WO2025122455A1

WO2025122455A1 - Methods for the use of 5'-adenosine diphosphate ribose (adpr) for vegf modulation

Info

Publication number: WO2025122455A1
Application number: PCT/US2024/058186
Authority: WO
Inventors: Robert Shalwitz
Original assignee: Invirsa Inc
Current assignee: Invirsa Inc
Priority date: 2023-12-04
Filing date: 2024-12-03
Publication date: 2025-06-12
Anticipated expiration: 2026-06-04

Abstract

The present invention is directed to methods for the use of 5'-adenosine diphosphate ribose (ADPR), and compositions thereof, for treating, managing, or preventing VEGF modulated diseases or conditions.

Description

METHODS FOR THE USE OF 5’-ADENOSINE DIPHOSPHATE RIBOSE (ADPR) FOR VEGF MODULATION

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63/605,852, filed December 4, 2023, 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 treating, managing, or preventing abnormal angiogenic disorders modulated by vascular endothelial growth factor (VEGF).

2 BACKGROUND OF THE INVENTION

[0003] Aberrant angiogenesis is implicated in the pathogenesis of a number of disorders, including solid tumors and metastasis as well as eye diseases. Numerous cytokines and growth factors that stimulate angiogenesis, such as VEGF, FGF-2, PDGF, IGF-1, TGF, TNF-a, G-CSF have been identified, among which, Vascular Endothelial Growth Factor (VEGF) plays a central role in angiogenesis. VEGF, also known as VEGF-A, was initially identified for its ability to induce vascular permeability and to promote vascular endothelial cell proliferation.

VEGF belongs to a gene family that includes placenta growth factor (PIGF), VEGF-B, VEGF- C, VEGF-D, VEGF-E and VEGF-F. Alternative splicing of mRNA of a single gene of human VEGF results in at least six isoforms (VEGF121, VEGF145, VEGF165, VEGF183, VEGF 189, and VEGF206), VEGF 165 being the most abundant isoform.

[0004] VEGF has been reported to be a pivotal regulator of both normal and abnormal angiogenesis (Ferrara and Davis-Smyth, Endocrine Rev. 1997, 18: 4-25; Ferrara J. MoL Med. 1999, 77: 527-543). Compared to other growth factors that contribute to the processes of vascular formation, VEGF is unique in its high specificity for endothelial cells within the vascular system. [0005] VEGF mRNA is overexpressed by the majority of human tumors. Tn the case of tumor growth, angiogenesis appears to be crucial for the transition from hyperplasia to neoplasia, and for providing nourishment for the growth and metastasis of the tumor (Folkman et al., 1989, Nature 339-58), which allows the tumor cells to acquire a growth advantage compared to the normal cells. Therefore, modulation of VEGF production may reduce angiogenesis and permit treatment of various tumors that are associated with aberrant angiogenesis.

[0006] VEGF is also involved in eye diseases. The concentration of VEGF in eye fluids is highly correlated with the presence of active proliferation of blood vessels in patients with diabetic and other ischemia-related retinopathies.

[0007] Consequently, there is a need to develop compounds that modulate VEGF levels.

3 SUMMARY OF THE INVENTION

[0008] In one embodiment, provided herein is a method for modulating the activity of VEGF protein in a subject, wherein the method comprises administering to the subject an effective amount of 5 ’-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 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.

[0009] In one embodiment, provided herein is a method of reducing an elevated level of VEGF in a subject having an elevated level of VEGF, wherein the method comprises administering to the subject an effective amount of 5’-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 method comprises topical administration of the effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof.

[0010] In one embodiment, provided herein is a method of modulating a VEGF level in a subject in need thereof, wherein the method comprises administering 5 ’-adenosine diphosphate ribose (ADPR), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof; and measuring a change in the VEGF level in the subject. In one embodiment, the method comprises topical administration of the effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof.

[0011] A further embodiment relates to a method of reducing a VEGF level in a human with an elevated VEGF level, wherein the method comprises administering to the subject an effective amount of 5 ’-adenosine diphosphate ribose (ADPR), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof; and measuring a reduction in the VEGF level in the human. In one embodiment, the method comprises topical administration of the effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof.

[0012] In one embodiment, provided herein is a method for treating, managing, or preventing an abnormal angiogenic disorder in a subject, wherein the method comprises administering to the subject an effective amount of 5 ’-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 method comprises topical administration of the effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof.

[0013] In one embodiment, provided herein is a method for inhibiting abnormal angiogenesis in a subject, wherein the method comprises administering to the subject an effective amount of 5 ’-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 method comprises topical administration of the effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof.

[0014] In one embodiment, provided herein is a method of achieving or maintaining vascular homeostasis in a subject, wherein the method comprises administering to the subject 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 method comprises topical administration of the effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof. In certain embodiments, vascular homeostasis refers to a balance between vascular injury and vascular repair.

[0015] In one embodiment, the abnormal angiogenic disorder is a disorder of an eye, lung, cervix or skin.

[0016] In one embodiment, provided herein is a method for treating, managing, or preventing excessive neovascularization in a subject, said method comprising administering to the subject an effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof; wherein the subject has or is at risk of developing a disease or condition associated with excessive neovascularization. In one embodiment, the method comprises topical administration of the effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof.

[0017] In one embodiment, provided herein is a method for treating, managing, or preventing a disease or condition associated with excessive neovascularization in a subject, said method comprising administering to the subject an effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof; wherein the subject has an elevated VEGF level. In one embodiment, the method comprises topical administration of the effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof.

[0018] In one embodiment, provided herein is a method for treating, managing, or preventing a disease or condition associated with excessive neovascularization in a subject, said method comprising administering to the subject an effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof; wherein the subject has or is at risk of developing a disease or condition associated with excessive neovascularization. In one embodiment, the method comprises topical administration of the effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof.

[0019] In one aspect, provided herein is a method of reducing the amount and/or the activity of VEGF in a subject in need thereof, wherein the method comprises administering to the subject an effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof; wherein the subject has or is at risk of developing a disease or condition treatable, manageable, or preventable by reducing the amount and/or the activity of VEGF. In one embodiment, the method comprises topical administration of the effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof.

[0020] In one aspect, provided herein is a method for normalization of regional VEGF level in a subject, wherein the method comprises administering to the subject an effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof; such that elevated levels of VEGF are reduced without causing complete suppression of the level of VEGF. In one embodiment, the method comprises topical administration of the effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof.

[0021] In another aspect, provided herein is a method of reducing the elevated level of VEGF while avoiding complete suppression of VEGF in a subject, wherein the method comprises administering to the subject 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 method comprises topical administration of the effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof.

[0022] In one embodiment, the methods provided herein comprise systemic 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. [0023] In certain embodiments, the methods provided herein comprise topically administering to the patient a pharmaceutical composition comprising ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, and an excipient, diluent, or carrier.

[0024] In a specific embodiment, the ADPR compound for use in the compositions and methods provided herein is in the form of its dilithium salt.

[0025] In certain embodiments, ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof; is administered topically in combination with a second agent. In certain embodiments, the second agent is an anti-VEGF agent.

[0026] 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

[0027] FIGURE 1 is Nanosep MF Centrifugal Device with Bio-Inert® Membrane 0.45 pm. [0028] FIGURE 2 provides plots for tear VEGF change from baseline on day 8 in patients having moderate symptomatic dry eye disease in 1) patients treated with Li2-ADPR twice a day, 2) patients treated with Li2-ADPR three times a day, and 3) control.

[0029] FIGURE 3 provides plots for tear VEGF change from baseline on day 15 in patients having moderate symptomatic dry eye disease in 1) patients treated with Li2-ADPR twice a day, 2) patients treated with Li2-ADPR three times a day, and 3) control.

[0030] FIGURE 4 provides plots for tear VEGF change from baseline on day 22 in patients having moderate symptomatic dry eye disease in 1) patients treated with Li2-ADPR twice a day, 2) patients treated with Li2-ADPR three times a day, and 3) control.

[0031] FIGURE 5 is a plot of tear VEGF change from baseline (pg/mL) vs. tear VEGF at baseline (pg/mL) on day 15 in patients having moderate symptomatic dry eye disease treated with Li2-ADPR twice a day.

[0032] FIGURE 6A depicts an Optical Coherence Tomography image at week 4 in a patient having diabetic retinopathy with non-center macular edema treated with 0.7% Li2ADPR twice a day. The numbers shown in the grid overlay indicate the mean subfield thickness for each region of the macula. FIGURE 6B depicts an Optical Coherence Tomography image at week 8 in the same patient who continued the U2ADPR treatment and started receiving 0.005% latanoprost once-a-day starting at week 6. The numbers shown in the grid overlay indicate the mean subfield thickness for each region of the macula.

5 DETAILED DESCRIPTION

5.1 Definitions

[0033] 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.

[0034] 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’. Consequently, the term “consisting of’ can be used in place of the terms “comprising” and “including” to provide for more specific embodiments of the invention.

[0035] 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.

[0036] 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. [0037] 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. [0038] 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).

[0039] 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.

