5'-adenosine diphosphate ribose (ADPR) for use in improving visual acuity

Abstract

The present invention is directed to methods for the use of 5'-adenosine diphosphate ribose (ADPR), and compositions thereof, for improving visual acuity, for example, in subjects having low / poor visual acuity resulting from an eye disease or condition.

Description

Attorney Docket No.: 14161-015-228METHODS FOR THE USE OF 5’-ADENOSINE DIPHOSPHATE RIBOSE (ADPR) FOR IMPROVING VISUAL ACUITYCROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 701,208, filed September 30, 2024, the disclosure of which is incorporated herein by reference in its entirety.1 FIELD OF THE INVENTION

[0002] The present invention is directed to methods for the use of 5 ’-adenosine diphosphate ribose (ADPR), and compositions thereof, for improving visual acuity in a subject in need thereof.2 BACKGROUND OF THE INVENTION

[0003] Visual acuity measures how sharp your vision is at a distance. It is usually tested by reading an eye chart. Best corrected visual acuity (BCVA) is an essential endpoint in clinical trials to evaluate the effectiveness of various treatments for eye diseases. It is a measure of how the patient responds to the experimental therapy and how it has affected their vision. BCVA is particularly important in the case of diseases of the eye, such as severe dry eye, inflammatory diseases of the eye, eye diseases associated with diabetes and aging, and others which can lead to severe vision loss and blindness if not treated in a timely manner.

[0004] Best corrected visual acuity (BCVA) is the best possible vision an eye can see with corrective lenses, measured using an eye chart. In clinical trials, the gold standard for measuring BCVA is with the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. The ETDRS used a standardized chart to measure visual acuity, with 14 lines of five letters per line in a logarithmic progression. In clinical trials, the ETDRS score is calculated as the total number of letters correctly read at 4 meters from the chart plus 30 (if 20 or more letters can be read at 4m). If fewer than 20 letters can be read at 4m, the patient’s position is adjusted to Im in front of the chart.

[0005] There is a need to develop compounds that improve and enhance visual function, including visual acuity. Particularly for subjects with chronic ocular conditions such as dry eye,1NAI-5003660114V1Attorney Docket No.: 14161-015-228 keratoconjunctivitis sicca, diabetes with diabetic keratopathy, and other conditions affecting the cornea and other tissues of the anterior segment of the eye, there is a significant need to enhance the quality of the repair, as indicated by visual acuity, without sacrificing the speed of the repair.3 SUMMARY OF THE INVENTION

[0006] In one aspect, provided herein are methods for improving visual acuity in a subject, wherein the method comprises administering to the subject an effective amount of a compound that is 5’-adenosine diphosphate ribose (ADPR), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof.

[0007] In one embodiment, the compound is ADPR in the form of its lithium salt. In one embodiment, the compound is dilithium ADPR. In one embodiment, the compound is ADPR in the form of its sodium salt. In one embodiment, the compound is ADPR in the form of its di sodium salt.

[0008] In one embodiment, the subject has diabetes or is one who has low / poor visual acuity resulting from an eye disease or condition. In one embodiment, the subject has diabetes or is one who has low / poor visual acuity resulting from an eye disease or condition that is wet adult macular degeneration (AMD), dry AMD, diabetic keratopathy, diabetic retinopathy, diabetic macular edema, retinal vein occlusion, uveitis, primary or secondary corneal neovascularization, red eye, pterygium, ocular cancer, chemical injury of the cornea associated with neoangiogenesis, dry eye disease, symptomatic dry eye disease, moderate symptomatic dry eye disease, or severe symptomatic dry eye disease. In one embodiment, the subject has diabetes or is one who has low / poor visual acuity resulting from an eye disease or condition that is diabetic keratopathy, dry eye disease, symptomatic dry eye disease, moderate symptomatic dry eye disease, or severe symptomatic dry eye disease. In one embodiment, the subject is one who has low / poor visual acuity resulting from an eye disease or condition that is moderate or severe symptomatic dry eye disease.

[0009] In one embodiment, the administering to the subject is via topical administration to the eye of the subject. In one embodiment, the administering to the subject is via intravitreal administration.

[0010] In another aspect, provided herein are methods for improving visual acuity in a subject, wherein the method comprises administering to the subject a pharmaceutical2NAI-5003660114V1Attorney Docket No.: 14161-015-228 composition comprising an effective amount of a compound that is 5’-adenosine diphosphate ribose (ADPR), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof. In one embodiment, the subject has diabetes or is one who has low / poor visual acuity resulting from an eye disease or condition that is diabetic keratopathy, dry eye disease, symptomatic dry eye disease, moderate symptomatic dry eye disease, or severe symptomatic dry eye disease. In one embodiment, the subject is one who has low / poor visual acuity resulting from an eye disease or condition that is moderate or severe symptomatic dry eye disease.

[0011] In one embodiment, the pharmaceutical composition is in the form of a solution and the administering to the subject is via topical administration to the eye of the subject.

[0012] In one embodiment, the pharmaceutical composition comprises (i) dilithium ADPR, or a solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, and (ii) one or more pharmaceutically acceptable excipients; wherein the amount of dilithium ADPR in the pharmaceutical composition is in the range of about 0.001% w / w to about 10 % w / w of the pharmaceutical composition.

[0013] In one embodiment, the amount of dilithium ADPR in the pharmaceutical composition is about 0.7% w / w of the pharmaceutical composition. In one embodiment, the solution is administered one to three times a day in a dose of 20-30 pL. In one embodiment, the solution is administered once a day in a dose of 30 pL each. In one embodiment, the solution is administered two times a day in a dose of 30 pL each. In one embodiment, the solution is administered three times a day in a dose of 30 pL each. In one embodiment, the solution is administered one to three times a day in a dose of 20-30 pL for a period of 1 to 30 days.

[0014] These and other aspects of the subject matter described herein will become evident upon reference to the following detailed description.4 BRIEF DESCRIPTION OF THE FIGURES

[0015] Figure 1 provides a plot of the change in visual acuity in all study subjects (n=109) as indicated by the change in the number of the letters read by subjects with their best corrected vision on a standard ETDRS vision chart. Visual acuity was determined prior to treatment on Day 1, and then on Days 15, 29, and 43. The solid line shows the change from Day 1 for subjects treated with dilithium ADPR (also known as INV-102) at a concentration of 0.7% and a3NAI-5003660114V1Attorney Docket No.: 14161-015-228 dose of 30 pL in each eye. The dashed line shows the change for subjects treated with vehicle. Subjects received doses twice per day on Days 1-14, and once per day on Days 15-28. No treatment was given after Day 28.

[0016] Figure 2 provides a plot of the linear correlation between the change in the corneal fluorescein staining (CFS) and the change in visual acuity.

[0017] Figure 3 provides a plot of the change in visual acuity in the diabetic subjects only (n=26) as indicated by the change in the number of the letters read by subjects with their best corrected vision on a standard ETDRS vision chart. Visual acuity was determined prior to treatment on Day 1, and then on Days 15, 29, and 43. The solid line shows the change from Day 1 for the diabetic subjects treated with dilithium ADPR at a concentration of 0.7% and a dose of 30 pL in each eye. The dashed line shows the change for diabetic subjects treated with vehicle. Subjects received doses twice per day on Days 1-14, and once per day on Days 15-28. No treatment was given after Day 28.

[0018] Figure 4 provides a plot of the linear correlation between the change in the CFS in the central and inferior regions of the cornea (which are the regions of the cornea that are most critical for visual acuity) and the change in visual acuity in the diabetics only on Day 15 of treatment.5 DETAILED DESCRIPTION5.1 Definitions

[0019] Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In general, the technical teaching of one embodiment can be combined with that disclosed in other embodiments provided herein.

[0020] As used herein, the terms “comprising” and “including” can be used interchangeably. The terms “comprising” and “including” are to be interpreted as specifying the presence of the stated features or components as referred to, but does not preclude the presence or addition of one or more features, or components, or groups thereof. Additionally, the terms “comprising” and “including” are intended to include examples encompassed by the term “consisting of’.4NAI-5003660114V1Attorney Docket No.: 14161-015-228Consequently, the term “consisting of’ can be used in place of the terms “comprising” and “including” to provide for more specific embodiments of the invention.

[0021] The term “consisting of’ means that a subject-matter has at least 90%, 95%, 97%, 98% or 99% of the stated features or components of which it consists. In another embodiment the term “consisting of’ excludes from the scope of any succeeding recitation any other features or components, excepting those that are not essential to the technical effect to be achieved.

[0022] As used herein, the term “or” is to be interpreted as an inclusive “or” meaning any one or any combination. Therefore, “A, B or C” means any of the following: “A; B; C; A and B; A and C; B and C; A, B and C”. An exception to this definition will occur only when a combination of elements, functions, steps or acts are in some way inherently mutually exclusive.

[0023] As used herein, the term “ADPR” is understood to include ADPR as well as a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof.

[0024] As used herein, the term “dose(s)” means a quantity of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, to be administered at one time. A dose may comprise a single unit dosage form, or alternatively may comprise more than a single unit dosage form (e.g., a single dose may comprise two tablets), or even less than a single unit dosage form (e.g., a single dose may comprise half of a tablet).

