METHODS AND COMPOSITIONS FOR THE TREATMENT OF AGE-RELATED MACULAR DEGENERATION

TECHNICAL FIELD

The present technology relates generally to methods and compositions for treating, preventing, or delaying (slowing) the progression of (wet or dry) age-related macular degeneration (AMD). In particular, the present technology relates to the use of elamipretide in effective amounts to treat, prevent and/or delay (slow) the progression of photoreceptor loss, AMD, geographic atrophy (GA) secondary to AMD, non-exudative (a.k.a., dry) AMD, intermediate AMD, AMD with photoreceptor loss or non-exudative (a.k.a., dry) AMD with photoreceptor loss in mammalian subjects.

INTRODUCTION

The following description is provided to assist the understanding of the reader. None of the information provided or references cited is admitted to be prior art to the compositions and methods disclosed herein.

Age-related macular degeneration (AMD) affects ˜11 million Americans and is the leading cause of irreversible blindness in people aged ≥50 years. (Pennington 2016) AMD prevalence (United States) is estimated to increase to over 20 million patients by 2050. (Rein 2009) AMD preferentially affects the macular (central) region of the retina, and is characterized as early, intermediate, or late stages based on number, location, and size of drusen with hyper- or hypopigmentary changes and the presence or absence of geographic atrophy (GA) or macular neovascularization (MNV) or choroidal neovascularization (CNV). Late stages of non-exudative (or dry) AMD are characterized by GA, which is an advanced form of AMD and leads to progressive and irreversible loss of visual function (Fleckenstein 2018). GA has a major negative impact on vision-related quality of life (QoL) (Chakravarthy 2018) and accounts for 20% and 25% of legal blindness in the US and UK, respectively (Holz 2014; Boyer 2017). Geographic atrophy is defined by the presence of sharply demarcated atrophic lesions of the outer retina, resulting from loss of photoreceptors, retinal pigment epithelium (RPE), and underlying choriocapillaris (Fleckenstein 2018). There is a need for better methods, compounds and compositions for the treatment, prevention and/or delaying (slowing) the progression of AMD.

SUMMARY

In one aspect, the present disclosure provides a method for treating, preventing or delaying (slowing) the progression of (wet or dry) age-related macular degeneration (AMD) in a mammalian subject in need thereof, comprising the steps of: a) selecting subjects diagnosed as having or suspected of having AMD; b) examining one or both eyes of the subject using optical coherence tomography (OCT) to produce a first OCT scan for each eye examined; c) analyzing each OCT scan to determine: (i) the area percent of partial EZ attenuation (pEZa); (ii) the area percent of total EZ attenuation (tEZa); and/or (iii) the center 1-mm ellipsoid zone-retinal pigment epithelium (EZ-RPE) thickness; and d) administering an effective amount of elamipretide to subjects presenting with AMD in at least one eye; (i) an area percent of partial EZ attenuation (pEZa) greater than zero and less than 100 percent; (ii) an area percent of total EZ attenuation (tEZa) is greater than zero and less than 100 percent; and/or (iii) a center 1-mm EZ-RPE thickness is greater than 20 μm. In some embodiments, the method is directed towards treating, preventing or delaying (slowing) the progression of wet (i.e., exudative) age-related macular degeneration (AMD). In some embodiments, the method is directed towards treating, preventing or delaying (slowing) the progression of dry (i.e., non-exudative) age-related macular degeneration (AMD).

In some embodiments, the elamipretide is administered to the subject on a daily, weekly, or monthly basis.

In some embodiments, the area percent of tEZa is greater than zero and less than 50 percent. In some embodiments, the area percent of tEZa is greater than zero and less than 30 percent. In some embodiments, the area percent of tEZa is greater than zero and less than 20 percent. In some embodiments, the subject has high-risk drusen (HRD).

In some embodiments, analyzing the first OCT scan comprises evaluating higher-order OCT features using automated machine-learning augmented multilayer retinal segmentation optionally with expert manual reader verification.

In some embodiments, the subject is also evaluated using a visual acuity test and at baseline has a best corrected visual acuity (BCVA) in at least one eye of at least 55 letters and a low luminance best corrected visual acuity (LL-BCVA) deficit of at least 5 letters.

In some embodiments, administration of elamipretide leads to at least a 2-line gain (i.e., at least 10 letters) in LL BCVA from baseline in the subject after at least one year of elamipretide administration/treatment. In some embodiments, administration of elamipretide leads to at least a 3-line gain (i.e., at least 15 letters) in LL BCVA from baseline in the subject after at least one year of elamipretide administration.

In some embodiments, the method further comprises examining one or both eyes of the subject using OCT to produce a second OCT scan for each eye examined.

In some embodiments, analyzing each second OCT scan comprises evaluating higher-order OCT features using automated machine-learning augmented multilayer retinal segmentation optionally with expert manual reader verification.

In some embodiments, the subject is a human.

In some embodiments, the elamipretide is administered intraocularly, iontophoretically, orally, topically, systemically, intravenously, subcutaneously, or intramuscularly.

In some embodiments, the method further comprises separately, sequentially, or simultaneously administering a second active agent.

In some embodiments, the second active agent comprises an AREDS or AREDS 2 vitamin formula. In some embodiments, the second active agent is selected from the group consisting of: an antioxidant, a metal complexer, an anti-inflammatory drug, an antibiotic, and an antihistamine. In some embodiments, the antioxidant is vitamin A, vitamin C, vitamin E, lycopene, selenium, α-lipoic acid, coenzyme Q, glutathione, or a carotenoid. In some embodiments, the second active agent is mometasone furoate, tacrolimus, quercetin, or diphenhydramine.

