Peptide compositions and methods for treating retinal diseases and disorders

Abstract

Provided are formulations and methods for treating drusen and / or AMD, such that the risk of vitreous flare and lens opacity or lens haziness, e.g., cataract formation, is reduced or substantially eliminated.

Description

Attorney Docket No.: 87JA-350811-WOPEPTIDE COMPOSITIONS AND METHODS FOR TREATING RETINAL DISEASES AND DISORDERSCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. §119(e) to U.S. Provisional Application Number 63 / 723,078, filed November 20, 2024, the entirety of which is incorporated by reference.BACKGROUND

[0002] Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in adults in the Western world. The early stage of AMD is characterized by the presence of small to medium-size drusen and pigmentary abnormalities such as hyperpigmentation or hypopigmentation of the retinal pigment epithelium (RPE). The intermediate stage of AMD is characterized by the presence of at least one of one large drusen, numerous medium-size drusen, hyperpigmentation, and / or hypopigmentation of the RPE, either without signs of geographic atrophy (GA), or with GA that does not extend to the center of the macula (non-central or para-central GA). GA represents the absence of a continuous pigmented layer and the death of at least some portion of RPE cells. Noncentral GA spares the fovea and thus preserves central vision. The advanced stage of AMD is characterized by the presence of drusen and GA that extends to the center of the macula (central GA). Central GA includes macular atrophy. Central GA involves the fovea and thus results in significant loss of central vision and visual acuity.

[0003] Age-related macular degeneration can result in severe loss of central vision, making it difficult to read, drive, or perform other daily activities that require fine central vision, and can even cause blindness.

[0004] The hallmark of early and intermediate AMD is the presence of drusen, visible on clinical examination as yellowish deposits located in the macula. Drusen have been shown to be compositionally diverse, where on histopathologic analyses, they have demonstrated heterogeneous staining patterns that reveal distinct substructures differentially composed of lipids, carbohydrates, and proteins. The functional significance of these drusen substructures, and how they may be related to AMD progression, are unclear.

[0005] Although drusen bodies are most commonly described in AMD, it is important to note that they are not pathognomonic of AMD. Drusen-like deposits can also be seen in some less prevalent inherited conditions such as Sorsby fundus dystrophy, North Carolina macular dystrophy, Stargardt’sAttorney Docket No.: 87JA-350811-WO disease, and Adult-onset foveomacular vitelliform dystrophy. Drusen deposits have also been noted in some systemic conditions such as dense deposit disease and Alport syndrome.SUMMARY

[0006] The formulations and methods described herein are designed to treat drusen and / or AMD, such that the risk of vitreous flare and lens opacity or lens haziness, e.g., cataract formation, is reduced or substantially eliminated.

[0007] The present disclosure, in one embodiment, provided herein is a method for eliminating or reducing the number and / or size (e.g., height) of drusen, or inhibiting formation or growth of drusen, in a patient, comprising administering to the eye of a patient in need thereof, an effective amount of pharmaceutical formulation comprising an effective amount of an apolipoprotein A-I mimetic peptide, or salt thereof; optionally at least one phospholipid; and an aqueous pharmaceutically acceptable carrier; wherein the amount of peptide is in a range sufficient to reduce the number and / or size of drusen, inhibit formation or growth of drusen, and / or reduce or substantially eliminate the occurrence and / or severity of lens opacity.

[0008] In some embodiments, provided herein is a method for treating age-related macular degeneration (AMD) in a patient in need thereof, comprising administering to the eye an effective amount of pharmaceutical formulation comprising: an apolipoprotein A-I mimetic peptide, or salt thereof; at least one phospholipid; and an aqueous pharmaceutically acceptable carrier.

[0009] In some embodiments, the apolipoprotein A-I mimetic peptide is Ac- DWFKAFYDKVAEKFKEAF-NH2(L4F) (SEQ. ID. NO.: 13) or a salt thereof. In some embodiments, the apolipoprotein A-I mimetic peptide is Ac-DWFKAFYDKVAEKFKEAF-NIU (SEQ. ID. NO.: 13) acetate (L4F-a).