[0025] As used herein, the term “daily dose” means a quantity of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof that is administered in a 24 hour period. Accordingly, a daily dose may be administered all at once (i.e., once daily dosing) or alternatively the daily dosing may be divided such that administration of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, is twice daily, three times daily, four times daily, five times daily, six times daily, or even continuously throughout the day.

[0026] As used herein, the term “patient” or “subject” include animals, such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, monkeys, chickens, turkeys, quails, or guinea pigs and the like. In one embodiment, as used herein, the term “patient” or “subject” means a mammal. In one5NAI-5003660114V1Attorney Docket No.: 14161-015-228 embodiment, as used herein, the term “patient” or “subject” means a human. Tn one embodiment, the administration is to a human patient.

[0027] As used herein, an “effective amount” or a “therapeutically effective amount” refers to an amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof that is sufficient to provide a therapeutic benefit, e.g., in improving visual acuity.

[0028] As used herein, the term “pharmaceutical composition” refers to compositions suitable for pharmaceutical use, e.g., in improving visual acuity.

[0029] As used herein, the term “pharmaceutically acceptable salt” refers to those salts that are, within the scope of sound medical judgment, suitable for use in contact with the human tissue without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit / risk ratio.

[0030] By “co-administer” it is meant that compounds, compositions or agents described herein are administered at the same time, just prior to, or just after the administration of one or more additional compounds, compositions or agents, including for example an anti-cancer agent. Co-administration is meant to include simultaneous or sequential administration of compounds, compositions or agents individually or in combination (more than one compound or agent). Co-administration includes administering two compounds, compositions or agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. Thus, co-administration can include administering one active agent (e.g. a compound described herein) within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Co-administration can also be accomplished by co-formulation, e.g., preparing a single dosage form including both active agents. The active agents can be formulated separately. In such instances, the active agents are admixed and included together in the final form of the dosage unit. Alternatively, co-administration as described herein can include administering two separate unit dosage forms of at least two separate active agents (e.g., 5 ’-adenosine diphosphate ribose (ADPR), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition and a second active agent described herein).

[0031] As used herein, and unless otherwise indicated, the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, 6NAI-5003660114V1Attorney Docket No.: 14161-015-228 which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means within 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.05%, or 0.005% of a given value or range.

[0032] All references to singular characteristics or limitations of the present invention shall include the corresponding plural characteristic or limitation, and vice-versa, unless otherwise specified or clearly implied to the contrary by the context in which the reference is made.

[0033] All combinations of method or process steps as used herein can be performed in any order, unless otherwise specified or clearly implied to the contrary by the context in which the referenced combination is made.

[0034] The compositions and methods of the present invention can comprise, consist of, or consist essentially of the essential elements and limitations of the invention described herein, as well as any additional or optional ingredients, components, or limitations described herein or otherwise useful in compositions and methods of the general type as described herein.5.2 5 ’-adenosine diphosphate ribose (AD PR)

[0035] The uses and compositions provided herein relate to 5'-adenosine diphosphate ribose (ADPR; ADP-ribose; adenosine 5'-(trihydrogen diphosphate),P'— >5-ester with D-ribose; adenosine 5 '-(trihydrogen pyrophosphate ),5'— >5-ester with D-ribofuranose; adenosine 5'- diphosphate, D-ribose ester; adenosine 5'-pyrophosphate, 5'^5-ester with D-ribofuranose; ribofuranose, 5-(adenosine 5'-pyrphosphoryl)-D-ribose; adenosine 5'-diphosphoribose; adenosine diphosphate ribose; adenosine diphosphoribose; adenosine pyrophosphate-ribose; ribose adenosinediphosphate).

[0036] ADPR is a naturally occurring small molecule well known in the chemical literature. It is often characterized by the general formula C15H23N5O14P2, and includes, for example, various salts such as sodium salt corresponding to the following general structure of formula (I):7NAI-5003660114V1Attorney Docket No.: 14161-015-228HO" "OH

[0037] ADPR can be readily prepared by methods well known in the chemical arts. It is also commercially available as a purified raw material, an example of which can be purchased from Sigma or Sigma-Aldrich Co.

[0038] The ADPR compound can also include those derivatives in which basic nitrogencontaining groups are quaternized with materials such as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aryl alkyl halides like benzyl and phenethyl bromides and many others.

[0039] Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts of ADPR include such inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.

[0040] Basic addition salts can be prepared in situ during the final isolation and purification of the ADPR by reacting an acidic moiety with a suitable base such as, but not limited to, the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal ion or with ammonia or an organic primary, secondary or tertiary amine. Non-limiting examples of pharmaceutically acceptable salts include those based on alkali metals, alkaline earth metals, transition metals, or post-transition metals, such as lithium (including dilithium), sodium (including disodium), potassium, calcium, magnesium, aluminum, zinc, cobalt, and copper salts and the like, and nontoxic quaternary ammonia and amine captions including ammonium, tetramethylammonium, tetraethyl ammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine,8NAI-5003660114V1Attorney Docket No.: 14161-015-228 ethylamine and the like. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

[0041] In one embodiment, the ADPR compound for use in the compositions and methods provided herein is synthesized via the hydrolysis of nicotinamide adenine dinucleotide (NAD+) in the presence of an alkaline base, such as, but not limited to, lithium hydroxide or sodium hydroxide. In such an embodiment, the ADPR thus synthesized is isolated in the form of its mono or di salt of the metal ion of the corresponding base.

[0042] In a specific embodiment, the ADPR compound for use in the compositions and methods provided herein is in the form of its sodium salt. In one embodiment, the ADPR compound is in the form of its monosodium salt. In another embodiment, the ADPR compound is in the form of its di sodium salt.

[0043] In another specific embodiment, the ADPR compound for use in the compositions and methods provided herein is in the form of its lithium salt. In one embodiment, the ADPR compound is in the form of its monolithium salt. In another embodiment, the ADPR compound is in the form of its dilithium salt. In one embodiment, the ADPR compound is dilithium ADPR. In one embodiment, the ADPR compound is in the form of a combination of one or more of sodium, lithium, potassium, calcium, magnesium, zinc, cobalt, and / or copper salts. In one embodiment, the dilithium ADPR is a compound having the following formula:5.3 Methods of Treatment

[0044] In one embodiment, provided herein is a method for improving visual acuity in a subject, wherein the method comprises administering to the subject an effective amount of 5’-9NAI-5003660114V1Attorney Docket No.: 14161-015-228 adenosine diphosphate ribose (ADPR), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof. In one embodiment, the subject has diabetes. In one embodiment, the subject is a diabetic patient. In one embodiment, the subject is a diabetic patient with one or more eye disease or condition. In one embodiment, provided herein is a method for preventing loss or worsening of visual acuity in a diabetic patient, e.g., a diabetic patient with one or more eye disease or condition. In one embodiment, the subject is one who has low / poor visual acuity resulting from an eye disease or condition. In one embodiment, the method comprises topical administration of an effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof. In one embodiment, the effective amount of ADPR as described herein is about 0.005 mg to about 1000 mg. In one embodiment, the effective amount of ADPR as described herein is about 0.01 mg / day to about 10 mg / day. In one embodiment, the effective amount of ADPR as described herein is about 0.1 mg / day to about 10 mg / day.

[0045] In one embodiment, the eye disease or condition includes, but is not limited to, wet adult macular degeneration (AMD), dry AMD, diabetic keratopathy, diabetic retinopathy, diabetic macular edema, retinal vein occlusion, uveitis, primary or secondary corneal neovascularization, red eye, pterygium, ocular cancer, chemical injury of the cornea associated with neoangiogenesis, dry eye disease, symptomatic dry eye disease, moderate symptomatic dry eye disease, or severe symptomatic dry eye disease. In one embodiment, the eye disease or condition is diabetic keratopathy. In one embodiment, the eye disease or condition is dry eye disease. In one embodiment, the eye disease or condition is symptomatic dry eye disease. In one embodiment, the eye disease or condition is moderate symptomatic dry eye disease. In one embodiment, the eye disease or condition is severe symptomatic dry eye disease.

[0046] In one embodiment, the method comprises topical administration of an effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof. In one embodiment, the effective amount is about 0.005 mg to about 1000 mg. In one embodiment, the effective amount is about 0.01 mg / day to about 10 mg / day. In one embodiment, the effective amount is about 0.1 mg / day to about 10 mg / day.10NAI-5003660114V1Attorney Docket No.: 14161-015-228

[0047] In one embodiment, the topical administration is to an exterior cellular or tissue surface, including, but not limited to, the eye (including, but not limited to, cornea, conjunctiva, and sclera). In one embodiment, the topical administration is to the eye. In one embodiment, the topical administration is to the cornea, conjunctiva, or sclera.

[0048] In one embodiment, the methods provided herein comprise intravitreal administration of an effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof.

[0049] In one embodiment, the administering step comprises administering ADPR as described herein, wherein the total amount of the ADPR is in the range of about 0.001 mg to about 5 mg per dose. In one embodiment, the administering step comprises administering ADPR as described herein, wherein the total amount of the ADPR is in the range of about 0.001 mg to about 5 mg per dose. In one embodiment, each dose is between 5 microliters to 100 microliters. In another embodiment, each dose is between 20 microliters to 80 microliters. In another embodiment, each dose is between 5 microliters to 10 microliters. In another embodiment, each dose is between 10 microliters to 20 microliters. In another embodiment, each dose is between 20 microliters to 30 microliters. In one embodiment, each dose is about 5, 7, 10, 15, 20, 30 or 40 pL.