In some embodiments, the second active agent is flavonoid, a coumarin, a phenol or a terpenoid. In some embodiments, the flavonoid is luteolin (3′,4′,5,7-tetrahydroxyflavone), diosmetin (5,7,3′-trihydroxy-4′-methoxyflavone), apigenin (4′,5,7-trihydroxyflavone), quercetin (3,3′,4′,5,7-pentahydroxyflavone), fisetin (2-(3,4-dihydroxyphenyl)-3,7-dihydroxychromen-4-one), kaempferol (3,4′,5,7-tetrahydroxyflavone), ginkgetin (7,4′-dimethylamentoflavone) or silymarin. In some embodiments, the coumarin is scopletin (6-methoxy-7 hydroxycoumarin), scaporone (6,7-dimethoxycoumarin), artekeiskeanol A (7-{[(2E,6E)-8-Hydroxy-3,7-dimethylocta-2,6-dien-1-yl]oxy}-6-methoxy-2H-chromen-2-one), selinidin ((8,8-dimethyl-2-oxo-9,10-dihydropyrano[2,3-h]chromen-9-yl) 2-methylbut-2-enoate), 5-methoxy-8-(2-hydroxy-3-butoxy-3-methylbutyloxy)-psoralen, cinnamic acid ((2E)-3-phenylprop-2-enoic acid) or ellagic acid (2,3,7,8-tetrahydroxy[1]benzopyrano[5,4,3-cde][1]benzopyran-5,10-dione). In some embodiments, the phenol is magnolol (5,5′-di(prop-2-en-1-yl)[1,1′-biphenyl]-2,2′-diol), honokiol (3′,5-di(prop-2-en-1-yl)[1,1′-biphenyl]-2,4′-diol), resveratrol (5-[E-2-(4-hydroxyphenyl)ethen-1-yl]benzene-1,3-diol), polydatin (3,4′,5-trihydroxystilbene-3-β-d-glucoside), curcumin ((1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione), α-mangostin (1,3,6-trihydroxy-7-methoxy-2,8-bis(3-methylbut-2-en-1-yl)-9H-xanthen-9-one), β-mangostin (1,6-dihydroxy-3,7-dimethoxy-2,8-bis(3-methylbut-2-enyl)xanthen-9-one) or γ-mangostin (1,3,6,7-tetrahydroxy-2,8-bis(3-methylbut-2-en-1-yl)-9H-xanthen-9-one). In some embodiments, the terpenoid is parthenolide ((1aR,4E,7aS,10aS,10bR)-2,3,6,7,7a,8,10a,10b-octahydro-1a,5-dimethyl-8-methylene-oxireno[9,10]cyclodeca[1,2-b]furan-9(1aH)-one), sinomenine, indoline (2,3-dihydro-1H-indole) or xestospongin C ([1R-(1R,4aR,11R,12aS,13S,16aS,23R,24aS)]-eicosahydro-5H,17H-1,23:11,13-diethano-2H,14H-[1,11]dioxacycloeicosino[2,3-b:12,13-b1]dipyridine).

In some embodiments, the second active agent is selected from the group consisting of: aceclidine, acetazolamide, anecortave, apraclonidine, atropine, azapentacene, azelastine, bacitracin, befunolol, betamethasone, betaxolol, bimatoprost, brimonidine, brinzolamide, carbachol, carteolol, celecoxib, chloramphenicol, chlortetracycline, ciprofloxacin, cromoglycate, cromolyn, cyclopentolate, cyclosporin, dapiprazole, demecarium, dexamethasone, diclofenac, dichlorphenamide, dipivefrin, dorzolamide, echothiophate, emedastine, epinastine, epinephrine, erythromycin, ethoxzolamide, eucatropine, fludrocortisone, fluorometholone, flurbiprofen, fomivirsen, framycetin, ganciclovir, gatifloxacin, gentamycin, homatropine, hydrocortisone, idoxuridine, indomethacin, isoflurophate, ketorolac, ketotifen, latanoprost, levobetaxolol, levobunolol, levocabastine, levofloxacin, lodoxamide, loteprednol, medrysone, methazolamide, metipranolol, moxifloxacin, naphazoline, natamycin, nedocromil, neomycin, norfloxacin, ofloxacin, olopatadine, oxymetazoline, pemirolast, pegaptanib, phenylephrine, physostigmine, pilocarpine, pindolol, pirenoxine, polymyxin B, prednisolone, proparacaine, ranibizumab, rimexolone, scopolamine, sezolamide, squalamine, sulfacetamide, suprofen, tetracaine, tetracyclin, tetrahydrozoline, tetryzoline, timolol, tobramycin, travoprost, triamcinulone, trifluoromethazolamide, trifluridine, trimethoprim, tropicamide, unoprostone, vidarbine, xylometazoline, pharmaceutically acceptable salts thereof, and combinations thereof.

In some embodiments, about 5 mg to about 80 mg of elamipretide, or a pharmaceutically acceptable salt thereof, is subcutaneously administered to the injection site of the subject.

In some embodiments, about 10 mg to about 60 mg of elamipretide, or a pharmaceutically acceptable salt thereof, is subcutaneously administered to the injection site of the subject.

In some embodiments, about 20 mg to about 60 mg of elamipretide, or a pharmaceutically acceptable salt thereof, is subcutaneously administered to the injection site of the subject.

In some embodiments, about 20 mg of elamipretide, or a pharmaceutically acceptable salt thereof, is subcutaneously administered to the injection site of the subject.

In some embodiments, about 40 mg of elamipretide, or a pharmaceutically acceptable salt thereof, is subcutaneously administered to the injection site of the subject.

In some embodiments, 40 mg of elamipretide, or a pharmaceutically acceptable salt thereof, is subcutaneously administered to the injection site of the subject.

In some embodiments, about 60 mg of elamipretide, or a pharmaceutically acceptable salt thereof, is subcutaneously administered to the injection site of the subject.

In some embodiments, 60 mg of elamipretide, or a pharmaceutically acceptable salt thereof, is subcutaneously administered to the injection site of the subject.

In some embodiments, the subject presents with an area percent of partial EZ attenuation (pEZa) is greater than 5 and less than 80 percent.

In some embodiments, the subject presents with a center 1-mm EZ-RPE thickness that is greater than 20 μm.