[0040] 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 one embodiment, as used herein, the term “patient” or “subject” means a human.

[0041] 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 in the treatment of the disease or to delay or minimize symptoms associated with the disease. In certain embodiments, the disease is a VEGF modulated disease or condition. In certain embodiments, the disease is an abnormal angiogenic disease modulated by VEGF. In certain embodiments, the disease is a disease or condition associated with an elevated level of VEGF or a disease or condition treatable, manageable, or preventable by reducing the elevated level of VEGF. In certain embodiments, the effective or therapeutically effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof is sufficient to modulate the level of VEGF in a subject to a level that is normal for a healthy population of the same species as the subject. In certain embodiments, the effective or therapeutically effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof is sufficient to reduce an elevated level of VEGF in a subject to a VEGF level that is normal for a healthy population of the same species as the subject. In certain embodiments, the effective or therapeutically effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof is sufficient to reduce an elevated level of VEGF in a subject without completely suppressing the VEGF level in the subject.

[0042] As used herein, “an elevated VEGF level” refers to a VEGF level in a subject that is higher than normal for that subject when healthy. In one embodiment, an elevated VEGF level is a VEGF level in a subject that is higher than normal for a healthy population of the same species as the subject. In a further embodiment, an elevated VEGF level is a VEGF level in a tissue of a subject that is locally higher than normal in that tissue when the subject is healthy. In another embodiment, an elevated VEGF level is a VEGF level in a tissue of a subject that is locally higher than normal for a healthy population of the same species as the subject. Shahidatul-Adha et al, in “Evaluation of vascular endothelial growth factor (VEGF) level in the tears and serum of age-related macular degeneration patients”, in Scientific Report, (2022) 12:4423 describe methods to evaluate VEGF levels in the tears and serum of AMD patients. In one embodiment, an elevated VEGF level may be about 10%, about 25%, about 50%, about 75%, about 100%, about 200%, about 300%, about 500%, about 1000%, or more than about 1000% higher than normal for the subject when healthy or for a healthy population.

[0043] As used herein, the terms “prevent”, “preventing” and “prevention” are art- recognized, and when used in relation to a condition, such as a disease or condition associated with excessive VEGF production, or a disease or condition treatable, manageable, or preventable by reducing VEGF activity, a disease or condition associated with abnormal angiogenesis, is well understood in the art, and includes administration of a compound which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a patient relative to a patient who does not receive the composition.

[0044] As used herein, the terms “treat”, “treating” and “treatment” refer to the reversing, reducing, or arresting the symptoms, clinical signs, and underlying pathology of a condition in manner to improve or stabilize a patient's condition. The terms “treat” and “treatment” also refer to the eradication or amelioration of the disease or symptoms associated with the disease. In certain embodiments, such terms refer to minimizing the spread or worsening of the disease resulting from the administration of a compound as disclosed herein to a patient with such a disease. In certain embodiments, the disease is a disease or condition associated with an elevated VEGF level or a disease or condition treatable, manageable, or preventable by reducing VEGF level. In certain embodiments, the disease is a disease or condition associated with abnormal angiogenesis or a disease or condition treatable, manageable, or preventable by reducing angiogenesis.

[0045] As used herein, the terms “manage”, “managing” and “management” encompasses preventing the recurrence of the particular disease or condition in a patient who had suffered from it, reducing mortality rates of the patients, and/or maintaining a reduction in severity or avoidance of a symptom associated with the disease or condition being managed.

[0046] As used herein, “modulation” means either an increase (stimulation) or a decrease (inhibition) in the level of VEGF.

[0047] As used herein, the term “pharmaceutical composition” refers to compositions suitable for use or prescribed treatment in treating, managing, or preventing a disease or condition associated with an elevated VEGF level, a disease or condition treatable, manageable, or preventable by reducing VEGF level, a disease or condition associated with abnormal angiogenesis, a disease or condition treatable, manageable, or preventable by reducing abnormal angiogenesis.

[0048] 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.

[0049] As used herein, “administer” or “administration” refers to the act of physically delivering a substance as it exists outside the body into a subject. Administration includes all forms known in the art for delivering therapeutic agents, including but not limited to topical, mucosal, injections, intradermal, intravenous, intramuscular delivery or other method of physical delivery described herein or known in the art (e.g, implantation of a slow-release device, such as a mini-osmotic pump to a subject; liposomal formulations; buccal; sublingual; palatal; gingival; nasal; vaginal; rectal; intra-arteriole; intraperitoneal; intraventricular; intracranial; or transdermal). [0050] 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).

[0051] 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, 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.

[0052] 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.

[0053] 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.

[0054] 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 (ADPR)

[0055] 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) .

[0056] 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):

[0057] 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.

[0058] 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.

[0059] 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.

[0060] 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, 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.

[0061] 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.

[0062] 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.

[0063] 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 in the form of a combination of one or more of sodium, lithium, potassium, calcium, magnesium, zinc, cobalt, and/or copper salts.

5.3 Methods of Treatment, Management and Prevention

[0064] In one embodiment, provided herein is a method for treating, managing, or preventing an abnormal angiogenic disorder in a subject, wherein the method comprises administering to the subject an effective amount of 5 ’-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 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. In one embodiment, the abnormal angiogenic disorder is a disorder associated with elevated levels of VEGF.

[0065] In one embodiment, provided herein is a method for inhibiting abnormal angiogenesis in a subject, wherein the method comprises administering to the subject an effective amount of 5 ’-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 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.

[0066] In one embodiment, provided herein is a method of achieving or maintaining vascular homeostasis in a subject, wherein the method comprises administering to the subject 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 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 certain embodiments, vascular homeostasis refers to a balance between vascular injury and vascular repair. In certain embodiments, vascular homeostasis refers to normal values of both angiogenic factors, namely, VEGF, VEGFR1, endothelial progenitor cell, and angiopoietin 1; and antiangiogenic factors, namely, VEGFR2 and angiopoietin 2. 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.

[0067] In one embodiment, the abnormal angiogenic disorder is a disorder of an eye, lung, cervix, skin, vagina, mouth, nose, larynx, esophagus or ear.

[0068] In one embodiment, the abnormal angiogenic disorder is an eye disorder, including but not limited to wet adult macular degeneration (AMD), dry AMD, diabetic retinopathy, diabetic macular edema, retinal vein occlusion, uveitis (iritis), primary or secondary corneal neovascularization, red eye, pterygium, ocular cancer or malignancy including ocular melanoma, ocular angioma, ocular rosacea and chemical injury of the cornea associated with neoangiogenesis. In one embodiment, the eye disorder is symptomatic dry eye disease. In one embodiment, the eye disorder is moderate symptomatic dry eye disease.

[0069] In one embodiment, the abnormal angiogenic disorder is a lung disorder, including but not limited to a lung cancer or malignancy. In one embodiment, the abnormal angiogenic disorder is non-small cell lung carcinoma, such as adenocarcinoma, squamous cell carcinoma and large cell (undifferentiated) carcinoma. In one embodiment, the abnormal angiogenic disorder is small cell lung carcinoma. In one embodiment, the abnormal angiogenic disorder is lung angioma.

[0070] In one embodiment, the abnormal angiogenic disorder is a cervix disorder. In one embodiment, the abnormal angiogenic disorder is a cancer or malignancy originating in the cervix (cervical carcinoma).

[0071] In one embodiment, the abnormal angiogenic disorder is a skin disorder. In one embodiment, the abnormal angiogenic disorder is a skin disorder, including but not limited to a skin cancer or malignancy. In one embodiment, the skin disorder is squamous cell carcinoma, basal cell carcinoma, or melanoma. In one embodiment, the skin disorder is skin angioma. [0072] In one embodiment, provided herein is a method for treating, managing, or preventing an abnormal angiogenic disorder of at least one tissue of the eye, mouth, nose, throat, larynx, trachea, lung (respiratory tract), skin, vagina, cervix, anus, and/or ear in a subject, wherein the method comprises topically administering to the subject an effective amount of 5’-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 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.

[0073] In one embodiment, provided herein is a method for modulating the activity of VEGF protein in a subject, wherein the method comprises administering to the subject an effective amount of 5 ’-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 method comprises topical administration of the 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.

[0074] In one embodiment, provided herein is a method of reducing an elevated level of VEGF in a subject having an elevated level of VEGF, wherein the method comprises administering to the subject an effective amount of 5’-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 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. [0075] In one embodiment, an elevated VEGF level is a VEGF level in a subject that is higher than normal for that subject when healthy. In another aspect, an elevated VEGF level is a VEGF level in a subject that is higher than normal for a healthy population of the same species as the subject. In a further embodiment, an elevated VEGF level is a VEGF level in a tissue of a subject that is locally higher than normal in that tissue when the subject is healthy. In another embodiment, an elevated VEGF level is a VEGF level in a tissue of a subject that is locally higher than normal for a healthy population of the same species as the subject. In an embodiment, an elevated VEGF level may be about 10%, about 25%, about 50%, about 75%, about 100%, about 200%, about 300%, about 500%, about 1000%, or more than about 1000% higher than normal for the subject when healthy or for a healthy population.