[0050] In one embodiment, the administering step comprises administering the pharmaceutical composition comprising ADPR as described herein in the form of a solution. In one embodiment, the solution is administered to the eye one to twenty-four times a day. In one embodiment, the solution is administered to the eye one to three times a day. In one embodiment, the solution is administered to the eye once a day. In one embodiment, the solution is administered to the eye two times a day. In one embodiment, the solution is administered to the eye three times a day.

[0051] In one embodiment, the method further comprises the step of storing the composition for at least one month, at least three months, at least six months, or at least 1 year before the administering step.

[0052] In certain embodiments, the ADPR used in the methods provided herein is Li2-ADPR (i.e., dilithium ADPR).11NAI-5003660114V1Attorney Docket No.: 14161-015-228

[0053] The improvement in visual acuity as described herein may be measured by commonly used methods known to one of skill in the art. In certain embodiments, the improvement in visual acuity is determined by utilizing corneal fluorescein staining (CFS). In certain embodiments, the CFS assessment is performed using the National Eye Institute (NEI) grading system to score each of 5 corneal zones (central, superior, lateral, medial, inferior) on a 0 to 3 scale (with a total score of 0 to 15). In this grading system higher scores indicate more corneal damage. In certain embodiments, the methods provided herein reduces the total CFS (all zones combined) score by 1 to 7 points. In certain embodiments, the methods provided herein reduce the total CFS score by 1 point, 2 points, 3 points, 4 points, 5 points, 6 points or 7 points. In certain embodiments, the methods provided herein reduce the total CFS (all zones combined) score by 1 to 7 points after at least 1 month of administration of ADPR as described herein to the eye of a subject, wherein the subject has a baseline CFS score of at least 7. In one embodiment, the subject has dry eye disease. In one embodiment, the subject has symptomatic dry eye disease. In one embodiment, the subject has moderate symptomatic dry eye disease. In one embodiment, the subject has severe symptomatic dry eye disease. In one embodiment, the subject has diabetic keratopathy. In one embodiment, the subject has diabetes. In one embodiment, the subject has dry eye disease without diabetes. In one embodiment, the subject has dry eye disease with diabetes. In certain embodiments, the methods provided herein reduce the total CFS (all zones combined) score by 1 to 7 points after at least 1 month of administration of ADPR as described herein to the eye of a subject, wherein the subject has dry eye disease and a baseline CFS score of at least 7. In certain embodiments, the methods provided herein reduce the total CFS (all zones combined) score by 1 point, 2 points, 3 points, 4 points, 5 points, 6 points or 7 points after at least 1 month of administration of ADPR as described herein to the eye of a subject, wherein the subject has dry eye disease and a baseline CFS score of at least 7.

[0054] In certain embodiments, the improvement in visual acuity is determined by measuring Best Corrected Visual Acuity (BCVA). In certain embodiments, the BCVA is measured for each eye using an Early Treatment Diabetic Retinopathy Study (ETDRS) chart. In certain embodiments, the methods provided herein increase the BCVA by one to four letters. In certain embodiments, the methods provided herein increase the BCVA by two to six letters. In certain embodiments, the methods provided herein increase the BCVA by one, two, three, four, five, six, seven, eight, nine, or ten letters. In certain embodiments, the methods provided herein increase 12NAI-5003660114V1Attorney Docket No.: 14161-015-228 the BCVA by one to four letters after one month of administration of ADPR as described herein to the eye of a subject. In certain embodiments, the methods provided herein increase the BCVA by two to six letters after one month of administration of ADPR as described herein to the eye of a subject. In one embodiment, the subject has dry eye disease. In one embodiment, the subject has symptomatic dry eye disease. In one embodiment, the subject has moderate symptomatic dry eye disease. In one embodiment, the subject has severe symptomatic dry eye disease. In one embodiment, the subject has diabetic keratopathy. In one embodiment, the subject has diabetes. In one embodiment, the subject has dry eye disease without diabetes. In one embodiment, the subject has dry eye disease with diabetes. In certain embodiments, the methods provided herein increase the BCVA by one to four letters after one month of administration of ADPR as described herein to the eye of a subject, wherein the subject has dry eye disease without diabetes. In certain embodiments, the methods provided herein increase the BCVA by two to six letters after one month of administration of ADPR as described herein to the eye of a subject, wherein the subject has dry eye disease with diabetes. In certain embodiments, the methods provided herein increase the BCVA by one letter, two letters, three letters or four letters after one month of administration of ADPR as described herein to the eye of a subject, wherein the subject has dry eye disease without diabetes. In certain embodiments, the methods provided herein increase the BCVA by two letters, three letters, four letters, five letters or six letters after one month of administration of ADPR as described herein to the eye of a subject, wherein the subject has dry eye disease with diabetes.5.4 Combination Therapy

[0055] In certain embodiments, ADPR or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof, may be administered in combination with a second agent. Such combination therapy may be achieved by way of the simultaneous, sequential, or separate dosing of the individual components of the treatment. Additionally, when administered as a component of such combination therapy, ADPR as disclosed herein, and the other medicament may be synergistic, such that the daily dose of either or both of the components may be reduced as compared to the dose of either component that would normally be given as a monotherapy. Alternatively, when administered as a component of such combination therapy, ADPR as13NAI-5003660114V1Attorney Docket No.: 14161-015-228 disclosed herein and the other medicament may be additive, such that the daily dose of each of the components is similar or the same as the dose of either component that would normally be given as a monotherapy.

[0056] In one embodiment, the methods provided herein further comprise administering a second agent, such as for example an agent useful in the treatment of diabetes, cancer or eye diseases or conditions. In one embodiment, the second agent is an agent useful in treatment of diabetes; eye disease or condition, such as wet adult macular degeneration (AMD), dry AMD, diabetic keratopathy, diabetic retinopathy, diabetic macular edema, retinal vein occlusion, uveitis (iritis), primary or secondary corneal neovascularization, red eye, pterygium, ocular cancers or malignancies including ocular melanoma, ocular angioma, ocular rosacea, chemical injury of the cornea associated with neoangiogenesis, dry eye disease, symptomatic dry eye disease, moderate symptomatic dry eye disease or severe symptomatic dry eye disease; lung cancer, such as nonsmall cell lung carcinoma (including adenocarcinoma, squamous cell carcinoma and large cell (undifferentiated) carcinoma), small cell lung carcinoma, and lung angioma; cervix cancer originating in the cervix (cervical carcinoma); skin cancer, such as squamous cell carcinoma, basal cell carcinoma, or melanoma. In one embodiment, the second agent is an agent useful in treatment of diabetes. In one embodiment, the second agent is an agent useful in treatment of diabetic keratopathy. In one embodiment, the second agent is an agent useful in treatment of dry eye disease. In one embodiment, the second agent is an agent useful in treatment of symptomatic dry eye disease. In one embodiment, the second agent is an agent useful in treatment of moderate symptomatic dry eye disease. In one embodiment, the second agent is an agent useful in treatment of severe symptomatic dry eye disease.

[0057] In one embodiment, the administering step comprises administering ADPR as described herein and a metal salt, wherein the total amount of the ADPR and the metal salt is in the range of about 0.001 mg to about 5 mg per dose. In one embodiment, the administering step comprises administering ADPR as described herein and a metal salt, wherein the total amount of the ADPR and the metal salt is in the range of about 0.001 mg to about 5 mg per dose. In one embodiment, each dose is between 5 microliters to 100 microliters. In another embodiment, each dose is between 20 microliters to 80 microliters. In another embodiment, each dose is between 5 microliters to 10 microliters. In another embodiment, each dose is between 1014NAI-5003660114V1Attorney Docket No.: 14161-015-228 microliters to 20 microliters. In another embodiment, each dose is between 20 microliters to 30 microliters. In one embodiment, each dose is about 5, 7, 10, 15, 20, 30 or 40 pL

[0058] In certain embodiments, the second agent is a lithium, zinc, cobalt, or copper salt. In certain embodiments, the second agent is lithium benzoate, lithium bromide, lithium chloride, lithium sulfate, lithium tetraborate, lithium acetate, zinc chloride, zinc sulfate, zinc bromide, cobalt chloride, cobalt bromide, copper bromide (CuBn), copper chloride (CuCh), or copper sulfate. In a specific embodiment, the second agent is lithium chloride.

[0059] In certain embodiments, the ADPR used in the combination therapies provided herein is Li - ADPR (i.e., dilithium ADPR).5.5 Doses and Dosing Regimens

[0060] In certain embodiments, the methods provided herein comprise administering an amount of about 0.005 mg to about 1000 mg, about 0.01 mg to about 100 mg, about 0.01 mg to about 10 mg, about 0.01 mg to about 1 mg, about 0.01 mg to about 0.1 mg, about 0.1 mg to about 10 mg, about 0.1 mg to about 5.0 mg, 0.1 mg to about 1 mg of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof.