In some embodiments, the aforementioned method further provides for treating, preventing or delaying (slowing) the progression of geographic atrophy (GA) secondary to age-related macular degeneration (AMD). In some embodiments, the aforementioned method further provides for treating, preventing or delaying (slowing) the progression of non-exudative (dry) age-related macular degeneration. In some embodiments, the aforementioned method provides for treating, preventing or delaying (slowing) the progression of intermediate age-related macular degeneration. In some embodiments, the aforementioned method further provides for treating, preventing or delaying (slowing) the progression of age-related macular degeneration with photoreceptor loss or non-exudative (dry) age-related macular degeneration with photoreceptor loss. In some embodiments, the aforementioned method further provides for treating, preventing or delaying (slowing) the progression of age-related macular degeneration by slowing the rate of photoreceptor loss.

In one aspect, the present disclosure provides a method comprising: a) examining one or both eyes of a mammalian subject using optical coherence tomography (OCT) to produce a 1^stOCT scan for each eye examined; b) reexamining one or both eyes of the subject using optical coherence tomography (OCT) to produce a 2^ndOCT scan for one or both of the subject's eyes on a day that is after performing the examination according to step (a); c) optionally repeating step (b) n-times, each n^threexamination occurring on a day that is after the n^th−1 examination, that produced an n^th−1 OCT scan, to thereby produce a n^thOCT scan for one or both eyes, where n is a whole number from 3 to 100; and d) examining the OCT scans to determine: (i) a rate of photoreceptor loss; (ii) a percent of photoreceptor loss; and/or (iii) a mean change in the macular area of photoreceptor loss; in each eye examined for the subject that has occurred from: a) the 1^stOCT scan to the 2^ndOCT scan or to any one or more of the n^thOCT scans; and/or b) between two later obtained OCT scans for a particular eye examined.

In some embodiments, the method further comprises prescribing the administration of elamipretide for the subject to thereby treat, prevent or delay (slow) progression of the subject's photoreceptor loss in one or both eyes. In some embodiments, the method further comprises identifying the subject as a candidate for the administration of elamipretide to thereby treat, prevent or delay (slow) progression of the subject's photoreceptor loss in one or both eyes. In some embodiments, the method further comprises administering elamipretide to the subject to thereby treat, prevent or delay (slow) progression of the subject's photoreceptor loss in one or both eyes. In some embodiments, elamipretide is administered subcutaneously to the subject once daily at 40 mg/dose.

In some embodiments, the 2^ndOCT scan is produced between 1 month and 3 months, or 3 months and 6 months, or 6 months and one year, after the 1^stOCT scan is produced. In some embodiments, each n^thOCT scan is produced between 1 month and 3 months, or 3 months and 6 months, or 6 months and one year, after the n^th−1 OCT scan is produced.

In some embodiments, delaying (slowing) progression of the subject's photoreceptor loss in one or both eyes corresponds with delaying (slowing) progression of (wet or dry) age-related macular degeneration (AMD) in one or both of the subject's eyes. In some embodiments, delaying (slowing) progression of the subject's photoreceptor loss in one or both eyes correspond with delaying (slowing) progression of geographic atrophy (GA) secondary to age-related macular degeneration (AMD) in one or both of the subject's eyes.

In some embodiments, the method further provides for treating, preventing or delaying (slowing) the progression of non-exudative (dry) age-related macular degeneration in one or both of the subject's eyes. In some embodiments, the method further provides for treating, preventing or delaying (slowing) the progression of intermediate age-related macular degeneration in one or both of the subject's eyes. In some embodiments, the method further provides for treating, preventing or delaying (slowing) the progression of age-related macular degeneration with photoreceptor loss or non-exudative (dry) age-related macular degeneration with photoreceptor loss in one or both of the subject's eyes. In some embodiments, the method further provides for treating, preventing or delaying (slowing) the progression of age-related macular degeneration by slowing the rate of photoreceptor loss in one or both of the subject's eyes.

In some embodiments, the method further comprises separately, sequentially, or simultaneously administering a second active agent.

In one aspect, the present disclosure provides a method comprising: a) examining one or both eyes of a mammalian subject using a visual acuity test to determine the subject's 1^stlow luminance best corrected visual acuity (1^stLL BCVA), collectively and/or on an eye-by-eye basis; b) reexamining one or both eyes of the subject using a visual acuity test, to thereby determine the subject's 2^ndlow luminance best corrected visual acuity (2^ndLL BCVA), collectively and/or on an eye-by-eye basis, on a day that is after performing the examination according to step (a); c) optionally repeating step (b) n-times, to thereby determine the subject's n^thlow luminance best corrected visual acuity (n^thLL BCVA), collectively and/or on an eye-by-eye basis, each n^threexamination occurring on a day that is after the n^th−1 examination, where n is a whole number from 3 to 100; and d) determining whether the subject has lost or gained one or more letters and/or one or more lines in LL BCVA, collectively or on an eye-by-eye basis: from the 1^stLL BCVA determination to the 2^ndLL BCVA determination or any one or more of the n^thLL BCVA determinations; and/or b) between two later LL BCVA determinations.

In some embodiments, the method further comprises prescribing the administration of elamipretide for the subject to thereby treat, prevent or delay (slow) progression of the subject's loss in LL BCVA, collectively or on an eye-by-eye basis. In some embodiments, the method further comprises identifying the subject as a candidate for the administration of elamipretide to thereby treat, prevent or delay (slow) progression of the subject's loss in LL BCVA, collectively or on an eye-by-eye basis. In some embodiments, the method further comprises administering elamipretide to the subject to thereby treat, prevent or delay (slow) progression of the subject's loss in LL BCVA, collectively or on an eye-by-eye basis. In some embodiments, elamipretide is administered subcutaneously to the subject once daily at 40 mg/dose.

In some embodiments of the method, the 2^ndLL BCVA determination is performed between 1 month and 3 months, or 3 months and 6 months, or 6 months and one year, after the 1S^tLL BCVA determination is performed. In some embodiments, each n^thLL BCVA determination is performed between 1 month and 3 months, or 3 months and 6 months, or 6 months and one year, after the n^th-LL BCVA determination is performed. In some embodiments, the subject's LL BCVA is determined on an annual basis.