[0076] In certain embodiments, an elevated VEGF level is a tear VEGF level that is greater than about 100 pg/mL, greater than about 105 pg/mL, greater than about 110 pg/mL, greater than about 115 pg/mL, greater than about 120 pg/mL, greater than about 125 pg/mL, greater than about 130 pg/mL, greater than about 135 pg/mL, greater than about 140 pg/mL, greater than about 145 pg/mL, greater than about 150 pg/mL, greater than about 160 pg/mL, greater than about 170 pg/mL, greater than about 180 pg/mL, greater than about 190 pg/mL, greater than about 200 pg/mL, greater than about 220 pg/mL, greater than about 250 pg/mL, greater than about 270 pg/mL, or greater than about 290 pg/mL, measured by for example, ELISA assay.

[0077] In certain embodiments, an elevated VEGF level is a serum VEGF level that is greater than about 110 pg/mL, greater than about 120 pg/mL, greater than about 130 pg/mL, greater than about 140 pg/mL, greater than about 150 pg/mL, greater than about 160 pg/mL, greater than about 170 pg/mL, greater than about 180 pg/mL, greater than about 190 pg/mL, greater than about 200 pg/mL, greater than about 210 pg/mL, greater than about 220 pg/mL, greater than about 230 pg/mL, greater than about 240 pg/mL, greater than about 250 pg/mL, or greater than about 260 pg/mL, measured by for example, ELISA assay.

[0078] In further embodiments, an elevated VEGF level is a serum VEGF level that is greater than about 150 pg/mL, greater than about 200 pg/mL, greater than about 250 pg/mL, greater than about 300 pg/mL, greater than about 350 pg/mL, greater than about 400 pg/mL, greater than about 450 pg/mL, greater than about 500 pg/mL, greater than about 550 pg/mL, greater than about 600 pg/mL, greater than about 650 pg/mL, greater than about 700 pg/mL, greater than about 750 pg/mL, greater than about 800 pg/mL, greater than about 900 pg/mL, greater than about 1000 pg/mL, greater than about 1250 pg/mL, or greater than about 1500 pg/mL, measured by for example, ELISA assay. [0079] In certain embodiments, the methods provided herein reduce the elevated level of VEGF in the subject without causing complete suppression of the VEGF level. In certain embodiments, the methods provided herein reduce the elevated level of VEGF in the subject to a normal level of VEGF. Without being limited by theory, it is thought that by reducing the elevated level of VEGF in a subject without causing complete suppression of the VEGF level allows for disorders associated with an elevated level of VEGF to be managed, prevented or treated while avoiding unwanted side effects associated with an abnormally low level of VEGF (e.g., hypertension, arterial thromboembolic or other cardiac events in diabetic subjects, as well as stroke and myocardial infarction).

[0080] In other embodiments, the elevated level of VEGF is reduced between about 10% and about 100%, between about 25% and about 99%, between about 33% and about 99%, between about 50% and about 99%, between about 75% and about 99%, or between about 92% and about 99%. In one embodiment, the elevated level of VEGF is reduced by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95% or more.

[0081] In one embodiment, the reduction in VEGF level is measured by comparing VEGF level before and after administration of 5 ’-adenosine diphosphate ribose (ADPR), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof. In an embodiment, VEGF level is measured at any time before administration of 5’-adenosine diphosphate ribose (ADPR), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof. In another embodiment, the VEGF level before administration is measured by measuring VEGF level at about 15 minutes, about 30 minutes, about 1 hour, about 3 hours, about 5 hours, about 10 hours, about 24 hours, about 2 days, about 5 days, about 7 days, about 10 days, about 20 days, about 30 days, about 60 days, about 100 days, or more than one year prior to administration of 5’-adenosine diphosphate ribose (ADPR), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof. In another embodiment, the VEGF level is measured at about 15 minutes, about 30 minutes, about 1 hour, about 3 hours, about 5 hours, about 10 hours, about 24 hours, about 2 days, about 5 days, about 7 days, about 10 days, about 15 days, about 20 days, about 22 days, about 30 days, about 60 days, about 100 days, more than one year, or more than five years after administration of 5’-adenosine diphosphate ribose (ADPR), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof.

[0082] In another embodiment, the VEGF level measured at any time before administration of 5 ’-adenosine diphosphate ribose (ADPR), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof is compared with the VEGF level measured at about 15 minutes, about 30 minutes, about 1 hour, about 3 hours, about 5 hours, about 10 hours, about 24 hours, about 2 days, about 5 days, about 7 days, about 10 days, about 20 days, about 30 days, about 60 days, about 100 days, more than one year, or more than five years after administration of 5 ’-adenosine diphosphate ribose (ADPR), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof. In a further embodiment, the VEGF level measured at about 1 hour, about 3 hours, about 5 hours, about 10 hours, about 24 hours, about 2 days, about 5 days, about 7 days, about 10 days, about 20 days, about 30 days before administration of 5’-adenosine diphosphate ribose (ADPR), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof is compared with the VEGF level measured at about 1 hour, about 3 hours, about 5 hours, about 10 hours, about 24 hours, about 2 days, about 5 days, about 7 days, about 10 days, about 15 days, about 20 days, about 22 days, about 30 days, about 60 days, about 100 days, or more than one year after administration of 5’- adenosine diphosphate ribose (ADPR), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof. In a further embodiment, the VEGF level measured at about 1 hour, about 3 hours, about 5 hours, about 10 hours, about 24 hours, about 2 days, about 5 days, about 7 days, about 10 days, about 20 days, about 30 days before administration of 5 ’-adenosine diphosphate ribose (ADPR), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof is compared with the VEGF level measured at about 7 days, about 15 days, about 22 days, or more after administration of 5’-adenosine diphosphate ribose (ADPR), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof. [0083] In an embodiment, the reduction in the elevated VEGF level may be expressed as a percentage change compared to the elevated VEGF level prior to administration of 5 ’-adenosine diphosphate ribose (ADPR), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof, for example as ((VEGF level before administering 5 ’-adenosine diphosphate ribose (ADPR), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof minus VEGF level after administration)/VEGF level before administration) X 100.

[0084] In one embodiment, the reduction of VEGF level is measured by a reduction in serum VEGF level. In another embodiment, the reduction of VEGF level is measured by a reduction in plasma VEGF level. In a further embodiment, the reduction of VEGF level is measured by a reduction in local VEGF level, including for example a reduction in VEGF level in a tumor, tissue sample, or bodily fluid. In a further embodiment, the reduction of VEGF level is measured by a reduction in VEGF level in bodily fluid. In one embodiment, the reduction of VEGF level is measured by a reduction in VEGF level in a tear sample.

[0085] In one embodiment, the reduction of VEGF level can be measured by ELISA assay or by quantitative immunofluorescence. In one embodiment, VEGF level can be measured by using a RayBio® BCA Protein Quantitation Kit.

[0086] In one embodiment, provided herein is a method of modulating a VEGF level in a subject in need thereof, wherein the method comprises administering 5’-adenosine diphosphate ribose (ADPR), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof; and measuring a change in the VEGF level in the subject. 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.

[0087] A further embodiment relates to a method of reducing a VEGF level in a human with an elevated VEGF level, wherein the method comprises administering to the subject an effective amount of 5 ’-adenosine diphosphate ribose (ADPR), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof; and measuring a reduction in the VEGF level in the human. 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/day mg to about 10 mg/day. In one embodiment, the effective amount is about 0.1 mg/day to about 10 mg/day.

[0088] In one embodiment, provided herein is a method for treating, managing, or preventing excessive neovascularization in a subject, said method comprising administering to the subject an effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof; wherein the subject has or is at risk of developing a disease or condition associated with excessive neovascularization. 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.

[0089] In one embodiment, provided herein is a method for treating, managing, or preventing a disease or condition associated with excessive neovascularization in a subject, said method comprising administering to the subject an effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof; wherein the subject has an elevated VEGF level. 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. [0090] In one embodiment, provided herein is a method for treating, managing, or preventing a disease or condition associated with excessive neovascularization in a subject, said method comprising administering to the subject an effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof; wherein the subject has or is at risk of developing a disease or condition associated with excessive neovascularization. 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. [0091] In one aspect, provided herein is a method of reducing the amount and/or the activity of VEGF in a subject in need thereof, wherein the method comprises administering to the subject an effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof; wherein the subject has or is at risk of developing a disease or condition treatable, manageable, or preventable by reducing the amount and/or the activity of VEGF. 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, provided herein is a method for treating, managing, or preventing a disease or condition treatable, manageable, or preventable by reducing VEGF activity in a subject, said method comprising topically administering to the subject an effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof; wherein the subject has or is at risk of developing a disease or condition treatable, manageable, or preventable by reducing VEGF activity. 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.

[0092] In one aspect, provided herein is a method for normalization of regional VEGF level in a subject, wherein the method comprises administering to the subject an effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof; such that elevated levels of VEGF are reduced without causing complete suppression of the level of VEGF. 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.

[0093] In another aspect, provided herein is a method of reducing the elevated level of VEGF while avoiding complete suppression of VEGF in a subject, wherein the method comprises administering to the subject 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 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.