[0061] In certain embodiments, the methods provided herein comprise administering an amount of about 1 mg to about 100 mg, about 0.01 mg to about 100 mg, about 0.01 mg to about 10 mg, about 0.01 mg to about 1 mg, about 0.01 mg to about 0.1 mg, about 0.1 mg to about 10 mg, about 0.1 mg to about 5.0 mg, 0.1 mg to about 1 mg of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof.

[0062] In certain embodiments, the methods provided herein comprise administering an amount of about 1 mg to about 100 mg, about 5 mg to about 90 mg, about 25 mg to about 85 mg of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof.

[0063] In certain embodiments, the methods provided herein comprise administering an amount of about 0.01 mg / day to about 15 mg / day, about 0.01 mg / day to about 10 mg / day, about 0.1 mg / day to about 15 mg / day, about 0.3 mg / day to about 15 mg / day, about 0.1 mg / day to about 10 mg / day, about 0.5 mg / day to about 10 mg / day, about 0.6 mg / day to about 10 mg / day, about 0.8 mg / day to about 10 mg / day, about 0.9 mg / day to about 10 mg / day, about 0.5 mg / day to15NAI-5003660114V1Attorney Docket No.: 14161-015-228 about 7.5 mg / day, about 0.6 mg / day to about 7.5 mg / day, about 0.8 mg / day to about 7.5 mg / day, about 0.9 mg / day to about 7.5 mg / day, about 0.6 mg / day to about 6.5 mg / day, about 0.9 mg / day to about 6.5 mg / day of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof.

[0064] In certain embodiments, the methods provided herein comprise administering an amount of about 0.6 mg / day, about 0.9 mg / day, about 1.8 m / day, 2.7 mg / day, about 4.2 mg / day or about 6.3 mg / day of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof.

[0065] In certain embodiments, the methods provided herein comprise administering an amount of about 0.6 mg / day, about 0.9 mg / day, about 1.8 m / day, 2.7 mg / day, about 4.2 mg / day or about 6.3 mg / day of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, wherein the amount is administered topically for 1 to 365 days. In certain embodiments, the amount is administered topically for 1 to 90 days. In certain embodiments, the amount is administered topically for 1 to 30 days. In certain embodiments, the amount is administered topically for 1 to 15 days. In certain embodiments, the amount is administered topically for 1 to 7 days.

[0066] In certain embodiments, the methods provided herein comprise administering from about 0.0001 mg / kg to about 1000 mg / kg, about 0.001 mg / kg to about 100 mg / kg, about 0.1 mg / kg to about 10 mg / kg or about 0.1 mg / kg to about 5.0 mg / kg of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof.

[0067] In certain embodiments, the pharmaceutical compositions provided herein may comprise from about 0.00001 to 100%, from 0.001 to 10%, from 0.01% to 2% or from 0.01% to 1% by weight of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof.

[0068] In certain embodiments, the methods provided herein comprise administering an amount of about 0.005 mg to about 1000 mg, about 0.01 mg to about 100 mg, about 0.01 mg to about 10 mg, about 0.01 mg to about 1 mg, about 0.01 mg to about 0.1 mg, about 0.1 mg to about 10 mg, about 0.1 mg to about 5.0 mg, 0.1 mg to about 1 mg of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof. In one embodiment, the concentration of ADPR, or a pharmaceutically16NAI-5003660114V1Attorney Docket No.: 14161-015-228 acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof is in the range of about 0.05 mg / mL to about 30 mg / mL. In another embodiment, the concentration of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof is in the range of about 1 mg / mL to about 20 mg / mL.

[0069] In a specific embodiment, the topical administration is to an eye. In another specific embodiment, the administration is intravitreal administration. In a specific embodiment, the ADPR as described herein is administered topically in a concentration ranging from about 0.05 mg / mL to about 30 mg / mL. In another embodiment, ADPR as described herein is administered topically in a concentration ranging from about 1 mg / mL to about 20 mg / mL.

[0070] In certain embodiments, the methods provided herein comprise administering a daily dose of about 0.005 mg to about 1000 mg, about 0.01 mg to about 100 mg, about 0.01 mg to about 10 mg, about 0.01 mg to about 1 mg, about 0.01 mg to about 0.1 mg, about 0.1 mg to about 10 mg, about 0.1 mg to about 5.0 mg, 0.1 mg to about 1 mg of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof. In one embodiment, the concentration of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof is in the range of about 0.05 mg / mL to about 30 mg / mL. In another embodiment, the concentration of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof is in the range of about 1 mg / mL to about 20 mg / mL. In one embodiment, ADPR as described herein is administered by topical administration. In a specific embodiment, the topical administration is to an eye. In another specific embodiment, the administration is intravitreal administration. In a specific embodiment, ADPR as described herein is administered topically in a concentration ranging from about 0.05 mg / mL to about 30 mg / mL. In another embodiment, ADPR as described herein is administered topically in a concentration ranging from about 1 mg / mL to about 20 mg / mL.

[0071] In certain embodiments, the administering of the aforementioned amounts of ADPR in this section is to a subject having diabetes or to a diabetic patient. In certain embodiments, the administering of the aforementioned amounts of ADPR in this section is to a subject having low / poor visual acuity resulting from an eye disease or condition. In one embodiment, the eye disease or condition is dry eye disease, symptomatic dry eye disease, moderate symptomatic dry 17NAI-5003660114V1Attorney Docket No.: 14161-015-228 eye disease, severe symptomatic dry eye disease or diabetic keratopathy. Tn one embodiment, the subject has dry eye disease. In one embodiment, the subject has symptomatic dry eye disease. In one embodiment, the subject has moderate symptomatic dry eye disease. In one embodiment, the subject has severe symptomatic dry eye disease. In one embodiment, the subject has diabetic keratopathy.

[0072] In certain embodiments, the methods provided herein comprise administering to a subject with dry eye disease a pharmaceutical composition comprising ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof; wherein the ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof in the pharmaceutical composition is in an amount of about 0.7% w / w of the pharmaceutical composition, and the pharmaceutical composition is for administration to the subject in a dose of 20-30 p.L. In certain embodiments, the methods provided herein comprise administering to a subject with symptomatic dry eye disease a pharmaceutical composition comprising ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof; wherein the ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof in the pharmaceutical composition is in an amount of about 0.7% w / w of the pharmaceutical composition, and the pharmaceutical composition is for administration to the subject in a dose of 20-30 |1L. In certain embodiments, the methods provided herein comprise administering to a subject with moderate symptomatic dry eye disease a pharmaceutical composition comprising ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof; wherein the ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof in the pharmaceutical composition is in an amount of about 0.7% w / w of the pharmaceutical composition, and the pharmaceutical composition is for administration to the subject in a dose of 20-30 |1L. In certain embodiments, the methods provided herein comprise administering to a subject with diabetes or to a diabetic patient a pharmaceutical composition comprising ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof; wherein the ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof in the pharmaceutical composition is in an18NAI-5003660114V1Attorney Docket No.: 14161-015-228 amount of about 0.7% w / w of the pharmaceutical composition, and the pharmaceutical composition is for administration to the subject in a dose of 20-30 |1L. In certain embodiments, the methods provided herein comprise administering to a subject with diabetic keratopathy a pharmaceutical composition comprising ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof; wherein the ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof in the pharmaceutical composition is in an amount of about 0.7% w / w of the pharmaceutical composition, and the pharmaceutical composition is for administration to the subject in a dose of 20-30 .L

[0073] In certain embodiments, the methods provided herein comprise administering to a subject with dry eye disease a pharmaceutical composition comprising dilithium ADPR, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof; wherein the dilithium ADPR, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof in the pharmaceutical composition is in an amount of about 0.7% w / w of the pharmaceutical composition, and the pharmaceutical composition is for administration to the subject in a dose of 30 pL. In certain embodiments, the methods provided herein comprise administering to a subject with symptomatic dry eye disease a pharmaceutical composition comprising dilithium ADPR, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof; wherein the dilithium ADPR, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof in the pharmaceutical composition is in an amount of about 0.7% w / w of the pharmaceutical composition, and the pharmaceutical composition is for administration to the subject in a dose of 30 pL In certain embodiments, the methods provided herein comprise administering to a subject with moderate symptomatic dry eye disease a pharmaceutical composition comprising dilithium ADPR, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof; wherein the dilithium ADPR, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof in the pharmaceutical composition is in an amount of about 0.7% w / w of the pharmaceutical composition, and the pharmaceutical composition is for administration to the subject in a dose of 30 pL. In certain embodiments, the methods provided herein comprise administering to a subject with diabetes or to a diabetic patient a pharmaceutical composition comprising dilithium ADPR, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof; wherein the dilithium ADPR, solvate,19NAI-5003660114V1Attorney Docket No.: 14161-015-228 hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof in the pharmaceutical composition is in an amount of about 0.7% w / w of the pharmaceutical composition, and the pharmaceutical composition is for administration to the subject in a dose of 30 pL. In certain embodiments, the methods provided herein comprise administering to a subject with diabetic keratopathy a pharmaceutical composition comprising dilithium ADPR, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof; wherein the dilithium ADPR, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof in the pharmaceutical composition is in an amount of about 0.7% w / w of the pharmaceutical composition, and the pharmaceutical composition is for administration to the subject in a dose of 30 pL.