In some embodiments, delaying (slowing) progression of the subject's loss in LL BCVA in one or both eyes correspond with delaying (slowing) progression of age-related macular degeneration (AMD) in one or both of the subject's eyes. In some embodiments, delaying (slowing) progression of the subject's loss in LL BCVA in one or both eyes correspond with delaying (slowing) progression of geographic atrophy (GA) secondary to age-related macular degeneration (AMD) in one or both of the subject's eyes.

In some embodiments, the method further comprises separately, sequentially, or simultaneously administering a second active agent.

In one aspect, the present disclosure provides a method for improving the low luminance best corrected visual acuity (LL BCVA) by 2 or more lines, collectively or on an eye-by-eye basis, in a mammalian subject having, or suspected of having, age-related macular degeneration (AMD), comprising administering elamipretide to the subject for a period of at least 12 weeks. In some embodiments, the elamipretide is administered subcutaneously. In some embodiments, the elamipretide is administered once daily at 40 mg/dose. In some embodiments, the subject's low luminance best corrected visual acuity (LL BCVA) is increased by 3 or more lines, by 4 or more lines or by 5 or more lines in one or both of the subject's eyes. In some embodiments, the subject has been diagnosed as having geographic atrophy (GA) secondary to age-related macular degeneration (AMD). In some embodiments, the subject has, or is suspected of having, non-exudative (dry) age-related macular degeneration. In some embodiments, the subject has, or is suspected of having, intermediate age-related macular degeneration. In some embodiments, the subject has, or is suspected of having, age-related macular degeneration with photoreceptor loss or non-exudative (dry) age-related macular degeneration with photoreceptor loss.

In some embodiments, the method further comprises separately, sequentially, or simultaneously administering a second active agent.

In one aspect, the present disclosure provides a method for reducing the ratio of tEZA to RPE loss as determined by an OCT scan in a mammalian subject having, or suspected of having, age-related macular degeneration (AMD), comprising administering elamipretide to the subject for a period of at least 12 weeks. In some embodiments, elamipretide is administered subcutaneously. In some embodiments, elamipretide is administered once daily at 40 mg/dose. In some embodiments, the administration of elamipretide reduces the ratio of tEZA to RPE loss until it approaches 1. In some embodiments, the subject has, or is suspected of having, geographic atrophy (GA) secondary to age-related macular degeneration (AMD). In some embodiments, the subject has, or is suspected of having, non-exudative (dry) age-related macular degeneration. In some embodiments, the subject has, or is suspected of having, intermediate age-related macular degeneration. In some embodiments, the subject has, or is suspected of having, age-related macular degeneration with photoreceptor loss or non-exudative (dry) age-related macular degeneration with photoreceptor loss.

In some embodiments, the method further comprises separately, sequentially, or simultaneously administering a second active agent.

In one aspect, the present disclosure provides a method for protecting against photoreceptor loss in a mammalian subject having, or suspected of having, age-related macular degeneration (AMD), comprising administering elamipretide to the subject for a period of at least 12 weeks. In some embodiments, elamipretide is administered to the subject for at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 18 months, at least 24 months or at least 48 months.

In some embodiments, protection against photoreceptor loss is determined by measuring the difference percentage of tEZa between two time points, each as determined by examination or an OCT scan or scans, between a treated individual or group of treated individuals as compared with an untreated individual or untreated group individuals.

In some embodiments, the elamipretide is administered subcutaneously once daily at 40 mg/dose.

In some embodiments, the subject has, or is suspected of having, geographic atrophy (GA) secondary to age-related macular degeneration (AMD). In some embodiments, the subject has, or is suspected of having, non-exudative (dry) age-related macular degeneration. In some embodiments, the subject has, or is suspected of having, intermediate age-related macular degeneration. In some embodiments, the subject has, or is suspected of having, age-related macular degeneration with photoreceptor loss or non-exudative (dry) age-related macular degeneration with photoreceptor loss.

In some embodiments, the method further comprises separately, sequentially, or simultaneously administering a second active agent.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic of the clinical study design as described in Example 1.

FIG. 2A is a bar graph showing the mean change in LL-BCVA. FIG. 2B is a bar graph showing the mean change in progression of GA secondary to AMD in subjects examined in the study.

FIG. 3 is a bar graph showing elamipretide mediated a categorical improvement in LL BCVA. The mITT population was used for the analysis, placebo n=48 and elamipretide n=82. Statistical analysis showing nominal significance levels.

FIG. 4A is a chart showing elamipretide reduces total EZ attenuation. FIG. 4B is a chart showing elamipretide reduces partial EZ attenuation. Least Square (LS) means estimated from a mixed-effects model for repeated measures (MMRM). The mITT population was used for the analysis, for total EZ attenuation (tEZa), placebo n=50 and 42 for 24 and 48 weeks, respectively while elamipretide n=89 and 71, respectively. From partial EZ attenuation (pEZa), placebo n=50 and 42, for 24 and 48 weeks, respectively while elamipretide n=89 and 71, respectively. Statistical analysis showing nominal “p values.”

FIG. 5 are representative ellipsoid zone integrity maps. Areas of dark gray represent total EZ attenuation and areas of black represent partial EZ attenuation. Maps were matched for degree of baseline tEZ attenuation and growth from baseline to week 48 in exemplary patients of the placebo treatment and elamipretide treatment arms are illustrated.

FIG. 6 are representative ellipsoid zone integrity maps. Areas of dark gray total EZ attenuation and areas of black represent partial EZ attenuation. Maps were matched for degree of baseline tEZ attenuation and growth from baseline to week 48 in exemplary patients of the placebo treatment and elamipretide treatment arms are illustrated.

FIGS. 7A and 7B are charts showing elamipretide reduced progression of EZ-GA gap. The total randomized population was used for the analysis. Placebo n=59, 52, and 41 for baseline, 24, and 48 weeks, respectively, while elamipretide n=115, 83, and 73, respectively. Least Square (LS) means estimated from a mixed-effects model for repeated measures (MMRM) is used in reporting change from baseline.