[0010] Also provided is an injectable intraocular formulation comprising: an apolipoprotein A-I mimetic peptide, or salt thereof; an effective amount of at least one phospholipid; and an aqueous pharmaceutically acceptable carrier; wherein the molar ratio of phospholipid to peptide is sufficient such that the occurrence and / or severity of one or both of lens opacity and / or vitreous flare is reduced or substantially eliminated.

[0011] In some embodiments, provided herein is an injectable intraocular formulation comprising: AC-DWFKAFYDKVAEKFKEAF-NH2 (L4F) (SEQ. ID. NO.: 13), or salt thereof; an effective amount of at least one phospholipid; and an aqueous pharmaceutically acceptable carrier.Attorney Docket No.: 87JA-350811-WOBRIEF DESCRIPTION OF DRAWINGS

[0012] Fig. 1 shows a real-time cell viability assay for L4F acetate salt (L4F-a) formulations with and without phospholipid.

[0013] Figs. 2A-2G show cell viability assays for L4F acetate salt (L4F-a) formulations with and without phospholipid.

[0014] Figs. 3A-3D show cell viability assays for L4F acetate salt (L4F-a) formulations with and without phospholipid and as compared to POPCDETAILED DESCRIPTION

[0015] All numerical designations, e.g., pH, temperature, time, concentration, and molecular weight, including ranges, are approximations which are varied ( + ) or ( - ) by increments of 0.1 or 20%, or 10%. It is to be understood, although not always explicitly stated that all numerical designations are preceded by the term “about”. Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 20%. In certain embodiments, the term “about” includes the indicated amount ± 10%. In other embodiments, the term “about” includes the indicated amount ± 5%. In certain other embodiments, the term “about” includes the indicated amount ± 1%. It also is to be understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents of such are known in the art.

[0016] As used herein, “substantially” (e.g., substantially in relation to a biological or chemical effect) refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest. One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and / or proceed to completeness or achieve or avoid an absolute result. The term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.

[0017] “Apolipoprotein A-I mimetic peptide,” “apo A-I mimetic peptide,” and the like, refer to a peptide having biological activity comparable to an Apolipoprotein A-I protein, as well as peptides that potentiate the effects of an apolipoprotein A-I protein.

[0018] The term “phospholipid,” as used herein, refers to an organic compound that has two fatty acid moieties attached at the sn-1 and sn-2 positions of glycerol and a head group linked by a phosphate residue at the sn-3 position of the glycerol. Exemplary headgroup moieties include choline, ethanolamine, serine, and inositol. The fatty acid moiety is the portion of the fatty acid molecule thatAttorney Docket No.: 87JA-350811-WO is bound at the sn-1 or sn-2 position, for example by an ester or ether linkage. When the fatty acid moiety is a fatty acyl, the aliphatic chain of the fatty acyl is attached via an ester linkage and when the fatty acid moiety is an aliphatic chain of a fatty acid, the aliphatic chain is attached via an ether linkage. When a particular fatty acid is mentioned in connection with a phospholipid of the invention, it should therefore be taken as a reference to the relevant fatty acyl group or to its aliphatic chain. For example, DHA-phospholipid refers to a mono- or di-DHA ester with a phospholipid, such as DHA phosphatidylcholine or DHA phosphatidylethanolamine.

[0019] “Lens opacity” refers generally to a condition where the lens of the eye, which is typically clear, becomes cloudy and impairs vision. The term “opacity” means a condition of lacking transparency, or a condition of opaqueness, e.g., in a part of an eye. Lens opacity can be congenital or degenerative. In certain embodiments, lens opacity is a result of, or is otherwise classified as, cataracts. A cataract is a clouding of the lens of the eye. Cataracts result from changes in the lens fiber cells, which make up the lens. These changes, which include modifications to the lens fiber cell membrane and especially a decrease in membrane cholesterol and increase in membrane alpha crystalline, reduce the transparency of the lens and are generally known clinically as cataracts. Symptoms of cataracts may include, but are not limited to, clouded, blurred or dim vision, trouble seeing at night, sensitivity to light and glare, need for brighter light for reading and other activities, seeing “halos” around lights, frequent changes in eyeglass or contact lens prescription, fading or yellowing of colors, and double vision in one eye. Certain forms of cataracts develop relatively quickly, while the great majority develop over a period of several decades. Severe forms of cataracts therefore typically occur in elderly patients.