[0074] The suitability of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, for improving visual acuity as described herein, can be confirmed by using the methods known to one of skill in the art and described herein.

[0075] In certain embodiments, the ADPR used in the dosage forms and dosing regimens provided herein is Li2-ADPR (i.e., dilithium ADPR).

[0076] In one embodiment, the method provided herein comprises administering to a subject a pharmaceutical composition comprising ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof; wherein the ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof in the pharmaceutical composition is in an amount of about 0.7% w / w of the pharmaceutical composition, and (b) the pharmaceutical composition is for administration to the subject two times a day in a dose of 30 pL each for a period of 1 to 14 days and thereafter once a day in a dose of 30 pL. In one embodiment, the method provided herein comprises administering to a subject a pharmaceutical composition comprising dilithium ADPR; wherein (a) the dilithium ADPR in the pharmaceutical composition is in an amount of about 0.7% w / w of the pharmaceutical composition, and (b) the pharmaceutical composition is for administration to the subject two times a day in a dose of 30 pL each for a period of 1 to 14 days and thereafter once a day in a dose of 30 pL. In one embodiment, the subject has diabetes or has low / poor visual acuity resulting from an eye disease or condition that is wet adult macular degeneration20NAI-5003660114V1Attorney Docket No.: 14161-015-228(AMD), dry AMD, diabetic keratopathy, diabetic retinopathy, diabetic macular edema, retinal vein occlusion, uveitis, primary or secondary corneal neovascularization, red eye, pterygium, ocular cancer, chemical injury of the cornea associated with neoangiogenesis, dry eye disease, symptomatic dry eye disease, moderate symptomatic dry eye disease, or severe symptomatic dry eye disease. In one embodiment, the subject has diabetes or has low / poor visual acuity resulting from an eye disease or condition that is diabetic keratopathy, dry eye disease, symptomatic dry eye disease, moderate symptomatic dry eye disease, or severe symptomatic dry eye disease.5.6 Pharmaceutical Compositions

[0077] Provided herein are pharmaceutical compositions comprising ADPR or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, effective for improving visual acuity in subjects having low / poor visual acuity. In one embodiment, the pharmaceutical composition is for topical administration. In one embodiment, the pharmaceutical composition is for topical administration to a subject having diabetes or to a diabetic patient. In one embodiment, the pharmaceutical composition is for topical administration to a subject having an eye disease or condition as described herein. In one embodiment, the pharmaceutical composition is for topical administration to a subject having low / poor visual acuity resulting from an eye disease or condition as described herein.

[0078] Pharmaceutical compositions may be used in the preparation of individual, single unit dosage forms. Pharmaceutical compositions and dosage forms of the present invention comprise ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof. The pharmaceutical compositions and dosage forms of the present invention can be prepared by any known or otherwise effective method for formulating or manufacturing the selected product form. For example, ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, can be formulated along with common excipients, diluents, or carriers, and formed into tablets, capsules, solutions, suspensions, emulsions, microemulsions, nanoemulsions, syrups, elixirs, sprays, powders, aerosols (e.g., dry powder aerosols, liquid aerosols), dissolving media (e.g., rapid dissolving tablet, film, strip), suppositories, ointments, or any other suitable dosage form. In a specific embodiment, the pharmaceutical composition is in the form of a solution.21NAI-5003660114V1Attorney Docket No.: 14161-015-228

[0079] Non-limiting examples of suitable excipients, diluents, and carriers include: fdlers and extenders such as starch, sugars, mannitol, and silicic derivatives; binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl pyrrolidone; moisturizing agents such as glycerol; disintegrating agents such as calcium carbonate and sodium bicarbonate; agents for retarding dissolution such as paraffin; resorption accelerators such as quaternary ammonium compounds; surface active agents such as acetyl alcohol, glycerol monostearate; adsorptive carriers such as kaolin and bentonite; carriers such as propylene glycol and ethyl alcohol, and lubricants such as talc, calcium and magnesium stearate, and solid polyethyl glycols. In certain embodiments, the pharmaceutical composition described herein comprises polyethylene glycol. In certain embodiments, the pharmaceutical composition described herein comprises polyethylene glycol 300 (PEG 300).

[0080] Like the amounts and types of excipients, the amount and specific type of the active ingredient (e.g., ADPR as disclosed herein) in a dosage form may differ depending on factors including, but not limited to, the route by which it is to be administered to subjects. Topical administration as described herein includes applying an effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, to any mucosal and / or epithelial surface of the body including that associated with, but not limited to, the skin, eyes, ears, nose, sinuses, mouth, lips, pharynx, larynx, epiglottis, trachea, bronchi, bronchioles, alveoli, esophagus, stomach, intestines, colon, rectum, anus, vagina, cervix, and any other portions of the dermatologic, gastrointestinal, respiratory, and / or genitourinary tracts.

[0081] Additionally, ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, can also be formulated as a sustained or prolonged release dosage forms including a dosage form that releases the active ingredient only or preferably in a particular part of the intestinal tract, preferably over an extended or prolonged period of time to further enhance effectiveness. In one embodiment, ADPR as described herein is formulated as a sustained or prolonged release dosage form including a dosage form that releases the active ingredient only or preferably in a particular part of the respiratory tract, preferably over an extended or prolonged period of time to further enhance effectiveness. The coatings, envelopes, and protective matrices in such a dosage form22NAI-5003660114V1Attorney Docket No.: 14161-015-228 may be made, for example, from polymeric substances or waxes well known in the pharmaceutical arts.

[0082] In one embodiment, provided herein are pharmaceutical compositions comprising ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, wherein the amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof in the pharmaceutical composition is in the range of about 0.0001% w / w to about 100% w / w of the pharmaceutical composition. In one embodiment, the amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof in the pharmaceutical composition is in the range of about 0.0001% w / w to about 90% w / w, about 0.0001% w / w to about 80% w / w, about 0.0001% w / w to about 70% w / w, about 0.0001% w / w to about 60% w / w, about 0.0001% w / w to about 50% w / w, about 0.0001% w / w to about 40% w / w, about 0.0001% w / w to about 30% w / w, about 0.0001% w / w to about 20% w / w, or about 0.0001% w / w to about 10% w / w of the pharmaceutical composition. In one embodiment, the pharmaceutical composition is in the form of a solution and the above- mentioned amounts of the ADPR are expressed in terms of ADPR percent weight by volume (i.e., % w / v).

[0083] In one embodiment, provided herein are pharmaceutical compositions comprising ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, wherein the amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof in the pharmaceutical composition is in the range of about 0.001% w / w to about 10% w / w of the pharmaceutical composition. In one embodiment, the amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof in the pharmaceutical composition is in the range of about 0.001% w / w to about 7% w / w, about 0.001% w / w to about 5% w / w, about 0.001% w / w to about 3% w / w, about 0.001% w / w to about 1% w / w, about 0.001% w / w to about 0.5% w / w, about 0.001% w / w to about 0.1% w / w, about 0.001% w / w to about 0.05% w / w, about 0.001% w / w to about 0.01% w / w, about 0.001% w / w to about 0.005% w / w, about 0.005% w / w to about 10% w / w, about 0.005% w / w to about 7% w / w, about 0.005% w / w to about 5% w / w, about 0.005% w / w to about 3% w / w, about 0.005% w / w to about 1% w / w, about 0.005% w / w to about 0.5% w / w, about 0.005% w / w to about 0.1% w / w, 23NAI-5003660114V1Attorney Docket No.: 14161-015-228 about 0.005% w / w to about 0.05% / i, about 0.005% w / w to about 0.01% w / w, about 0.01% w / w to about 10% w / w, about 0.01% w / w to about 7% w / w, about 0.01% w / w to about 5% w / w, about 0.01% w / w to about 3% w / w, about 0.01% w / w to about 1% w / w, about 0.01% w / w to about 0.5% w / w, about 0.01% w / w to about 0.1% w / w, about 0.01% w / w to about 0.05% w / w, about 0.05% w / w to about 10% w / w, about 0.05% w / w to about 7% w / w, about 0.05% w / w to about 5% w / w, about 0.05% w / w to about 3% w / w, about 0.05% w / w to about 1% w / w, about 0.05% w / w to about 0.5% w / w, about 0.05% w / w to about 0.1% i N, about 0.1% w / w to about 10% w / w, about 0.1% w / w to about 7% w / w, about 0.1% w / w to about 5% w / w, about 0.1% w / w to about 3% w / w, about 0.1% w / w to about 1% w / w, about 0.1% w / w to about 0.5% w / w, about 0. 5% w / w to about 10% w / w, about 0. 5% w / w to about 7% w / w, about 0. 5% w / w to about 5% w / w, about 0. 5% w / w to about 3% w / w, about 0. 5% w / w to about 1% w / w, about 1% w / w to about 10% w / w, about 1% w / w to about 7% w / w, about 1% w / w to about 5% w / w, about 1% w / w to about 3% w / w, about 3% w / w to about 10% w / w, about 3% w / w to about 7% w / w, about 3% w / w to about 5% w / w, about 5% w / w to about 10% w / w, about 5% w / w to about 7% w / w, or about 7% w / w to about 10% w / w of the pharmaceutical composition. In one embodiment, the pharmaceutical composition is in the form of a solution and the above-mentioned amounts of the ADPR are expressed in terms of ADPR percent weight by volume (i.e., % w / v).