FIG. 8 is a graphical representation of elamipretide induced attenuation of progression of overall retinal damage. The inner ring of each band represents the baseline area for each parameter (black (innermost band) for geographic atrophy (GA); light gray (middle band) for total EZ attenuation (tEZa); and dotted (outermost ring) for partial EZ attenuation) and the outer ring of each band shows growth over the 48-week study period.

DETAILED DESCRIPTION

It is to be appreciated that certain aspects, modes, embodiments, variations and features of the invention are described below in various levels of detail in order to provide a substantial understanding of the present invention.

In practicing the present technology, many conventional techniques in molecular biology, protein biochemistry, cell biology, immunology, microbiology and recombinant DNA are used. These techniques are well-known and are explained in, e.g., Current Protocols in Molecular Biology, Vols. I-III, Ausubel, Ed. (1997); Sambrook et al., Molecular Cloning: A Laboratory Manual, Second Ed. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1989); DNA Cloning: A Practical Approach, Vols. I and II, Glover, Ed. (1985); Oligonucleotide Synthesis, Gait, Ed. (1984); Nucleic Acid Hybridization, Hames & Higgins, Eds. (1985); Transcription and Translation, Hames & Higgins, Eds. (1984); Animal Cell Culture, Freshney, Ed. (1986); Immobilized Cells and Enzymes (IRL Press, 1986); Perbal, A Practical Guide to Molecular Cloning; the series, Meth. Enzymol., (Academic Press, Inc., 1984); Gene Transfer Vectors for Mammalian Cells, Miller & Calos, Eds. (Cold Spring Harbor Laboratory, NY, 1987); and Meth. Enzymol., Vols. 154 and 155, Wu & Grossman, and Wu, Eds., respectively.

The definitions of certain terms as used in this specification are provided below. 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 invention belongs.

As used in this specification and the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the content clearly dictates otherwise. For example, reference to “a cell” includes a combination of two or more cells, and the like.

As used herein, “about” will be understood by persons of ordinary skill in the art and will vary to some extent depending upon the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art, given the context in which it is used, “about” will mean up to plus or minus 10% of the enumerated value.

As used herein, the “administration” of an agent, drug, or peptide to a subject includes any route of introducing or delivering to a subject a compound to perform its intended function. Administration can be conducted by any suitable route, including orally, intraocularly, intranasally, parenterally (intravenously, intramuscularly, intraperitoneally, or subcutaneously), or topically. Administration includes self-administration, the administration by another or administration by a device.

As used herein, the term “amino acid” includes naturally-occurring amino acids and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally-occurring amino acids. Naturally-occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, γ-carboxyglutamate, and O-phosphoserine. Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally-occurring amino acid, i.e., an α-carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally-occurring amino acid. Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally-occurring amino acid. Amino acids can be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission.

As used herein, “area of photoreceptor loss” refers to the area (in mm²) of the macular where the EZ-RPE thickness equals 0 μm on en-face map and is synonymous with the term “area of total EZ attenuation (tEZa)”.

As used herein, the term “area of total EZ attenuation” or “area of total ellipsoid zone attenuation” refers to the area (in mm²) of the macular where the EZ-RPE thickness equals 0 μm on en-face map, generally as determined by analysis of an optical coherence tomography (OCT) scan.

As used herein, the term “baseline” refers to the first study visit with a subject after determining that they meet the criteria for a certain clinical trial through the screening process. The baseline is considered the date (often referred to as Day 1 of the study or t=0) and time of initiation of the study for that subject with respect to the study protocol and the associated data collected for that subject at that first study visit.

As used herein “center 1-mm EZ-RPE thickness” refers to the thickness of the combined EZ-RPE layers at 1 mm diameter surrounding the foveal center.

As used herein “central 1 mm of the EZ-RPE” refers to the combined EZ and RPE layers at 1 mm diameter surrounding the foveal center.

As used herein, the term “effective amount” refers to a quantity of a therapeutic agent sufficient to achieve a desired therapeutic and/or prophylactic effect, e.g., an amount which results in the prevention of, or a decrease in, the signs or symptoms (e.g., deterioration of vision or photoreceptor loss) associated with the disease to be treated (e.g., AMD). The amount of a therapeutic agent administered to the subject will depend on the characteristics of the individual, such as general health, age, sex, body weight and tolerance to drugs. It will also depend on the degree, severity and type of disease. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. The compositions can also be administered in combination with one or more additional therapeutic compounds/agents. In the methods described herein, elamipretide may be administered to a subject having one or more signs or symptoms of AMID. For example, a “therapeutically effective amount” of elamipretide is meant levels in which the physiological effects of AMD are, at a minimum, ameliorated (e.g., slowing the rate of growth of photoreceptor loss over time).

As used herein, “elamipretide” refers to the tetrapeptide with the amino acid sequence: H-D-Arg-2′,6′Dmt-Lys-Phe-NH₂, where 2′,6′-Dmt is the amino acid 2′,6′-dimethyltyrosine. Elamipretide has the structure:

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Elamipretide is also referred to in the scientific literature as SS-31, bendavia and MTP-131. Elamipretide is typically administered as the pharmaceutically acceptable salt, such as a tris-HCl salt having the structure:

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Elamipretide is commonly administered as in its pharmaceutically acceptable salt form rather than as a free-base. Whenever the term elamipretide is used herein, its use is intended to also encompass all possible pharmaceutically acceptable salts thereof, unless the context of its use is clearly contradictory to such an interpretation.

As used herein “ellipsoid zone” or “EZ” refers to the mitochondria-rich hyper-reflective outer retinal band (as seen in OCT) located just above the retinal pigment epithelium or RPE.

As used herein “en-face map” refers to an image derived using, for example, spectral domain optical coherence tomography (SD-OCT). Such en-face map generally represents a two dimensional (e.g., 6 mm×6 mm) image taken of the subject's eye.

As used herein “EZ attenuation area” refers to the area of attenuated ellipsoid zone expressed in mm².

As used herein “ellipsoid zone integrity” or “EZ integrity” refers to the state of the organization or arrangement and size of photoreceptor outer segments of the macula scan area of an individual eye in a disease state as compared to a non-diseased state.