[0094] In one aspect, provided herein is a method of reducing one or more adverse side effects of complete suppression of VEGF in a subject, wherein the method comprises administering to the subject 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 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. Exemplary side effects of VEGF suppression are described by Zafar et al. W JAMA Ophthalmol. 2023; 141(7):658-666 and Chen et cz/. in Eye (2022) 36: 153-159. In one embodiment, the one or more adverse side effects of complete suppression of VEGF are selected from myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, chronic pulmonary disease, rheumatic disease, peptic ulcer disease, mild liver disease, hemiplegia, paraplegia, kidney disease, malignancy (including lymphoma and leukemia except malignant neoplasm of skin), moderate or severe liver disease, metastatic solid tumor, AIDS or HIV. In one embodiment, the one or more adverse side effects of complete suppression of VEGF are selected from arterial thromboembolic events (ATEs) such as stroke and acute myocardial infarction (AMI). In one embodiment, the one or more adverse side effects of complete suppression of VEGF are selected from hypertension, arterial thromboembolic or other cardiac events in diabetic subjects, as well as stroke and myocardial infarction.

[0095] In certain embodiments, the disease or condition associated with an elevated VEGF level is a disease or condition of an eye, lung, cervix or skin.

[0096] In one embodiment, the disease or condition associated with an elevated VEGF level is an eye disease, including but not limited to wet adult macular degeneration (AMD), dry AMD, diabetic retinopathy, diabetic macular edema, retinal vein occlusion, uveitis (iritis), primary or secondary corneal neovascularization, red eye, pterygium, ocular cancer or malignancy including ocular melanoma, ocular angioma, ocular rosacea and chemical injury of the cornea associated with neoangiogenesis. In one embodiment, the eye disorder is symptomatic dry eye disease. In one embodiment, the eye disorder is moderate symptomatic dry eye disease.

[0097] In one embodiment, the disease or condition associated with an elevated VEGF level is a lung disease, including but not limited to a lung cancer or malignancy. In one embodiment, the disease or condition associated with an elevated VEGF level is non-small cell lung carcinoma, such as adenocarcinoma, squamous cell carcinoma and large cell (undifferentiated) carcinoma. In one embodiment, the disease or condition associated with an elevated VEGF level is small cell lung carcinoma. In one embodiment, the disease or condition associated with an elevated VEGF level is lung angioma.

[0098] In one embodiment, the disease or condition associated with an elevated VEGF level is a cancer or malignancy originating in the cervix (cervical carcinoma).

[0099] In one embodiment, the disease or condition associated with an elevated VEGF level is a skin disease. In one embodiment, the disease or condition associated with an elevated VEGF level is a skin disease, including but not limited to a skin cancer or malignancy. In one embodiment, the skin disorder is squamous cell carcinoma, basal cell carcinoma, or melanoma. In one embodiment, the skin disorder is skin angioma.

[00100] In one embodiment, the methods provided herein comprise topical administration to an interior cellular or tissue surface. In a specific embodiment, the topical administration to an interior cellular or tissue surface is by aerosolization, spray, oral delivery, infusion or similar method to any surface of the respiratory tract. In another specific embodiment, the topical administration to an interior cellular or tissue surface is by oral delivery, infusion, or enema to any surface of the gastrointestinal tract (e.g., from the mouth to the anus). In another specific embodiment, the topical administration to an interior cellular or tissue surface is by parenteral injection or infusion to any internal organ. In another 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, retina, iris, and lens), mouth, nose, throat, larynx, trachea, lung (respiratory tract), skin, vagina, cervix, anus, and ear.

[00101] In one embodiment, the methods provided herein comprise systemic 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.

[00102] In one embodiment, the administering step comprises administering ADPR and a metal salt, wherein the total amount of 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 and a metal salt, wherein the total amount of 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 10 microliters to 100 microliters. In another embodiment, each dose is between 20 microliters to 80 microliters. In one embodiment, each dose is about 20, 30 or 40 pL.

[00103] In one embodiment, the administering step comprises administering the pharmaceutical composition 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 two times a day. In one embodiment, the solution is administered to the eye three times a day.

[00104] 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.

[00105] In certain embodiments, the ADPR used in the methods provided herein is Li2-ADPR. 5.4 Combination Therapy

[00106] 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 as 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.

[00107] In one embodiment, the method provided herein further comprises administering a second agent, such as for example an agent useful in the treatment of cancer or eye diseases. In one embodiment, the second agent is an agent useful in treatment of eye disease, such as wet adult macular degeneration (AMD), dry AMD, 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; lung cancer, such as non-small 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 eye disorder is symptomatic dry eye disease. In one embodiment, the second agent is an agent useful in treatment of moderate symptomatic dry eye disease.

[00108] In certain embodiments, the second agent is an additional VEGF modulator. In certain embodiments, the additional VEGF modulator is selected from BDM-E, VGX100 antibody (VGX100 CIRCADIAN), VGX200 (c-fos inducible growth factor monoclonal antibody), VGX300, COSMIX, DLX903/1008 antibody, ENMD2076, Sunitinib malate

(Sutent®), INDUS815C, R84 antibody, KD019, NM3, allogeneic mesenchymal progenitor cells in combination with anti-VEGF antagonist (e.g., anti-VEGF antibody), MGCD265, MG516, VEGF-receptor kinase inhibitor, MP0260, NT503, anti-DLL4/VEGF dual Specific antibody, PAN90806, Palomid 529, BD0801 antibody, XV615, Lusitanib (AL3810, E3810), AMG706 (motesanib diphosphate), AAV2-sFLT01, Soluble Fltl receptor, Cediranib (Recentin™), AV- 951 , tivozanib (KRN-951), regorafenib (Stivarga®), vorasertib (BI6727), CEP11981, KH903, lenvatinib (E7080), lenvatinib mesylate, terameprocol (EM1421), ranibizumab (Lucentis®) Trademark)), brolucizumab (Beovu®), faricimab-svoa (VABYSMO®), bevacizumab (Avastin®), pazopanib hydrochloride (Votrient™), PF00337210, PRS050, SP01 (curcumin), carb oxami dotri azole orotate, hydroxychloroquine, linifanib (ABT869, RG3635), fluocinolone acetonide (Irbien®), ALG1001, AGN150998, DARPin MP0112, AMG386, ponatinib (AP24534), AVA101, nintedanib (Baragatef™), BMS690514, KH902, gorbatinib (E7050), everolimus (Afinitor®), dovitinib lactate (TKI258, ), ORA101, ORA102, Axitinib (Inwriter®, AGO 13736), Plitidepsin (Aplidine®), Aflibercept (Zaltrap®, Eylea®), Pegaptanib sodium (McGen® ), LI900015), Verteporfin (Visdyne®), Bucillamine (Rimatil, Lamin, Brimani, Ramit, Boomik), R3 antibody, AT001/r84 antibody, Troponin (BLS0597), EG3306, Vatalanib (PTK787), BmablOO, GSK2636771, CEP7055, GW654652, JNJ 17029259, TAK593, CP- 564959, AG-028262, AG13958, CVX241, SU14813, PRS055, PG501, PG545, PTI101, TG100948, ICS283, XL647, enzastaurin hydrochloride, LY317615, BC194, C9257, SOI 16, J9035, Q2024, J2778, C9233, J0178, Q2046, C9291, J3490, J3590, C9399, quinoline, COT601M06.1, COT604M06.2, Mabion VEGF, conjugated to anti-VEGF or VEGF-R antibody SIR-Spheres, apatinib (YN968D1), and AL3818.

[00109] In certain embodiments, the second agent is selected from brolucizumab (Beovu®), aflibercept (Eylea®), ranibizumab (Lucentis®), faricimab-svoa (VABYSMO®), ranibizumab injection for intravitreal use via ocular implant (SUSVIMOTM)* and Avastin® (bevacizumab). [00110] In certain embodiments, the second agent is an anti-glaucoma drug, i.e., a drug used for the treatment of glaucoma. In some embodiments, the second agent is a prostaglandin analog. In some embodiments, the second agent is prostaglandin F2a (PGF2a) or an analog thereof. In some embodiments, the second agent is latanoprost, bimatoprost, travoprost, tafluprost, latanoprostene bunod, dinoprost, or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the second agent comprises latanoprost, bimatoprost, travoprost, tafluprost, latanoprostene bunod, or dinoprost. In some embodiments, the second agent is an anti-glaucoma drug whose active ingredient is latanoprost, bimatoprost, travoprost, tafluprost, latanoprostene bunod, or dinoprost. In some embodiments, the second agent is IYUZEH, LATANOPROST, ROCKLATAN, VYZULTA, XALATAN, XELPROS, LUMIGAN, BIMATOPROST, TRA VATAN Z, TRAVOPROST, ZIOPTAN, or TAFLUPROST. In certain embodiments, the ADPR as described herein (e.g., dilithium ADPR) is administered in combination with prostaglandin F2a or a prostaglandin F2a analog for the treatment of retinal edema, including, but not limited to, diabetic macular edema, age related macular degeneration, retinal vein occlusion and other causes of macular edema.