[0020] The term “age-related macular degeneration” or “AMD” refer to a medical condition which usually affects elderly patients (e.g., patients over 50 years of age) and results in a loss of vision in the center of the visual field (the macula) because of damage to the retina. As used herein, the term “AMD” includes early AMD, intermediate AMD, late / advanced AMD, “dry” (i.e. non-exudative) AMD, and “wet” (i.e. exudative or neovascular) AMD. Early AMD typically refers to a stage of AMD characterized by the presence of drusen or at least one medium-sized druse, within Bruch’s membrane adjacent to the RPE layer. Patients with early AMD typically do not present with significant vision loss. Intermediate AMD generally refers to a stage of AMD characterized by large drusen and / or pigment changes in the retina. Intermediate AMD may be accompanied by some vision loss. Late AMD generally refers to a stage of AMD, which can be characterized by vision loss, e.g., severe central vision loss, due to damage to the macula, and typically either the presence of drusen, or since drusen can collapse after RPE death in GA, drusen are often not present and instead a loss of RPE and photoreceptors are observed. Late AMD encompasses “dry” and “wet” AMD. In dry AMD, there is a gradual breakdown of the light-sensitive cells in the macula that convey visual informationAttorney Docket No.: 87JA-350811-WO to the brain and of the supporting tissue beneath the macula. An advanced form of dry AMD is also referred to as “geographic atrophy.” In wet AMD, abnormal blood vessels grow underneath and into the retina. These vessels can leak fluid and blood which can lead to swelling and damage of the macula and subsequent scar formation. The damage may be rapid and severe.

[0021] “Drusen” refers to deposits of extracellular material (e.g., protein and lipids) that develop under the retina, such as between Bruch’s membrane and the retinal pigment epithelium (RPE) of the eye. Drusen comprise hard drusen and soft drusen. Hard drusen are usually round or hemispherical, without sloped borders. Soft drusen are usually larger and nonhomogeneous, typically contain inclusions and spherical profiles. Drusen can be different sizes — small (e.g., a diameter of smaller than 63 micron), medium (e.g., a diameter of 63-125 micron), and large (e.g., a diameter of greater than 125 micron). The term “drusen” as described herein, in some embodiments, may include optic disc drusen (also known as optic nerve drusen), which occur in the optic nerve and are made up of protein and calcium salts. Optic disc drusen are not related to aging, may be inherited, and typically appear in children. Optic disc drusen usually do not affect vision, while some patients with these drusen may lose peripheral (side) vision.

[0022] As used herein, the term “majority” refers to greater than 50%, such as 55% or greater, 60% or greater, 70% or greater, 80% or greater, or 90% or greater. For example, “majority of drusen” refers to greater than 50% of drusen, such as 55% or greater, 60% or greater, 70% or greater, 80% or greater, or 90% or greater of drusen. In some embodiments, a percentage is calculated based on the number or amount of drusen. In some embodiments, a percentage is calculated based on the estimated surface area or volume of drusen.

[0023] As used herein, the terms “inhibit,” “inhibition,” “inhibiting,” and the like, refer to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0024] A “pharmaceutical formulation” is intended to include the combination of one or more active agents (e.g., statin) with one or more carriers, inert or active, making the composition suitable for therapeutic use in vitro, in vivo, or ex vivo.

[0025] The term “pharmaceutically acceptable carrier,” as used herein, refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject, i.e., can be administered without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.Attorney Docket No.: 87JA-350811-WO

[0026] “An effective amount” refers to the amount of an agent sufficient to induce a desired biological and / or therapeutic result. That result can be alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.

[0027] As used herein, the terms “treating,” “treatment,” and the like are used herein to mean obtaining a desired pharmacologic and / or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disorder or sign or symptom thereof, and / or may be therapeutic in terms of a partial or complete cure for a disorder and / or adverse effect attributable to the disorder.