As used herein “EZ-RPE thickness” refers to thickness of the combined ellipsoid zone (EZ) and retinal pigment epithelium (RPE).

As used herein “fovea” refers to the small depression in the retina of the eye where: (i) retinal cones are particularly concentrated; and (ii) the center of the field of vision is focused; and (iii) visual acuity is highest.

As used herein “foveal center” refers to the small, flat spot located exactly in the center of the posterior portion of the retina.

As used herein “GA area” refers to the total area (in mm²) of geographic atrophy within an individual macula of a subject's eye, which total area can be determined by examination of an en-face map for evidence of loss of photoreceptors, retinal pigment epithelium (RPE), and underlying choriocapillaris.

As used herein “geographic atrophy” or “GA” refers to a chronic progressive degeneration of the macula, as part of late-stage age-related macular degeneration (AMD), wherein geographic atrophy (GA) is defined by the presence of sharply demarcated atrophic lesions of the outer retina, resulting from loss of photoreceptors, retinal pigment epithelium (RPE), and underlying choriocapillaris.

As used herein “macular percentage of partial EZ attenuation” or “macular percentage of pEZa,” “percentage of partial EZ attenuation,” “percentage of pEZa,” “area percent of partial EZ attenuation,” or “area percent of pEZa” refers to the percentage of the macular area where the EZ-RPE thickness is ≤20 μm on en-face map (typically determined with respect to the area (in mm²) where the EZ-RPE thickness is ≤20 m divided by the total area (in mm²) of the entire en-face map to derive the percentage).

As used herein “macular percentage of total EZ attenuation” or “macular percentage of tEZa,” “percentage of total EZ attenuation,” “percentage of tEZa,” “area percent of total EZ attenuation,” or “area percent of tEZa” refers to the percentage of the macular area where the EZ-RPE thickness is 0 μm on en-face map (typically determined with respect to the area (in mm²) where the EZ-RPE thickness is 0 μm on en-face map divided by the total area (in mm²) of the entire en-face map to derive the percentage).

As used herein “optical coherence tomography” or “OCT” refers to a noninvasive imaging modality using a beam of light (i.e., light interference) to rapidly scan the eye to generate direct cross-sectional image of a subject's retina and optic nerve suitable to produce measurements of the thickness/volume of individual layers/structures of the eye. There are several types of OCT that can be used to produce a suitable OCT scan for the practice of this disclosure, including, but not limited to, time-domain OCT (i.e., TD-OCT), spectral domain OCT (i.e., SD-OCT) and swept-source (SS-OCT). If not otherwise specified, when used herein, a general reference to “optical coherence tomography” or “OCT” refers to all of the above forms of optical coherence tomography and any other form of optical coherence tomography that can be used for the examination of a subject's/patient's eyes.

As used herein “outer nuclear layer” or “ONL” refers to the outer-most layer of the retina, which contains the cell bodies of rod and cone photoreceptors.

As used herein “outer retinal parameters” refers to the outer nuclear layer (ONL) to RPE thickness.

As used herein “partial EZ attenuation” or “pEZa” refers to the portion of the macular tissue where the EZ-RPE thickness is ≤20 μm.

As used herein, “percent photoreceptor loss” refers to the percentage of the macular scan area where EZ-RPE thickness of 0 μm on en-face map (synonymous with percentage of tEZa).

As used herein, the term “pharmaceutically acceptable salt” refers to a salt of a therapeutically active compound that can be prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Salts derived from pharmaceutically acceptable inorganic bases include ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, and zinc salts, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-methylmorpholine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperadine, polyamine resins, procaine, purines, theobromine, triethylamine (NEt₃), trimethylamine, tripropylamine, tromethamine and the like, such as where the salt includes the protonated form of the organic base (e.g., [HNEt₃]⁺). Salts derived from pharmaceutically acceptable inorganic acids include salts of boric, carbonic, hydrohalic (hydrobromic, hydrochloric, hydrofluoric or hydroiodic), nitric, phosphoric, sulfamic and sulfuric acids. Salts derived from pharmaceutically acceptable organic acids include salts of aliphatic hydroxyl acids (e.g., citric, gluconic, glycolic, lactic, lactobionic, malic, and tartaric acids), aliphatic monocarboxylic acids (e.g., acetic, butyric, formic, propionic and trifluoroacetic acids), amino acids (e.g., aspartic and glutamic acids), aromatic carboxylic acids (e.g., benzoic, p-chlorobenzoic, diphenylacetic, gentisic, hippuric, and triphenylacetic acids), aromatic hydroxyl acids (e.g., o-hydroxybenzoic, p-hydroxybenzoic, 1-hydroxynaphthalene-2-carboxylic and 3-hydroxynaphthalene-2-carboxylic acids), ascorbic, dicarboxylic acids (e.g., fumaric, maleic, oxalic and succinic acids), glucuronic, mandelic, mucic, nicotinic, orotic, pamoic, pantothenic, sulfonic acids (e.g., benzenesulfonic, camphorsulfonic, edisylic, ethanesulfonic, isethionic, methanesulfonic, naphthalenesulfonic, naphthalene-1,5-disulfonic, naphthalene-2,6-disulfonic, p-toluenesulfonic acids (PTSA)), xinafoic acid, and the like. In some embodiments, the pharmaceutically acceptable counterion is selected from the group consisting of acetate, benzoate, besylate, bromide, camphorsulfonate, chloride, chlorotheophyllinate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucoronate, hippurate, iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, mesylate, methylsulfate, naphthoate, sapsylate, nitrate, octadecanoate, oleate, oxalate, pamoate, phosphate, polygalacturonate, succinate, sulfate, sulfosalicylate, tartrate, tosylate, and trifluoroacetate. In some embodiments, the salt is a tartrate salt, a fumarate salt, a citrate salt, a benzoate salt, a succinate salt, a suberate salt, a lactate salt, an oxalate salt, a phthalate salt, a methanesulfonate salt, a benzenesulfonate salt, a maleate salt, a trifluoroacetate salt, a hydrochloride salt, or a tosylate salt. Also included are salts of amino acids such as arginate and the like, and salts of organic acids such as glucuronic or galactunoric acids and the like (see, e.g., Berge et al, Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present application may contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts or exist in zwitterionic form. These salts may be prepared by methods known to those skilled in the art. Other pharmaceutically acceptable carriers known to those of skill in the art are suitable for the present technology.

