic agent.

138. The method of any one of claims 1-135, wherein upon daily administration of the therapeutic agent to the subject for at least 60 days, the subject does not experience tachyphylaxis of the therapeutic agent.

139. The method of any one of claims 1-135, wherein upon daily administration of the therapeutic agent to the subject for at least 6 weeks, the subject does not experience tachyphylaxis of the therapeutic agent.

140. The method of any one of claims 1-135, wherein upon daily administration of the therapeutic agent to the subject for at least 12 weeks, the subject does not experience tachyphylaxis of the therapeutic agent.

141. The method of any one of claims 1-135, wherein upon daily administration of the therapeutic agent to the subject for at least 24 weeks, the subject does not experience tachyphylaxis of the therapeutic agent.

142. The method of any one of claims 1-135, wherein upon daily administration of the therapeutic agent to the subject for at least 48 weeks, the subject does not experience tachyphylaxis of the therapeutic agent.

143. The method of any one of claims 1-142, wherein the subject experiences an improvement in patient reported outcome evaluating visual performance.

144. The method of claim 143, wherein the improvement in patient reported outcome is at least a 5% improvement in patient reported outcome.

145. The method of claim 143, wherein the improvement in patient reported outcome is at least a 10% improvement in patient reported outcome.

146. The method of claim 143, wherein the improvement in patient reported outcome is at least a 15% improvement in patient reported outcome.

147. The method of any one of claims 143-146, where the patient reported outcome is from a vision and night driving questionnaire (VND-Q).7833915088 399256-OPI-030WO (214984)148. The method of any one of claims 143-146, where the patient reported outcome is from a vision and night driving questionnaire (VND-Q) that characterizes subj ect response to one or more of the following (i) seeing dark coloured cars when driving at night, (ii) seeing pedestrians or animals on the roadside when driving at night, (iii) reading street signs when driving at night, (iv) seeing the road because of oncoming headlights when driving at night, (v) seeing because of glare when driving at awn or dusk, (vi) adjusting after passing headlights from oncoming cars when driving at night, (vii) judging the distance to your turnoff or exit while driving at night, (viii) judging the distance between you and another moving cars when driving at night, or (ix) seeing the road in rain or poor weather when driving at night.

149. The method of any one of claims 1-148, wherein the subject experiences an improvement in seeing dark coloured cars when driving at night.

150. The method of any one of claims 1-149, wherein the subject experiences an improvement in seeing pedestrians or animals on the roadside when driving at night.

151. The method of any one of claims 1-150, wherein the subject experiences an improvement in reading street signs when driving at night.

152. The method of any one of claims 1-151, wherein the subject experiences an improvement in seeing the road because of oncoming headlights when driving at night.

153. The method of any one of claims 1-152, wherein the subject experiences an improvement in seeing because of glare when driving at dawn or dusk.

154. The method of any one of claims 1-153, w herein the subject experiences an improvement in adjusting after passing headlights from oncoming cars when driving at night.

155. The method of any one of claims 1-154, wherein the subject experiences an improvement in judging the distance to your turnoff or exit while driving at night.

156. The method of any one of claims 1-155, wherein the subject experiences an improvement in judging the distance betw een you and another moving cars when driving at night.

157. The method of any one of claims 1-156, wherein the subject experiences an improvement in seeing the road in rain or poor weather when driving at night.7933915088 399256-OPI-030WO (214984)

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