[00111] 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.

[00112] In certain embodiments, the ADPR used in the combination therapies provided herein is Li2-ADPR.

5.5 Doses and Dosing Regimens

[00113] In certain embodiments, the methods provided herein comprise administering to a subject having, or at risk of developing, the disease or condition as described herein 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. [00114] In certain embodiments, the methods provided herein comprise administering to a subject having, or at risk of developing, the disease or condition as described herein 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.

[00115] In certain embodiments, the methods provided herein comprise administering to a subject having, or at risk of developing, the disease or condition as described herein 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.

[00116] In certain embodiments, the methods provided herein comprise administering to a subject having, or at risk of developing symptomatic dry eye disease 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.

[00117] In certain embodiments, the methods provided herein comprise administering to a subject having, or at risk of developing, the disease or condition as described herein 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 to 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.

[00118] In certain embodiments, the methods provided herein comprise administering to a subject having, or at risk of developing symptomatic dry eye disease 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 to 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.

[00119] In certain embodiments, the methods provided herein comprise administering to a subject having, or at risk of developing symptomatic dry eye disease 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 to 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.

[00120] In certain embodiments, the methods provided herein comprise administering to a subject having, or at risk of developing, the disease or condition as described herein an amount of about 0.6 mg/day, about 0.9 mg/day, about 1.8 mg/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.

[00121] In certain embodiments, the methods provided herein comprise administering to a subject having, or at risk of developing, the disease or condition as described herein an amount of about 0.6 mg/day, about 0.9 mg/day, about 1.8 mg/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 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 or 1 to 15 days. In certain embodiments, the amount is administered topically for 1 to 7 days. In certain embodiments, the amount is administered topically for 1 to 15 days.

[00122] In certain embodiments, the methods provided herein comprise administering to a subject having, or at risk of developing symptomatic dry eye disease an amount of about 0.1 mg/day, about 0.6 mg/day, about 0.9 mg/day, about 1.8 mg/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.

[00123] In certain embodiments, the methods provided herein comprise administering to a subject having, or at risk of developing symptomatic dry eye disease an amount of about 0.1 mg/day, about 0.6 mg/day, about 0.9 mg/day, about 1.8 mg/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 or 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 or 1 to 15 days. In certain embodiments, the amount is administered topically for 1 to 7 days. In certain embodiments, the amount is administered topically for 1 to 15 days.

[00124] In certain embodiments, the methods provided herein comprise administering to a subject having, or at risk of developing, the disease or condition as described herein 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. [00125] In certain embodiments, the pharmaceutical composition 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.

[00126] In certain embodiments, the methods provided herein comprise administering to a subject having, or at risk of developing, the disease or condition as described herein 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 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.

[00127] In a specific embodiment, the topical administration to an interior cellular or tissue surface is by aerosolization, nebulization, spray, oral delivery, intra-tracheal infusion, intrabronchial, or infusion to a surface of the respiratory tract. In another specific embodiment, the topical administration to an interior cellular or tissue surface is by oral delivery, infusion, or enema to any surface of the gastrointestinal tract (e.g., from the mouth to the anus). In another specific embodiment, the topical administration to an interior cellular or tissue surface is by parenteral injection or infusion to any internal organ. In another embodiment, the topical administration is to an exterior cellular or tissue surface. Tn one embodiment, the exterior cellular or tissue surface includes, but is not limited to, the surface of the skin, eye, nail, hair, or ear. 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.

[00128] In certain embodiments, the methods provided herein comprise administering to a subject having or at risk of developing a disease or condition as described herein 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 one embodiment, the topical administration is to an interior cellular or tissue surface. In a specific embodiment, the topical administration to an interior cellular or tissue surface is by aerosolization, spray, oral delivery, infusion or similar method to any surface of the respiratory tract. In another specific embodiment, the topical administration to an interior cellular or tissue surface is by oral delivery, infusion, or enema to any surface of the gastrointestinal tract (e.g., from the mouth to the anus). In another specific embodiment, the topical administration to an interior cellular or tissue surface is by parenteral injection or infusion to any internal organ. In another embodiment, the topical administration is to an exterior cellular or tissue surface, including, but not limited to, the skin, eye, nail, hair, or ear. 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. [00129] 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 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. 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 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 pl..

[00130] 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 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 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.

[00131] The suitability of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, for the treatment, management, or prevention of a disease or condition described herein, can be confirmed by using the assays known to one of skill in the art and described herein. [00132] In certain embodiments, the ADPR used in the dosage forms and dosing regimens provided herein is Li2-ADPR.

5.6 Pharmaceutical Compositions

[00133] Provided herein are pharmaceutical compositions comprising ADPR or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, effective for treating, managing, or preventing a disease or condition modulated by VEGF. In one embodiment, the pharmaceutical composition is for topical administration.

[00134] 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, fdm, strip), suppositories, ointments, or any other suitable dosage form. In a specific embodiment, the pharmaceutical composition is in the form of a solution.

[00135] Non-limiting examples of suitable excipients, diluents, and carriers include: fillers 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. [00136] 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.

[00137] 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 form may be made, for example, from polymeric substances or waxes well known in the pharmaceutical arts.

[00138] 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.

[00139] 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, about 0.005% w/w to about 0.05% w/w, 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% w/w, 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. [00140] 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.

[00141] 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 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 moderate 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, isotopologue, or polymorph thereof is administered to a subject with symptomatic dry eye disease (DED) in a dose of 30 pL.

[00142] 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 disorder 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 disorder 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.

[00143] In one embodiment, provided herein is a pharmaceutical composition suitable for topical administration to the eye, respiratory tract, and/or gastrointestinal tract effective for treatment and/or prophylaxis of an abnormal angiogenic disorder of at least one tissue of the eye, mouth, nose, throat, larynx, trachea, lung (respiratory tract), skin, vagina, cervix, anus, and/or ear, wherein the pharmaceutical composition comprises ADPR, wherein the amount of ADPR is in the range of about 0.01% w/w to about 1% w/w of the pharmaceutical composition.

[00144] In one embodiment, the prophylaxis is prophylaxis of infection following corneal abrasion or ocular surgery.

[00145] 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.

[00146] 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.

[00147] 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 by weight of the pharmaceutical composition. In a specific embodiment, the pharmaceutical composition is in the form of a solution.

[00148] 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 of the pharmaceutical composition.

[00149] 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 of the pharmaceutical composition. In a specific embodiment, the pharmaceutical composition is in the form of a solution.

[00150] 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.

[00151] In certain embodiments, the ADPR used in the pharmaceutical compositions provided herein is Li2-ADPR.

5.6.1 Topical ocular formulations

[00152] 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.

[00153] 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.

[00154] 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.

[00155] 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 0.3 to 0.4 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.

[00156] 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.

[00157] 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.

[00158] 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-P- cyclodextrin, hydroxypropyl-y-cyclodextrin, dimethyl-P- cyclodextrin and dimethyl-y- cyclodextrin.

[00159] 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.

[00160] 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.

[00161] In certain embodiments, the frequency of administration can vary greatly. Depending on the needs of each subject and the severity of the disease 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.

[00162] In certain embodiments, the frequency of administration can vary greatly, depending on the needs of each subject and the severity of the disease 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.

[00163] In certain embodiments, the ADPR used in the topical ocular formulations provided herein is Li2-ADPR.

5.6.2 Formulations for intranasal administration or by inhalation

[00164] In certain embodiments, the pharmaceutical composition provided herein is administered intranasally or by inhalation to the respiratory tract. The pharmaceutical composition can be provided in the form of an aerosol or solution for delivery using a pressurized container, pump, spray, atomizer, such as an atomizer using electrohydrodynamics to produce a fine mist, or nebulizer, alone or in combination with a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane. The pharmaceutical composition can also be provided as a dry powder for insufflation, alone or in combination with an inert carrier such as lactose or phospholipids; and nasal drops. For intranasal use, the powder can comprise a bioadhesive agent, including chitosan or cyclodextrin.

[00165] Solutions or suspensions for use in a pressurized container, pump, spray, atomizer, or nebulizer can be formulated to contain ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active ingredient provided herein; a propellant as solvent; and/or a surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.

[00166] The pharmaceutical composition provided herein can be micronized to a size suitable for delivery by inhalation, such as about 50 micrometers or less, or about 10 micrometers or less. Particles of such sizes can be prepared using a comminuting method known to those skilled in the art, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

[00167] Capsules, blisters, and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mix of the pharmaceutical compositions provided herein; a suitable powder base, such as lactose or starch; and a performance modifier, such as 1-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate. Other suitable excipients or carriers include, but are not limited to, dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. The pharmaceutical compositions provided herein for inhaled/intranasal administration can further comprise a suitable flavor, such as menthol and levomenthol; and/or sweeteners, such as saccharin and saccharin sodium.

[00168] In certain embodiments, the ADPR used in the formulations for intranasal administration or by inhalation provided herein is Li?- ADPR.

Evaluation of Activity

[00169] Standard physiological, pharmacological and biochemical procedures are available for testing the compounds to identify those that possess the desired activity.