As used herein, the terms “polypeptide”, “peptide” and “protein” are used interchangeably herein to mean a polymer comprising two or more amino acids joined to each other by peptide bonds or modified peptide bonds, i.e., peptide isosteres. Polypeptide refers to both short chains, commonly referred to as peptides, glycopeptides or oligomers, and to longer chains, generally referred to as proteins. Polypeptides may contain amino acids other than the 20 gene-encoded amino acids. Polypeptides include amino acid sequences modified either by natural processes, such as post-translational processing, or by chemical modification techniques that are well known in the art.

As used herein, “prevention” or “preventing” of a disorder or condition refers to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

As used herein “retinal pigment epithelium” or “RPE” refers to the single layer of tightly joined pigmented cells just outside the neurosensory retina that nourishes retinal visual cells and forms a barrier between the retina and underlying choroid.

As used herein, the term “separate” refers to an administration of at least two therapeutic agents at the same time or at substantially the same time by different routes.

As used herein, the term “sequential” refers to administration of at least two different therapeutic agents at different times, the administration route being identical or different. More particularly, sequential use refers to the whole administration of one of the at least two different therapeutic agents before administration of the other or others commences. It is thus possible to administer one of the therapeutic agents over several minutes, hours, or days before administering the other active ingredient or ingredients. There is no simultaneous treatment in this case.

As used herein, the term “simultaneous” refers to the administration of at least two different therapeutic agents by the same route and at the same time or at substantially the same time.

As used herein, the terms “subject” and “patient” are used interchangeably.

As used herein “sub-RPE anatomical metrics” refers to refers to anatomical measurements and features of the subretinal pigment epithelium.

As used herein, the terms “treating” or “treatment” or “alleviation” refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) the targeted pathologic condition or disorder (e.g., loss of vision or loss of photoreceptors). A subject is successfully “treated” for the condition if, after receiving a therapeutic amount of a therapeutic agent (e.g., elamipretide) according to the methods described herein, the subject shows observable and/or measurable reduction in or absence of one or more signs and symptoms of the condition (e.g., loss of vision or loss of photoreceptors). It is also to be appreciated that the various modes of treatment or prevention of medical conditions as described are intended to mean “substantial,” which includes total but also less than total treatment or prevention, and wherein some biologically or medically relevant result is achieved.

As used herein “total EZ attenuation” or “tEZa” refers to the portion of the tissue of the macular where the EZ-RPE thickness is 0 μm.

Age-Related Macular Degeneration

The pathophysiology of AMD is thought to involve multiple converging pathways, including complement activation, lipid metabolism, and mitochondrial injury (Tan et al., Redox Biology, 2020). Because of the multifactorial etiology involved, effective disease management may require treatment of multiple targets that may differ across various stages of disease (Handa et al., Nature Communications, 2019). Although the multi-faceted pathophysiology of AMD is complex and not fully understood, investigations confirm that the root cause of irreversible vision loss is photoreceptor death. Therefore, protecting photoreceptors from damage and delaying their degeneration are key to the successful treatment of clinical symptoms and disease progression (Scholl et al., Ophthalmic Res, 2021).

Photoreceptor dysfunction/loss/death in AMD can be quantified by changes in the ellipsoid zone (EZ), which is a mitochondria-rich tissue layer containing photoreceptors, and the associated loss (i.e., death) of photoreceptor cells leading to (and correlated with) progressive loss of visual function (Abraham, et al., Ophthamol Ret, 2022; Sarici, et al., Ophthamol. Surg Lasers Imag. Ret, 2022; Itoh, et al., Br J Ophthamol, 2015). These observed EZ changes are typically associated with the eventual loss (i.e., death) of sections of the retinal pigment epithelium (RPE) and the underlying choriocapillaris leading to areas of GA. Notably, EZ loss/death or attenuation has been shown to predict areas of GA, as well as precede its onset by two to three years (Pasricha et al., Ophthalmol Retina, 2021, Sarici Ophthalmic Surg Lasers Imaging Retina. 2022), suggesting that photoreceptor dysfunction/loss/death may precede the loss of underlying RPE. EZ loss/death has been associated with GA progression (Abraham et al., ASRS, 2022), and there is emerging data suggesting that attenuation (e.g., reduction in rate) of EZ loss (i.e., death) may mitigate/slow/delay GA progression (Mai et al., Am J Ophthalmol, 2022; Ehlers, et al., Macula Society, 2022; Vogl, et al. Ophthalmol Retina, 2023). Longitudinal studies have also demonstrated that the EZ loss/death-to-GA boundary distance (EZ-GA gap) is prognostic for future GA progression rates (Pfau et al., JAMA Ophthalmol., 2020; Ehlers, et al., Macula Society, 2022). Accordingly, it has been postulated that imaging photoreceptor degeneration may serve not only as a prognostic biomarker, but as attractive clinical end points in dry AMD since they are accurate, with high prognostic validity, and have been concurrently validated in multiple structure-function correlation studies in dry AMD (Pfau et al., JAMA Ophthalmol., 2020).

Patients with dry AMD usually report or present early in the course of the disease with visual functional impairments including difficulty reading or limited vision at night or in reduced lighting conditions (Chandramohan 2016, Bressler 2003). This early loss of low luminance best corrected visual acuity (LL BCVA) occurs despite relative preservation of best-corrected visual acuity (BCVA) in the absence of foveal atrophy (Fleckenstein 2018). Low luminance visual dysfunction has been shown to be predictive of subsequent best corrected visual dysfunction in eyes with GA (Sunness 2008). LL BCVA is also significantly associated with patient-reported visual quality of life (Künzel et al., Invest Ophthalmol Vis Sci., 2020). Accordingly, the preservation of LL BCVA is an important and relevant clinical endpoint for dry AMD (Sunness 2008; Oct. 2, 2018, Type C Meeting Preliminary Comments). Notably, in the setting of intermediate AMD, degeneration of EZ-RPE thickness and reflectivity is strongly associated with loss of mesopic and scotopic light sensitivity (Pfau et al., JAMA Ophthalmol., 2020) which in turn is associated with LL BCVA decline (Pondorfer et al., PLOS One, 2020).