[0084] In one embodiment, the amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof in the pharmaceutical composition is in the range of about 0.01% w / w to about 10% w / w of the pharmaceutical composition. In one embodiment, the amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof in the pharmaceutical composition is in the range of about 0.1% w / w to about 2.5% w / w of the pharmaceutical composition. In another embodiment, the amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof in the pharmaceutical composition is in the range of about 0.5% w / w to about 2% w / w of the pharmaceutical composition. In another embodiment, the amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof in the pharmaceutical composition is in the range of about 0.01% w / w to about 1% w / w of the pharmaceutical composition. In one embodiment, the24NAI-5003660114V1Attorney Docket No.: 14161-015-228 pharmaceutical composition is in the form of a solution and the above-mentioned amounts of the ADPR are expressed in terms of ADPR percent weight by volume (i.e., % w / v).

[0085] In one embodiment, the pharmaceutical composition comprising ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof is administered to a subject in need thereof in a dose of 5-50 pL. In one embodiment, the pharmaceutical composition comprising ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof is administered to a subject in need thereof in a dose of 20-50, 20-40 or 20-30 pL. In one embodiment, the pharmaceutical composition comprising ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof is administered to a subject in need thereof in a dose of 5-10, 10-15, 15-20, 20-25, or 25-30 pL. In one embodiment, the pharmaceutical composition comprising ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof is administered to a subject with dry eye disease (DED) in a dose of 20-40 pL. In one embodiment, the pharmaceutical composition comprising ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof is administered to a subject with dry eye disease (DED) in a dose of 5, 7, 10, 15, 20, 30 or 40 pL. In one embodiment, the pharmaceutical composition comprising ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof is administered to a subject with dry eye disease (DED) in a dose of 30 pL. In one embodiment, the ADPR is dilithium ADPR.

[0086] In one embodiment, the pharmaceutical composition comprising ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof is administered to a subject with symptomatic dry eye disease (DED) in a dose of 20-40 pL. In one embodiment, the pharmaceutical composition comprising ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof is administered to a subject with symptomatic dry eye disease (DED) in a dose of 20, 30 or 40 pL. In one embodiment, the pharmaceutical composition comprising ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer,25NAI-5003660114V1Attorney Docket No.: 14161-015-228 isotopologue, or polymorph thereof is administered to a subject with symptomatic dry eye disease (DED) in a dose of 30 pL. In one embodiment, the ADPR is dilithium ADPR.

[0087] In one embodiment, the pharmaceutical composition comprising ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof is administered to a subject with moderate symptomatic dry eye disease (DED) in a dose of 20-40 pE. In one embodiment, the pharmaceutical composition comprising ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof is administered to a subject with moderate symptomatic dry eye disease (DED) in a dose of 20, 30 or 40 pE. In one embodiment, the pharmaceutical composition comprising ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof is administered to a subject with moderate symptomatic dry eye disease (DED) in a dose of 30 pL. In one embodiment, the ADPR is dilithium ADPR.

[0088] In one embodiment, the pharmaceutical composition comprising ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof is administered to a subject having diabetes or to a diabetic patient in a dose of 20-40 pL. In one embodiment, the pharmaceutical composition comprising ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof is administered to a subject having diabetes or to a diabetic patient in a dose of 20, 30 or 40 pE. In one embodiment, the pharmaceutical composition comprising ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof is administered to a subject having diabetes or to a diabetic patient in a dose of 30 pL. In one embodiment, the ADPR is dilithium ADPR.

[0089] In one embodiment, the pharmaceutical composition comprising ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof is administered to a subject with diabetic keratopathy in a dose of 20-40 pL. In one embodiment, the pharmaceutical composition comprising ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof is administered to a subject with diabetic keratopathy in a dose of 20, 30 or 40 pE. In one embodiment, the pharmaceutical composition comprising ADPR, or a pharmaceutically26NAI-5003660114V1Attorney Docket No.: 14161-015-228 acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof is administered to a subject with diabetic keratopathy in a dose of 30 pL. In one embodiment, the ADPR is dilithium ADPR.

[0090] In certain embodiments, the pharmaceutical composition provided herein comprises(i) dilithium ADPR, or a solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, and (ii) one or more pharmaceutically acceptable excipients; wherein the amount of dilithium ADPR in the pharmaceutical composition is in the range of about 0.001% w / w to about 10% w / w of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition provided herein comprises (i) dilithium ADPR, or a solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, and (ii) one or more pharmaceutically acceptable excipients; wherein the amount of dilithium ADPR in the pharmaceutical composition is in the range of about 0.01% w / w to about 1% w / w of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition provided herein comprises (i) dilithium ADPR, or a solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, and(ii) one or more pharmaceutically acceptable excipients; wherein the amount of dilithium ADPR in the pharmaceutical composition is in the range of about 0.1% w / w to about 1.0% w / w of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition provided herein comprises (i) dilithium ADPR, or a solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, and (ii) one or more pharmaceutically acceptable excipients; wherein the amount of dilithium ADPR in the pharmaceutical composition is about 0.7% w / w of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition provided herein comprises (i) dilithium ADPR, or a solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, and (ii) one or more pharmaceutically acceptable excipients; wherein the amount of dilithium ADPR in the pharmaceutical composition is about 0.7% w / w of the pharmaceutical composition, and the pharmaceutical composition is for administration to a subject with an eye disease or condition in a dose of 20-40 pL In certain embodiments, the pharmaceutical composition provided herein comprises (i) dilithium ADPR, or a solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, and (ii) one or more pharmaceutically acceptable excipients; wherein the amount of dilithium ADPR in the pharmaceutical composition is about 0.7% w / w of the pharmaceutical composition, and the pharmaceutical composition is for administration to a subject with an eye disease or condition in27NAI-5003660114V1Attorney Docket No.: 14161-015-228 a dose of 30 pL. In certain embodiments, the pharmaceutical composition provided herein comprises (i) dilithium ADPR, or a solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, and (ii) one or more pharmaceutically acceptable excipients; wherein the amount of dilithium ADPR in the pharmaceutical composition is about 0.7% w / w of the pharmaceutical composition, and the pharmaceutical composition is for administration to a subject with dry eye disease in a dose of 30 pL. In certain embodiments, the pharmaceutical composition provided herein comprises (i) dilithium ADPR, or a solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, and (ii) one or more pharmaceutically acceptable excipients; wherein the amount of dilithium ADPR in the pharmaceutical composition is about 0.7% w / w of the pharmaceutical composition, and the pharmaceutical composition is for administration to a subject with symptomatic dry eye disease in a dose of 30 pL. In certain embodiments, the pharmaceutical composition provided herein comprises (i) dilithium ADPR, or a solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, and (ii) one or more pharmaceutically acceptable excipients; wherein the amount of dilithium ADPR in the pharmaceutical composition is about 0.7% w / w of the pharmaceutical composition, and the pharmaceutical composition is for administration to a subject with moderate symptomatic dry eye disease in a dose of 30 pL. In certain embodiments, the pharmaceutical composition provided herein comprises (i) dilithium ADPR, or a solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, and (ii) one or more pharmaceutically acceptable excipients; wherein the amount of dilithium ADPR in the pharmaceutical composition is about 0.7% w / w of the pharmaceutical composition, and the pharmaceutical composition is for administration to a subject having diabetes or to diabetic patient in a dose of 30 pL. In certain embodiments, the pharmaceutical composition provided herein comprises (i) dilithium ADPR, or a solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, and (ii) one or more pharmaceutically acceptable excipients; wherein the amount of dilithium ADPR in the pharmaceutical composition is about 0.7% w / w of the pharmaceutical composition, and the pharmaceutical composition is for administration to a subject with diabetic keratopathy in a dose of 30 pL. In one embodiment, the pharmaceutical composition is in the form of a solution and the above-mentioned amounts of dilithium ADPR are expressed in terms of ADPR percent weight by volume (i.e., % w / v).28NAI-5003660114V1Attorney Docket No.: 14161-015-228

[0091] In one embodiment, the pharmaceutical composition is suitable for administration to the eye. In a specific embodiment, the pharmaceutical composition suitable for administration to the eye further comprises a topical anesthetic which relieves pain. In one embodiment, the topical anesthetic is proparacaine, lidocaine, tetracaine or combinations thereof.

[0092] In one embodiment, the pharmaceutical composition further comprises a penetration enhancer which enhances the penetration of ADPR into the tissues of the eye, mouth, nose, throat, larynx, trachea, lung (respiratory tract), skin, vagina, cervix, anus, and / or ear. In a specific embodiment, the penetration enhancer is a topical anesthetic.

[0093] In one embodiment, the pharmaceutical composition further comprises an antimicrobial preservative. In one embodiment, the antimicrobial preservative is sodium tetraborate, boric acid, benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, EDTA, sorbic acid, Onamer M or combinations thereof. In one embodiment, the amount of antimicrobial preservative in the pharmaceutical composition is in the range of about 0.001% w / w to about 1.0% w / w or about 0.001% w / v to about 1.0% w / v of the pharmaceutical composition. In a specific embodiment, the pharmaceutical composition is in the form of a solution.