[00170] Such assays include, for example, cell based assays, including the RayBiotech Quantibody® Human Dry Eye Disease Array assay described in the Example section. 6 EXAMPLES

6.1 Example 1. Tear Sample Processing and Analysis

[00171] This study describes a method of extracting and diluting proteins from tear samples collected via Schirmer strip that were used for protein quantification and cytokine measurement.

Samples:

Tear samples collected via Schirmer strips without anesthetic were received in glass storage tubes transported on dry ice. Samples were stored and maintained frozen in a -80°C freezer until processing.

Extraction Procedure:

• Warm samples to room temperature

• Cut 5mm off the applied end of the Schirmer strip to be used for testing o Mince the 5mm segment of Schirmer strip pieces with scissors o Place all the Schirmer strip pieces from the 5mm segment into the upper reservoir of a Nanosep centrifugal device with 0.45pm pore size (Figure 1)

• Add 100 pL of extraction buffer (0.5 M NaCl and 0.5% Tween-20) to the upper reservoir of the centrifugal device containing the Schirmer strip pieces

• Incubate samples for 3 hours on a rocker at ambient temperature

• After incubation, place samples on ice until ready for next step

• Collect residual liquid by centrifuging tube at 1000 rpm for 10 seconds o Remove and discard the upper portion of centrifugal device containing the now extracted Schirmer strip pieces o Cap and retain the lower reservoir of the device that contains the fdtrate for analysis o Freeze sample at -80°C if not ready to analyze immediately

Protein Quantification:

• Protein concentration of the extracted sample was determined using a RayBiotech BCA

Protein Quantitation Kit (https:// vww.raybiotech.com/bca--prot.ein-quantitati on-kit/)

Targeted Cytokine Detection:

• Extracted samples were analyzed for targeted cytokines using a RayBiotech Quantibody® Human Dry Eye Disease Array Kit (https://www.raybiotech.com/human-dry-eye-disease- array -ql ~en/). Samples were diluted with assay diluent from the Quantibody kit to Img/mL and prepped for the assay per the manual.

References

1. VanDerMeid KR, Su SP, Krenzer KL, Ward KW, Zhang JZ. A method to extract cytokines and matrix metalloproteinases from Schirmer strips and analyze using Luminex. Mol Vis. 2011;17: 1056-1063. 28.

2. Shoji J, Kitazawa M, Inada N, et al. Efficacy of tear eosinophil cationic protein level measurement using filter paper for diagnosing allergic conjunctival disorders. Jpn J Ophthalmol. 2003;47:64-68

3. VanDerMeid KR, Su SP, Ward KW, Zhang JZ. Correlation of tear inflammatory cytokines and matrix metalloproteinases with four dry eye diagnostic tests. Invest Ophthalmol Vis Sci. 2012 Mar 21;53(3): 1512-8. doi: 10.1167/iovs.11-7627. PMID: 22323462.

6.2 Example 2. Phase 1/2, Multicenter, Randomized, Double-Masked, Vehicle- Controlled, Multiple Ascending Dose (MAD) (Part 1) and Optional Dose Expansion (Part 2) Study of dilithium ADPR Ophthalmic Solution in Adult Subjects With Moderate Symptomatic Dry Eye Disease

Study description:

[00172] Phase 1/2, first-in -hum an (FIH), randomized, double-masked, vehicle controlled, 2- part study to assess topically administered eyedrops of dilithium ADPR during 2-week repeat dosing in subjects with moderate symptomatic dry eye disease (DED); also called keratoconjunctivitis sicca. Part 1 will be a Dose Escalation phase across 4 cohorts of subjects to assess safety, tolerability, and systemic pharmacokinetics (PK) of dilithium ADPR, and Part 2 will be an Optional Dose Expansion phase in a fifth cohort of subjects conducted pending the outcome of Part 1, to assess efficacy of dilithium ADPR in the treatment of moderate symptomatic DED.

Objective: Part 1 (Dose Escalation):

[00173] Primary Objective:

To characterize the safety profile of dilithium ADPR in subjects with moderate symptomatic DED using multiple concentrations and dosing regimens [00174] Other Objectives:

To further characterize specific safety measures in subjects with moderate symptomatic DED using multiple concentrations and dosing regimens

To characterize the systemic PK of dilithium ADPR in subjects with moderate symptomatic DED

To identify DED biomarkers in tears that characterize the pharmacodynamic effects of dilithium ADPR or potentially predict response to dilithium ADPR

To evaluate preliminary efficacy of dilithium ADPR in subjects with moderate symptomatic DED

Part 2 (Optional Dose Expansion):

[00175] Primary Objective:

To evaluate the efficacy of dilithium ADPR in subjects with moderate symptomatic DED in an expanded cohort [00176] Secondary Objective:

To evaluate the efficacy of dilithium ADPR using signs and symptoms in a combined outcome score in subjects with moderate symptomatic DED [00177] Safety endpoints:

Changes in vital sign measurements

Changes in best-corrected visual acuity (BCVA)

Changes in slit lamp examination findings

Changes in Drop Comfort Assessment scores

Changes in intraocular pressure (IOP)

Changes in fundus examination findings

Changes in pachymetry

Changes in endothelial cell count

Changes in corneal fluorescein staining

Changes in conjunctival lissamine green staining

Changes in conjunctival hyperemia

Changes in tear break-up time (TBUT)

Changes in the frequency of over-the-counter (OTC) ocular lubricant use

[00178] Plasma PK endpoints: PK assessment (maximum drug concentration [Cmax], time to reach maximum drug concentration [Tmax], area under the concentration-time curve [AUC]) after a single-dose of dilithium ADPR administration

PK assessment (Cmax, Tmax, AUC) after repeated dilithium ADPR administration [00179] Biomarker endpoint:

Changes in concentration of DED biomarkers and inflammatory cytokines in tears [00180] Efficacy endpoints:

Eye Dryness Composite Score at Day 15 (combines the change from Baseline in eye dryness score from the 7-item DED symptom visual analog scale (VAS) plus the change from Baseline in corneal fluorescein staining)

Eye Discomfort Composite Score at Day 15 (combines the change from Baseline in eye discomfort score from the 7-item DED symptom VAS plus the change from Baseline in corneal fluorescein staining)

Changes in VAS (individual item scores and overall score)

Changes in Symptom Assessment iN Dry Eye (SANDE)

Part 2 (Optional Dose Expansion):

[00181] Primary Endpoint:

Efficacy endpoint of change from Baseline to Day 15 in either the eye dryness score or eye discomfort score from the 7-item DED symptom VAS (the specific endpoint for Part 2 will be chosen based on results from Part 1 [Dose Escalation] Cohorts 1 to 4 and determined by the safety review committee [SRC] in conjunction with the Sponsor) [00182] Secondary Endpoint:

Chosen as per primary endpoint (change from Baseline to Day 15):

Eye Dryness Composite Score, or

Eye Discomfort Composite Score

[00183] Other Endpoints:

[00184] Additional efficacy endpoints:

Changes in VAS (individual item scores and overall score)

Changes in SANDE

Changes in corneal fluorescein staining

Changes in conjunctival lissamine green staining Changes in conjunctival hyperemia

Changes in TBUT

Changes in the frequency of OTC ocular lubricant use

[00185] Biomarker endpoint:

Change from Baseline to Day 15 in concentration of DED biomarkers and inflammatory cytokines in tears [00186] Safety endpoints:

TEAEs

Changes in vital sign measurements Changes in BCVA

Changes in slit lamp examination findings Changes in Drop Comfort Assessment scores Study Design:

[00187] This FIH, multicenter, Phase 1/2 study has a randomized, double-masked, vehicle- controlled MAD part (Part 1) and an optional randomized, double masked, vehicle-controlled dose-expansion part (Part 2) to evaluate dilithium ADPR in subjects with moderate symptomatic DED.

[00188] Prescription eyedrops/medications for DED must be washed out and contact lens wear must be discontinued for 2 weeks prior to start of dosing of study drug (dilithium ADPR or vehicle) and both are prohibited throughout the dosing and follow-up phases of the study. OTC eyedrops, other than lubricant eyedrops or artificial tears, are also prohibited throughout the dosing and follow-up phases of the study. Subjects are permitted to use OTC lubricant eyedrops or artificial tears during the study and should continue to use the same brand or type as compared to prior to enrolling in the study. Dosing of OTC lubricant eyedrops or artificial tears are not permitted for 30 minutes before or until 30 minutes after dosing of the study drug at any point during the study.

[00189] In Part 1 (Dose Escalation), subjects will be enrolled in a sequential manner into 1 of 4 cohorts, where they will be randomized 2: 1 to receive either dilithium ADPR or vehicle, respectively. Enrollment of the next cohort can begin once the current cohort is fully enrolled and the sixth subject of the current cohort has completed dosing. [00190] In Part 1, subjects will instill topical ocular study drug (dilithium ADPR or vehicle) in both eyes (OU) for 2 weeks (Note: study drug will be dosed in both eyes in Part 1 regardless of whether both eyes meet the criteria as a Qualifying Eye). The formulation concentration and frequency of dosing will be determined by cohort, with Cohorts 1 to 3 receiving twice daily (BID) dosing (approximately every 12 hours with at least 6 hours between doses) and Cohort 4 receiving 3 times daily (TID) dosing (approximately every 8 hours with at least 6 hours between doses). Subjects who fail to take a dose of study drug within the dosing window should skip that dose and not attempt to make it up.