Prophylactic and Therapeutic Uses of Elamipretide.

Elamipretide can be useful in the prevention or treatment of AMD, GA secondary to AMD, non-exudative (dry) age-related macular degeneration, exudative (wet) age-related macular degeneration, intermediate age-related macular degeneration, age-related macular degeneration with photoreceptor loss or non-exudative (dry) age-related macular degeneration with photoreceptor loss. Specifically, the present disclosure provides for both prophylactic and therapeutic methods of treating a subject having or suspected of having AMD, GA secondary to AMD, non-exudative (dry) age-related macular degeneration, exudative (wet) age-related macular degeneration, intermediate age-related macular degeneration, age-related macular degeneration with photoreceptor loss or non-exudative (dry) age-related macular degeneration with photoreceptor loss. Accordingly, the present methods provide for the treatment, prevention or delay (slowing) of the progression of AMID in a mammalian subject by administering an effective amount of elamipretide to a subject in need thereof. For example, a subject can be administered elamipretide containing compositions in an effort to improve one or more of the factors contributing to AMD or to delay the effects of deterioration/loss of vision and/or the tissue/photoreceptors that lead to AMD, GA secondary to AMD, non-exudative (dry) age-related macular degeneration, exudative (wet) age-related macular degeneration, intermediate age-related macular degeneration, age-related macular degeneration with photoreceptor loss or non-exudative (dry) age-related macular degeneration with photoreceptor loss.

One aspect of the technology provides for a method of treating, preventing or delaying (slowing) the progress of AMID, GA secondary to AMD, non-exudative (dry) age-related macular degeneration, exudative (wet) age-related macular degeneration, intermediate age-related macular degeneration, age-related macular degeneration with photoreceptor loss or non-exudative (dry) age-related macular degeneration with photoreceptor loss in a mammalian subject for therapeutic purposes. In therapeutic applications, compounds (e.g., elamipretide), compositions or medicaments (e.g., formulations comprising elamipretide) are administered to a subject suspected of, or already suffering from AMD in an amount sufficient to at least partially arrest (i.e., delay or slow), the signs or symptoms of the disease, including its complications and intermediate pathological phenotypes in development of the disease. As such, the disclosure provides methods of treating an individual afflicted with AMD. Furthermore, this disclosure provided methods for preventing or delaying (slowing) the progression of AMD (including wet- or dry-AMD) as well as treating, preventing or delaying (slowing) the progression of GA secondary to AMD, non-exudative (dry) age-related macular degeneration, intermediate age-related macular degeneration, age-related macular degeneration with photoreceptor loss or non-exudative (dry) age-related macular degeneration with photoreceptor loss.

In one aspect, the present disclosure provides a method for treating, preventing or delaying (slowing) the progression of age-related macular degeneration (AMD) in a mammalian subject in need thereof, comprising the steps of: a) selecting subjects diagnosed as having or suspected of having AMD; b) examining one or both eyes of the subject using optical coherence tomography (OCT) to produce a first OCT scan for each eye examined; c) analyzing each OCT scan to determine: (i) the area percent of partial EZ attenuation (pEZa); (ii) the area percent of total EZ attenuation (tEZa); and/or (iii) the center 1-mm ellipsoid zone-retinal pigment epithelium (EZ-RPE) thickness; and d) administering an effective amount of elamipretide to subjects presenting with; (i) an area percent of partial EZ attenuation (pEZa) greater than zero and less than 100 percent; (ii) an area percent of total EZ attenuation (tEZa) is greater than zero and less than 100 percent; and/or (iii) a center 1-mm EZ-RPE thickness is greater than 20 μm.

In some embodiments, the elamipretide is administered to the subject on a daily, weekly, or monthly basis.

In some embodiments, the subject is also evaluated using a visual acuity test and at baseline has a best corrected visual acuity (BCVA) in at least one eye of greater than or equal to 55 letters and a low luminance best corrected visual acuity (LL-BCVA) deficit of at least 5 letters.

In some embodiments, administration of elamipretide leads to at least a 2 line gain (i.e., at least 10 letters) in LL BCVA from baseline in the subject after at least one year of elamipretide administration. In some embodiments, administration of elamipretide leads to at least a 3 line gain (i.e., at least 15 letters) in LL BCVA from baseline in the subject after at least one year of elamipretide administration.

In some embodiments, the method further comprises examining one or both eyes of the subject using OCT to produce an additional OCT scan for each eye examined.

In some embodiments, analyzing the additional OCT scan comprises evaluating higher-order OCT features using automated machine-learning augmented multilayer retinal segmentation optionally with expert manual reader verification.

In some embodiments, the subject is a human.

In some embodiments, the elamipretide is administered intraocularly, iontophoretically, orally, topically, systemically, intravenously, subcutaneously, or intramuscularly.

In some embodiments, the method further comprises separately, sequentially, or simultaneously administering a second active agent.

In some embodiments, the second active agent comprises an AREDS or AREDS2 vitamin formula. The AREDS vitamin formula comprises 400 IU of vitamin E, 15 mg of beta-carotene, 80 mg zinc as zinc oxide and 2 mg copper as cupric oxide. The AREDS2 vitamin formula comprises 10 mg of lutein, 2 mg of zeazanthin, 500 mg of vitamin C, 400 IU of vitamin E, 80 (or 25) mg of zinc oxide and 2 mg of cupric oxide.

In some embodiments, the second active agent is selected from the group consisting of: an antioxidant, a metal complexer, an anti-inflammatory drug, an antibiotic, and an antihistamine.

In some embodiments, the antioxidant is vitamin A, vitamin C, vitamin E, lycopene, selenium, α-lipoic acid, coenzyme Q, glutathione, or a carotenoid.