[0094] In one embodiment, the pharmaceutical composition further comprises a cosolvent / surfactant. In one embodiment, the cosol vent / surfactant is polysorbate 20, polysorbate 60, polysorbate 80, Pluronic F68, Pluronic F84, Pluronic P103, cyclodextrin, tyloxapol or combinations thereof. In one embodiment, the amount of the cosolvent / surfactant in the pharmaceutical composition is in the range of about 0.01% w / w to about 2% w / w or about 0.01% w / v to about 2% w / v of the pharmaceutical composition.

[0095] In one embodiment, the pharmaceutical composition further comprises one or more viscosity increasing agents. In one embodiment, the viscosity increasing agent is polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose, polyethylene glycol, or combinations thereof. In one embodiment, the amount of the viscosity increasing agent in the pharmaceutical composition is in the range of about 0.01% w / w to about 2% w / w or about 0.01% w / v to about 2% w / v of the pharmaceutical composition. In a specific embodiment, the pharmaceutical composition is in the form of a solution.29NAI-5003660114V1Attorney Docket No.: 14161-015-228

[0096] In one embodiment, the pharmaceutical composition is in the form of a solution, suspension, emulsion, ointment, cream, gel, or a controlled release / sustained release formulation. In one embodiment, the pharmaceutical composition is in the form of a solution, suspension, suspension, emulsion, microemulsion, nanoemulsion, syrup, elixir, dry powder, aerosol, liquid aerosol, tablet, or dissolving media. In one embodiment, the dissolving media is a rapid dissolving tablet, film or strip. In one embodiment, the pharmaceutical composition is in the form of an aqueous solution.

[0097] In certain embodiments, the ADPR used in the pharmaceutical compositions provided herein is Li2-ADPR (i.e., dilithium ADPR).5.6.1 Topical ocular formulations

[0098] In certain embodiments, a pharmaceutical formulation described in above may be specifically adjusted for topical application to the eye. In certain specific embodiments, disclosed herein are pharmaceutical formulations comprising ADPR as described herein as topical ophthalmic solutions or suspensions (eye drops), which are normally available as a sterile, isotonic (i.e., a pH of between about 3 and about 8, between about 4 to about 8, between about 7 to about 8, or about 7.4) solution, optionally further comprising a preservative and / or a viscosity enhancer. In one embodiment, the pharmaceutical composition comprising ADPR as described herein is in the form of eye drops. In one embodiment, the pharmaceutical composition comprising ADPR as described herein is administered in the form of eye drops.

[0099] The term “eye drops” as used herein refers to a pharmaceutical liquid formulation which is administered in the form of drops on the external surface of the eye and which has a local effect on the posterior segment of the eye, including the choroids, retinal pigment epithelium, retina, macula, fovea, optic nerve and vitreous humor.

[0100] Accordingly, in certain embodiments, a pharmaceutical formulation provided herein comprising ADPR as described herein, may be formulated with purified water and adjusted for physiological pH and isotonicity. Examples of buffering agents to maintain or adjust pH include, but are not limited to, acetate buffers, citrate buffers, phosphate buffers and borate buffers. Examples of tonicity adjustors are sodium chloride, mannitol and glycerin.30NAI-5003660114V1Attorney Docket No.: 14161-015-228

[0101] The eye drop formulation is then optionally aliquoted into either a plurality of discrete, sterile disposable cartridges each of which is suitable for unit dosing, or a single cartridge for unit dosing. Such a single disposable cartridge may be, for example, a conical or cylindrical specific volume dispenser, with a container having side-walls squeezable in a radial direction to a longitudinal axis in order to dispense the container contents therefrom at one end of the container. Such disposable containers can be used to dispense eye drops at about 0.01 to about 1 mL per unit dosing, about 0.01 to about 0.5 mL per unit dosing, about 0.01 to about 0.1 mL per unit dosing, about 0.03 to 0.04 mL per unit dosing, and are ideally adaptable for the delivery of eye drops. In one embodiment, disposable containers can be used to dispense eye drops at about 20 pL to about 30 pL per unit dosing, and are ideally adaptable for the delivery of eye drops.

[0102] Ophthalmic eye-drop solutions or suspensions may also be packaged in multi-dose form, for example, as a plastic bottle with an eye dropper. In such formulations, preservatives are optionally added to prevent microbial contamination after opening of the container. Suitable preservatives include, but are not limited to, sodium tetraborate, boric acid, benzalkonium chloride, thimerosal, chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol, edetate disodium, sorbic acid, polyquaternium-1, or other agents known to those skilled in the art, and all of which are contemplated for use in the present invention. Preservative-containing formulations may comprise from about 0.001 to about 1.0% weight / volume of the preservative.

[0103] In certain embodiments, polymers may be added to ophthalmic solutions or suspensions in order to increase the viscosity of the vehicle, thereby prolonging contact of the solution or suspension with the cornea and enhancing bioavailability. In certain embodiments, such polymers are selected from cellulose derivatives (e.g., methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose or carboxymethylcellulose), dextran 70, gelatin, polyols, glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate 80, propylene glycol, polyvinyl alcohol and povidone, or a combination thereof.

[0104] In certain embodiments ophthalmic solutions or suspensions as disclosed herein may further comprise stabilizer / solubilizer such as a cyclodextrin. In certain such embodiments, the cyclodextrin is selected from a-cyclodextrin, P-cyclodextrin, y-cyclodextrin, hydroxypropyl-0- cyclodextrin, hydroxypropyl-y-cyclodextrin, dimethyl-[3- cyclodextrin and dimethyl-y- cyclodextrin.31NAI-5003660114V1Attorney Docket No.: 14161-015-228

[0105] In certain embodiments, a pharmaceutical formulation as disclosed herein, such as a pharmaceutical formulation comprising ADPR as described herein, may be administered in a sustained release ophthalmic solution or suspension formulation.

[0106] In certain embodiments, a pharmaceutical formulation as disclosed herein, such as a pharmaceutical formulation comprising ADPR as described herein, may be formulated for administration through an ocular drug delivery system, such as, but not limited to, a colloidal dosage form, such as nanoparticles, nanomicelles, liposomes, microemulsions, bioadhesive gels and fibrin sealant-based approaches to sustain drug levels at the target site. Other ocular drug delivery systems include drug-eluting contact lenses, ultrasound-mediated drug delivery, ocular iontophoresis, and drug-coated microneedles.

[0107] In certain embodiments, the frequency of administration can vary greatly. Depending on the needs of each subject and the severity of the disease or condition to be treated, such administration may occur once every 6 months, once every 5 months, once every 4 months, once every 3 months, once every 2 months, once a month, once every 3 weeks, once every 2 weeks, once a week, once every 6 days, once every 5 days once every 4 days once every 3 days, once every 2 days, or once a day.

[0108] In certain embodiments, the frequency of administration can vary greatly, depending on the needs of each subject and the severity of the disease or condition to be treated, such administration may be from about once a week to about ten times a day, such as from about three times a week to about three times a day, or once or twice a day.

[0109] In certain embodiments, the ADPR used in the topical ocular formulations provided herein is Li2-ADPR (i.e., dilithium ADPR).

[0110] Evaluation of Activity

[0111] Standard physiological, pharmacological and biochemical procedures are available for testing the compounds to identify those that possess the desired activity.6 EXAMPLES6.1 Example 1. Human Study

[0112] A Phase 2 randomized, double-masked, and vehicle-controlled study was conducted to evaluate INV-102 (dilithium ADPR) in subjects with moderate to severe dry eye disease (DED). One hundred and nine (109) subjects were randomized 1 : 1 to INV-102 or vehicle, and 32NAI-5003660114V1Attorney Docket No.: 14161-015-228 instilled topical ocular study drug INV-102 in both eyes for 4 weeks (twice daily [BID] for Days 1-14, then once daily [QD] for Days 15-28; no treatment was given after Day 28). INV-102 was administered as a solution comprising 0.7% dilithium ADPR and at a dose of 30 pL in each eye. The solution was a clear, colorless, aqueous, sterile-filtered solution containing INV-102 and the excipients sodium chloride, boric acid, polyethylene glycol 300, and glycerine. The pH of the drug product solution was adjusted with 1 N HC1 or NaOH solutions, with a finished product specification of pH 6.0 to 7.5. All excipients and water used were either National Formulary or United States Pharmacopeia grade. INV-102 was provided in a concentration of 0.7%. Vehicle Ophthalmic Solution was identical to the formulation of INV-102 Ophthalmic Solution but did not contain the active ingredient. For each subject one eye was designated as the “Study Eye” and the other eye was the “Fellow Eye.” Multiple endpoints were measured including but not limited to comeal fluorescein staining (CFS) and visual acuity. There were 26 subjects (15 treated with INV-102 and 11 treated with Vehicle) who had a medical history of diabetes and were on standard treatment(s) for their diabetes.

[0113] CFS is a valuable clinical tool to assess the viability of the epithelium. The elementary lesions that characterize dry eye disease (DED) are small epithelial erosions staining with fluorescein scattered over the corneal surface, which sometimes become confluent in larger areas where single lesions are no longer visible. The density and the extent of the corneal staining provide useful information to assess disease severity and to monitor the response to treatment.