• Cohort 1 (0.1% dilithium ADPR vs vehicle): 1 drop OU on Day 1, then BID OU for 13 days (Days 2-14), then 1 drop OU on Day 15

• Cohort 2 (0.25% dilithium ADPR vs vehicle): 1 drop OU on Day 1, then BID OU for

13 days (Days 2-14), then 1 drop OU on Day 15

• Cohort 3 (0.7% dilithium ADPR vs vehicle): 1 drop OU on Day 1, then BID OU for 13 days (Days 2-14), then 1 drop OU on Day 15

• Cohort 4 (0.7% dilithium ADPR vs vehicle): 1 drop OU on Day 1, then TID OU for 13 days (Days 2-14), then 1 drop OU on Day 15

[00191] An SRC will oversee safety aspects of the study and will informally review and discuss available safety data from each cohort prior to the initiation of the subsequent cohort (ie, prior to the initiation of Cohorts 2, 3, 4, and 5) and at the completion of the final cohort.

[00192] After Part 1 (Dose Escalation) Cohorts 1 to 4 have been completed the study may advance to the optional Part 2 based on review of available efficacy and safety data by the SRC in coordination with the Sponsor.

[00193] In Part 2 (Optional Dose Expansion) Cohort 5, subjects will be randomized 2: 1 to dilithium ADPR or vehicle, respectively, and will instill topical ocular study drug in eligible eye(s) (ie, Qualifying Eyes) for 2 weeks either BID (1 drop on Day 1, then BID for 13 days, then 1 drop on Day 15) or TID (1 drop on Day 1, then TID for 13 days, then 1 drop on Day 15). Frequency and dose will be chosen by the SRC in coordination with the Sponsor based on the results from Part 1 (Dose Escalation) Cohorts 1 to 4 (Note: study drug may be dosed in a single eye or in both eyes in Part 2, depending on whether each eye individually meets the criteria as a Qualifying Eye. For subjects dosing only one eye in Part 2 [ie, having only one Qualifying Eye], assessments will only be performed on the eye being dosed). Estimated Number of Subjects:

[00194] Part 1 (Dose Escalation) Cohorts 1 to 4: Approximately 9 subjects in each cohort (6 active: 3 vehicle; total of approximately 36 subjects)

[00195] Part 2 (Optional Dose Expansion) Cohort 5: Approximately 48 subjects (32 active: 16 vehicle)

Study Population:

[00196] Inclusion criteria:

1. Healthy male or female subject >18 years of age

2. Presence of moderate DED in at least one eye at both Screening and Baseline as defined by the following criteria (for an eye to qualify, all criteria must be present in the same eye): o Eye dryness score from the VAS >40/100 o Conjunctival hyperemia with a bulbar redness score >1 on the Cornea and Contact Lens Research Unit grading scale o Corneal fluorescein staining score >3/15 and <8/15 on the National Eye Institute/Industry scale

3. Ability to comply with all protocol-mandated procedures and to attend all scheduled office visits

4. Able to self-administer study drug or to have the study drug administered by a caregiver throughout the study period

Exclusion criteria:

1. BCVA worse than 0.5 logMAR in either eye as assessed using an Early Treatment Diabetic Retinopathy Study (ETDRS) chart

2. IOP >22 mmHg in either eye at the Screening Visit

3. Presently using prescription eyedrops, except those used for DED (eg, Restasis, Xiidra, Cequa, Eysuvis). Prescription eyedrops for DED, as well as nasally administered Tyrvaya, must be discontinued 2 weeks prior to initiation of study drug dosing and are prohibited throughout the duration of the study (through the follow-up visit)

4. Use of OTC eyedrops (eg, oxymetazoline, naphazoline), except for lubricant eyedrops or artificial tears (eg, Systane, Refresh), within 1 week prior to initiation of study drug dosing and throughout the duration of the study. Dosing of OTC lubricant eyedrops or artificial tears is not permitted for 30 minutes before through 30 minutes after dosing of the study drug of other investigational drugs (including investigational eyedrops for DED) within 2 months prior to initiation of study drug dosing

6. Alteration (initiation, discontinuation, or change in dose) of any chronically used systemic medication within 30 days prior to initiation of study drug dosing

7. External eye disease (eg, blepharitis, conjunctivitis, neurotrophic keratitis) except primary DED

8. DED secondary to scarring (such as that seen with irradiation, alkali burns, cicatricial pemphigoid)

9. Systemic disease associated with DED (eg, Stevens- Johnson Syndrome, primary or secondary Sjogren syndrome, lupus)

10. In either eye, current nonabsorbable punctal plug, or implantation of absorbable punctal plug within 2 to 6 months (depending on type of absorbable plug) prior to initiation of study drug dosing, or punctal plug removal within 2 months prior to initiation of study drug dosing. Permanent punctal occlusion in 1 or more puncta or nasolacrimal duct obstruction in either eye is excluded

11. Allergic conjunctivitis requiring treatment (including prescription and OTC eyedrops and/or systemic medication) within 30 days prior to initiation of study drug dosing or throughout the duration of the study

12. History or evidence of ocular infection within 30 days prior to initiation of study drug dosing

13. History or evidence of ocular herpes simplex or ocular herpes zoster

14. Blepharitis or meibomian gland disease requiring the use of either topical or systemic antibiotics within 2 months prior to initiation of study drug dosing

15. Use of lid scrubs (such as OCuSOFT or SteriLid, and including baby shampoos) within 1 week prior to initiation of study drug dosing and throughout the duration of the study (warm compresses are permitted within 1 week prior to initiation of study drug dosing but not on the day of Screening or throughout the duration of the study)

16. Actively wearing contact lenses (contact lenses must be discontinued for 2 weeks prior to initiation of study drug dosing and are prohibited for the duration of the study) 17. Any eye (laser or non-laser) or eyelid surgery within 12 months prior to initiation of study drug dosing

18. Ocular trauma, ocular surgery, or non-refractive laser treatment within 6 months prior to initiation of study drug dosing

19. Previous inclusion in dilithium ADPR clinical study 20. Systemic chemotherapy or immunotherapy within 6 months prior to initiation of study drug dosing or throughout the duration of the study. Vaccinations and allergy desensitization treatments are allowed

21. Any significant chronic illness or ocular anatomical abnormality (eg, pinguecula, pterygium) that, in the opinion of the investigator, could interfere with the study parameters

22. Females who are pregnant or nursing. Females of childbearing potential or non- vasectomized males who are unwilling or not using a medically acceptable form of birth control. Acceptable methods include the use of at least one of the following: intrauterine device, hormonal (oral, injection, patch, implant, ring), barrier with spermicide (condom, diaphragm), a vasectomized partner, or abstinence. A female is considered to be of childbearing potential unless she is 1 year postmenopausal or 3 months post-surgical sterilization. All females of childbearing potential must have a negative urine pregnancy test result at both Screening and Baseline and must intend to not become pregnant during the study

Description of Study Intervention:

[00197] Dilithium ADPR Ophthalmic Solution in concentrations of 0.1%, 0.25%, and 0.7%. Vehicle Ophthalmic Solution is identical to the formulation of dilithium ADPR Ophthalmic Solution but does not contain the active ingredient.

[00198] Study duration: Approximately 6 months from first subject first visit to last subject last visit

[00199] Subject duration: Up to 28 days of Screening (including a 2-week washout period for subjects on prescription dry eye medications and/or who wear contact lenses), 2 weeks of dosing, and 1 week of follow-up.

Statistical considerations:

[00200] Eyes meeting the study-defined DED eligibility criteria will be deemed Qualifying Eyes and each subject may have either 1 or 2 Qualifying Eyes. All subjects, regardless of whether they receive study drug in one or both eyes, will have only one eye designated as the Study Eye. The Study Eye is defined as the eye with more severe disease based on corneal fluorescein staining. The other eye is designated as the Fellow Eye. If both eyes have the same corneal fluorescein staining score, the eye with the more severe eye dryness score from the 7- item DED symptom VAS will be the Study Eye. If both eyes have the same eye dryness score, the right eye will be the Study Eye.

[00201] In Part 1 (Dose Escalation) Cohorts 1 to 4, both eyes will receive study drug regardless of whether both eyes meet the criteria as Qualifying Eyes, and study assessments will be performed for both eyes (unless noted otherwise). Safety data from each eye will be analyzed. Non-eye-specific safety data (adverse event [AE] data) will be collected and analyzed at the subject level, and eye-specific safety data and efficacy data will be collected and analyzed at the eye level (Study Eye and Fellow Eye).

[00202] In Part 2 (Optional Dose Expansion) Cohort 5, only eyes meeting DED eligibility (Qualifying Eyes) will receive study drug and be assessed. Safety data from only those eyes will be analyzed. Non-eye-specific safety data (AE data) will be collected and analyzed at the subject level, and eye specific safety data and efficacy data will be collected and analyzed at the eye level (Study Eye and, if applicable, Fellow Eye).

[00203] All continuous variables will be summarized by study drug and time point (as applicable) using descriptive statistics (n, mean, median, standard deviation, minimum, and maximum). All categorical variables will be summarized by study drug and time point (as applicable) using frequency counts and percentages.

[00204] All study data will be presented by study drug and time point (as applicable).

[00205] All statistical tests will be performed using a significance level of 5% (2 -tailed). The p-values for the analysis of efficacy endpoints will be considered descriptive.

Study Results:

[00206] Cohort 3, from Part 1 of the study, included subjects treated with dilithium ADPR 0.7% BID or vehicle (n=9, randomized 2: 1).

[00207] Cohort 4, from Part 1 of the study, included subjects treated with dilithium ADPR 0.7% TID or vehicle (n=9, randomized 2: 1).

[00208] Cohort 5, from Part 2 of the study, included subjects treated with dilithium ADPR 0.7% BID or vehicle (n=48, randomized 2: 1).

[00209] Using the data from Cohorts 3, 4, and 5, a standard least squares model was created using JMP (v 17.0). The model was created to analyze the relationship and interaction of the treatment groups (dilithium ADPR 0.7% BID, dilithium ADPR 0.7% TID, and vehicle) and VEGF baseline to effect absolute change in VEGF from Day 1 to Day 15 (end of treatment). [00210] The following parameters were used:

VEGF baseline as a continuous variable, Treatment as nominal variable, and The interaction of the aforementioned variables.

[00211] The VEGF change from baseline where an interaction term was incorporated between VEGF on Day 1 and Treatment (dilithium ADPR 0.7% BID vs vehicle BID). Figure 2 provides the VEGF change from baseline on day 8 in patients treated twice a day and three times a day, where an interaction term was incorporated between VEGF on Day 1. Figure 3 provides the VEGF change from baseline on day 15 in patients treated twice a day and three times a day, where an interaction term was incorporated between VEGF on Day 1. Figure 4 provides the VEGF change from baseline on day 22 in patients treated twice a day and three times a day, where an interaction term was incorporated between VEGF on Day 1. Figures 2-4 clearly show that the TID dosing caused a more profound steepening of the line relative to the BID dose. This was particularly evident in Figure 3 on Day 15. Figure 5 provides a plot of VEGF Change from Baseline (pg/mL) vs. VEGF at Baseline in patients treated twice a day.

6.3 Example 3. Dilithium ADPR (L ADPR) and Latanoprost Combination Study

[00212] This example describes results from a case study in a human subject receiving ADPR (in the form of dilithium ADPR) in combination with latanoprost.

[00213] The subject was diagnosed with diabetic retinopathy with non-center macular edema in both eyes. The subject began treatment in the left eye with topical dilithium ADPR, which was administered at a concentration of 0.7% topically with one drop to the eye, two times per day.

[00214] At the week 4 visit, it was noted that the subject did not show improvement in edema. At week 6, subject was diagnosed with glaucoma. While continuing on the dilithium ADPR treatment, the subject was treated with latanoprost, which was administered at a concentration of 0.005% topically with one drop to the eye each evening. At the week 8 visit, a very significant improvement in edema was noted in in the left eye, with all regions of the OCT (ocular coherence tomography) grid showing notable reductions in average subfield thickness. In the left eye, there was a 137 micron decrease (460 at Wk 4 (Figure 6A) and 323 at Wk 8 (Figure 6B)) in the average thickness of the nasal inner region of the grid, and a 48 micron decrease in edema in the fovea (center region, 318 at Wk 4 (Figure 6A) and 270 at Wk 8 (Figure 6B)) from the week 4 visit.

[00215] The above improvement observed in this patient was very notable and highly unexpected, especially because latanoprost by itself is known to cause an increase in Cystoid Macular Edema (CME) (Lin, W-C, et al., 2023, “Latanoprost-associated cystoid macular edema in a patient with phakic eyes”, Taiwan J. Ophthalmol., 13(2):242-244). This side-effect of latanoprost is also noted in the WARNINGS AND PRECAUTIONS section of the package insert of XALATAN (which is the commercial name for latanoprost): “Macular edema, including cystoid macular edema, has been reported during treatment with XALATAN. XALATAN should be used with caution in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema.” The pathway by which latanoprost worsens CME has been hypothesized to be related to the effect on the blood retinal barrier and upregulation of VEGF caused by latanoprost (Sabaner, M. C., et al., 2021, “Effects of topical prostaglandin drops on angiogenesis in an in ovo chick chorioallantoic membrane model,” Cutan Ocul. Toxicol., 40(l):54-60). Thus, the significant improvement in reduction in edema observed in the patient receiving dilithium ADPR in combination with latanoprost was highly unexpected, especially in view of the above-mentioned known side-effect of latanoprost.

[00216] 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.

[00217] 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.

Claims

1. A method for modulating a level of VEGF protein in a subject, wherein the method comprises administering to the subject an effective amount of 5 ’-adenosine diphosphate ribose (ADPR), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof.

2. A method for reducing an elevated level of VEGF protein in a subject, wherein the method comprises administering to the subject an effective amount of 5 ’-adenosine diphosphate ribose (ADPR), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof.

3. A method for treating, managing, or preventing an abnormal angiogenic disorder in a subject, wherein the method comprises administering to the subject an effective amount of 5’-adenosine diphosphate ribose (ADPR), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof.

4. A method for inhibiting abnormal angiogenesis in a subject, wherein the method comprises administering to the subject an effective amount of 5’-adenosine diphosphate ribose (ADPR), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof.

5. A method for treating, managing, or preventing a disease or condition associated with excessive neovascularization in a subject, said method comprising administering to the subject an effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof; wherein the subject has an elevated VEGF level.

6. A method for modulating a level of VEGF in a subject in need thereof, wherein the method comprises administering to the subject an effective amount of 5 ’-adenosine diphosphate ribose (ADPR), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof; and measuring a change in the level of VEGF in the subject.

7. A method for normalization of a level of regional VEGF in a subject having an elevated level of VEGF, wherein the method comprises administering to the subject an effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof; such that the elevated level of VEGF is reduced without causing complete suppression of the level of VEGF.

8. A method of achieving or maintaining vascular homeostasis in a subject, wherein the method comprises administering to the subject an effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof.

9. The method of any one of claims 1 to 8, wherein the method comprises topical administration of the effective amount of ADPR, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopologue, or polymorph thereof, or a pharmaceutical composition thereof.

10. The method of any one of claims 1 to 9, wherein the subject has a disorder of an eye, lung, cervix or skin.

11. The method of any one of claims 1 to 10, wherein the subject has an eye disorder.

12. The method of claim 11, wherein the eye disorder is wet adult macular degeneration (AMD), dry AMD, 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 or symptomatic dry eye disease.

13. The method of claim 12, wherein the eye disorder is symptomatic dry eye disease.

14. The method of any one of claims 9 to 13, wherein the topical administration is to an interior cellular or tissue surface of the subject.

15. The method of claim 14, wherein the topical administration is by aerosolization, nebulization, spray, oral delivery, intra-tracheal infusion, intra-bronchial, or infusion to a surface of the respiratory tract.

16. The method of claim 14, wherein the topical administration is to an exterior cellular or tissue surface of the eye.

17. The method of claim 16, wherein the pharmaceutical composition is in the form of a solution.

18. The method of claim 17, wherein 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.

19. The method of claim 18, wherein the amount of dilithium ADPR in the pharmaceutical composition is about 0.7% w/w of the pharmaceutical composition.

20. The method of any one of claims 17 to 19, wherein the solution is applied to the exterior cellular or tissue surface of the eye one to three times a day in a dose of 20-30 pL.

21 . The method of claim 20, wherein the solution is applied to the exterior cellular or tissue surface of the eye two times a day in a dose of 30 pL each.

22. The method of claim 20, wherein the solution is applied to the exterior cellular or tissue surface of the eye three times a day in a dose of 30 pL each.

23. The method of any one of claims 17 to 22, wherein the solution is applied to the exterior cellular or tissue surface of the eye two to three times a day in a dose of 20-30 pL for a period of 1 to 15 days.

24. The method of any one of claims 1-23, wherein the ADPR or pharmaceutical composition comprising ADPR is administered in combination with a second active agent.

25. The method of claim 24, wherein the second active agent is a VEGF modulator.

26. The method of claim 24, wherein the second active agent is selected from brolucizumab, aflibercept, ranibizumab, faricimab-svoa, and bevacizumab.

27. The method of any one of claims 1 to 26, wherein the ADPR is in the form of its sodium salt.

28. The method of claim 27, wherein the ADPR is in the form of its disodium salt.

29. The method of any one of claims 1 to 26, wherein the ADPR is in the form of its lithium salt.

30. The method of claim 29, wherein the ADPR is in the form of its dilithium salt.

1 . The method of any one of claims 1 to 30, wherein the ADPR is in the form of a combination of one or more of sodium, lithium, potassium, calcium, magnesium, zinc, cobalt, and/or copper salts.