[0114] CFS was measured using the National Eye Institute (NEI) industry scale, which divides the ocular surface into five regions (with the central and inferior regions being the most clinically relevant as those are the regions that can affect visual acuity) and assigns a value from 0 (absent) to 3 (severe) to each section, based on the amount, size, and confluence of the epithelial lesions, for a maximum of 15 points. Each region was graded on a scale of 0-3. Total CFS was the cumulative score of all five regions.

[0115] Visual acuity was measured as Best Corrected Visual Acuity (BCVA). BCVA was measured for each eye using an Early Treatment Diabetic Retinopathy Study (ETDRS) chart as per the Investigator’s standard clinical practice and performed with best correction. Best- corrected visual acuity refraction was used for all visual acuity assessments for the duration of the study. Subject wore the same glasses / trial frame (if applicable) at each visit.33NAI-5003660114V1Attorney Docket No.: 14161-015-228

[0116] Results

[0117] As measured on Days 15 and 29, for all the subjects treated with INV-102 (dilithium ADPR), there was a significant rise in visual acuity (p<0.05) from Day 1 in the number of letters read (see Figure 1). Significance was determined by a paired t-test. The vehicle treated group did not have a significant increase in visual acuity on Days 15 or 29 (see Figure 1).

[0118] In addition, in subjects with low visual acuity at baseline (<50 letters), on Day 29, in the Study Eye, INV-102 change in Total corneal fluorescein staining (CFS) was correlated with change in visual acuity (Pearson correlation coefficient = -0.297, p = 0.1783). There was a clear trend for an inverse correlation between change in CFS and change in visual acuity only in the INV-102 treated subjects (see Figure 2) who initiated the study with reduced visual acuity (<50 letters). This indicated that as CFS staining was reduced, visual acuity was improved. Thus, as CFS staining was reduced from Day 1, there was a concurrent increase in the visual acuity in the INV-102 treated group (Figure 2). This pattern was not present in the vehicle treated group.

[0119] The Vehicle group had both a poor correlation (Pearson correlation coefficient = - 0.169, p = 0.4640) and sloped into the nonsensical direction of increasing CFS and increasing visual acuity. There were 22 subjects in the INV-102 group and 21 subjects in the Vehicle group with visual acuity ^50 letters. The best fit lines were calculated using JMP to illustrate the correlation and the directionality of the two groups.

[0120] In evaluating the study eye of the diabetic subjects (n=26), INV-102 treatment led to a significant rise in visual acuity (increase in the number of letters read) from baseline at Days 15 and 29 (p<0.05 and p=0.0509 respectively). Difference from baseline significance was determined by a paired t-test (see Figure 3). The vehicle treated group did not have a significant increase on Days 15 or 29. In fact, the vehicle group showed a modest decrease in visual acuity. The increase in visual acuity in the INV-102 treated diabetic subjects was significantly greater than vehicle treated subjects on Days 15 and 29 (p<0.05). The significant difference from vehicle was determined by a t-test of two independent samples.

[0121] In the diabetics, when looking at the average of the two eyes on Day 15, the average inferior CFS change in the INV-102 group was significantly correlated with change in average visual acuity (Pearson correlation coefficient = -0.699, p = 0.0037) (see Figure 4). The average central CFS change exhibited a near significant correlation with change in average visual acuity34NAI-5003660114V1Attorney Docket No.: 14161-015-228(Pearson correlation coefficient = -0.431, p = 0.1085). The Vehicle group exhibited no meaningful correlation. The best fit lines were calculated using JMP Software (version 18) to illustrate the correlation and the directionality of the two groups. Figure 4 provides a plot of the linear correlation between the change in the CFS in the central and inferior regions of the cornea (which are the regions of the cornea that are most critical for visual acuity) and the change in visual acuity in the diabetics only on Day 15 of treatment. Figure 4 shows that as CFS staining was reduced from Day 1, there was a concurrent increase in the visual acuity in the dilithium ADPR treated group. This pattern was not present in the vehicle treated group. The correlation was most significant (p=0.0037) for the inferior region, though the pattern was identical for the central region. There was no correlation evident for the vehicle treated subjects.

[0122] Overall, data from this study indicated that INV-102 treated subjects demonstrated a significant increase in visual acuity relative to baseline, whereas the vehicle treated subjects did not change their visual acuity. The effect on visual acuity was even significantly greater in diabetic patients.

[0123] The changes in visual acuity paired with improvement in CFS indicate a novel mechanism whereby visual acuity (e.g., diabetic visual acuity) is improved through a front of the eye mechanism involving the cornea, conjunctiva, and / or sclera. Through targeting the anterior segment of the eye, visual acuity may be improved in patients with an eye disease or condition, particularly in diabetic patients.

[0124] The data above indicate that INV-102 could be useful for regaining vision loss caused by certain complications (e.g., diabetic complications) in the anterior segment of the eye. While INV-102 impacts DNA damage repair in normal conditions, diabetic patients may be especially impacted by its mechanism of action.

[0125] Embodiments provided herein may be more fully understood by reference to the following examples. These examples are meant to be illustrative of pharmaceutical compositions and dosage forms provided herein, but are not in any way limiting.

[0126] The embodiments described above are intended to be merely exemplary, and those skilled in the art will recognize, or will be able to ascertain using no more than routine experimentation, numerous equivalents of specific compounds, materials, and procedures. All such equivalents are considered to be within the scope of the invention and are encompassed by the appended claims.35NAI-5003660114V1

Claims

Attorney Docket No.: 14161-015-228CLAIMS1. A method for improving visual acuity in a subject, wherein the method comprises administering to the subject an effective amount of a compound that is 5’-adenosine diphosphate ribose (ADPR), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof.

2. The method of claim 1, wherein the compound is ADPR in the form of its lithium salt.

3. The method of claim 1, wherein the compound is dilithium ADPR.

4. The method of claim 1, wherein the compound is ADPR in the form of its sodium salt.

5. The method of claim 1, wherein the compound is ADPR in the form of its disodium salt.

6. The method of any one of the preceding claims, wherein the subject has diabetes or is one who has low / poor visual acuity resulting from an eye disease or condition.

7. The method of any one of the preceding claims, wherein the subject has diabetes or is one who has low / poor visual acuity resulting from an eye disease or condition that is wet adult macular degeneration (AMD), dry AMD, diabetic keratopathy, diabetic retinopathy, diabetic macular edema, retinal vein occlusion, uveitis, primary or secondary corneal neovascularization, red eye, pterygium, ocular cancer, chemical injury of the cornea associated with neoangiogenesis, dry eye disease, symptomatic dry eye disease, moderate symptomatic dry eye disease, or severe symptomatic dry eye disease.

8. The method of any one of the preceding claims, wherein the subject has diabetes or is one who has low / poor visual acuity resulting from an eye disease or condition that is diabetic keratopathy, dry eye disease, symptomatic dry eye disease, moderate symptomatic dry eye disease, or severe symptomatic dry eye disease.36NAI-5003660114V1Attorney Docket No.: 14161-015-2289. The method of any one of the preceding claims, wherein the subject is one who has low / poor visual acuity resulting from an eye disease or condition that is moderate or severe symptomatic dry eye disease.

10. The method of any one of the preceding claims, wherein the administering to the subject is via topical administration to the eye of the subject.

11. The method of any one of the preceding claims, wherein the administering to the subject is via intravitreal administration.

12. A method for improving visual acuity in a subject, wherein the method comprises administering to the subject a pharmaceutical composition comprising an effective amount of a compound that is 5 ’-adenosine diphosphate ribose (ADPR), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof.

13. The method of claim 12, wherein the subject has diabetes or is one who has low / poor visual acuity resulting from an eye disease or condition that is diabetic keratopathy, dry eye disease, symptomatic dry eye disease, moderate symptomatic dry eye disease, or severe symptomatic dry eye disease.

14. The method of claim 13, wherein the subject is one who has low / poor visual acuity resulting from an eye disease or condition that is moderate or severe symptomatic dry eye disease.

15. The method of claim 13 or 14, wherein the pharmaceutical composition is in the form of a solution and the administering to the subject is via topical administration to the eye of the subject.

16. The method of any one of claims 12-15, wherein the pharmaceutical composition comprises (i) dilithium ADPR, or a solvate, hydrate, tautomer, stereoisomer,37NAI-5003660114V1Attorney Docket No.: 14161-015-228 isotopologue, or polymorph thereof, and (ii) one or more pharmaceutically acceptable excipients; wherein the amount of dilithium ADPR in the pharmaceutical composition is in the range of about 0.001% w / w to about 10 % w / w of the pharmaceutical composition.

17. The method of claim 16, wherein the amount of dilithium ADPR in the pharmaceutical composition is about 0.7% w / w of the pharmaceutical composition.

18. The method of any one of claims 15-17, wherein the solution is administered one to three times a day in a dose of 20-30 pL.

19. The method of claim 18, wherein the solution is administered once a day in a dose of 30 pL each.

20. The method of claim 18, wherein the solution is administered two times a day in a dose of 30 pL each.

21. The method of claim 18, wherein the solution is administered three times a day in a dose of 30 pL each.

22. The method of claim 18, wherein the solution is administered one to three times a day in a dose of 20-30 pL for a period of 1 to 30 days.38NAI-5003660114V1

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