[0028] The term “pharmaceutically acceptable salt” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid. In addition, if the forms described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Salts derived from organic acids include, e.g., acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.Injectable Intraocular Formulations

[0029] Provided herein is an injectable intraocular formulation comprising an apolipoprotein A-I mimetic peptide, or salt thereof, and an aqueous pharmaceutically acceptable carrier. Apolipoprotein A-I, or ApoA-I, interacts with its cellular receptor, the ATP-binding cassette subfamily A, member 1Attorney Docket No.: 87JA-350811-WO(ABCA1), to facilitate cholesterol efflux out of cells to form nascent high-density lipoprotein particles. It has been observed that intraocular administration of an apolipoprotein A-I mimetic peptide, specifically L4F, lead to cataract formation (lens opacity) in vivo. It has now been found that formulating an apolipoprotein A-I mimetic peptide, such as L4F, or a salt thereof, with a phospholipid, reduces the risk for or occurrence of, or the severity of, lens opacity, e.g., cataract. The intraocular formulations described herein comprise at least one phospholipid to peptide in an amount that is sufficient such that the occurrence and / or severity of one or both of lens opacity and / or vitreous flare is reduced or substantially eliminated.

[0030] In some embodiments, provided herein is an injectable intraocular formulation comprising: an apolipoprotein A-I mimetic peptide, or salt thereof; an effective amount of at least one phospholipid; and an aqueous pharmaceutically acceptable carrier; wherein the molar ratio of phospholipid to peptide is sufficient such that the occurrence and / or severity of one or both of lens opacity and / or vitreous flare is reduced or substantially eliminated.Apolipoprotein A-I Mimetic Peptides

[0031] ApoA-I mimetic peptides have an amphipathic a-helical structure that resembles the secondary structure of the native apoA-I protein, which is a tandem array of 10 class A amphipathic a-helices that mediate interactions with lipids. Apo A-I mimetic peptides can facilitate reverse cholesterol transfer out of cells, as well as promote anti-inflammatory, antioxidant, and other antiatherogenic effects. Advantages of apoA-I mimetic peptides over full-length apoA-I relate to the relative ease and lower cost of synthesis. The D4F and L4F apoA-I mimetic peptides are an 18 amino acid peptide comprised of D-amino acids and L-amino acids, respectively. The 5 A apoA-I mimetic peptide is composed of two 18 amino acid peptides linked by a proline, one of which is a high lipid affinity helix and the other is a low lipid affinity helix.

[0032] In some embodiments, apolipoprotein A-I mimetic peptide include amphipathic helical domains of apolipoproteins which bind to / associate with lipids and are capable of removing / clearing lipids. In certain embodiments, lipid-binding, amphipathic helical domains of apolipoproteins include, but are not limited to:1) sequences from about amino acid (aa) 209 to about aa 219, sequences from about aa 220 to about aa 241, and sequences from about aa 209 to about aa 241 of wild-type (wt) human apo A-I;2) sequences from about aa 39 or 40 to about aa 50, sequences from about aa 51 to about aa 71 or 77, sequences from about aa 39 or 40 to about aa 71, and sequences from about aa 39 or 40 to about aa 77 of wt human apoA-II;Attorney Docket No.: 87JA-350811-WO3) sequences from about aa 7 to about aa 32, sequences from about aa 33 to about aa 53, and sequences from about aa 7 to about aa 53 of wt human apoC-I;4) sequences from about aa 43 to about aa 55 of wt human apoC-II;5) sequences from about aa 40 to about aa 67 of wt human apoC-III; and6) sequences from about aa 203 to about aa 266 of wt human apoE.

[0033] In further embodiments, apolipoprotein mimetics include polypeptides (including fusion proteins and chimeras) that comprise such lipid-binding, amphipathic helical domains of apolipoproteins or variants thereof.

[0034] Non-limiting examples of apoA-I mimetics include 2F, 3F, 3F-I, 3F-2, 3F-I4, 4F (e.g., E4F and D4F), 4F2, 5A, 5F, 6F, 7F, I8F, 37 pA, 4F-P-4F, 4F-IHS-4F, EEK-2K2A2E (or ELK-2A2K2E), FAMP (Fukuoka apoA-I mimetic peptide), FREE, KRES, apoJ (113-122), CGVLESFKASFLSALEEWTKKLQ-NH2 (SEQ. ID. NO. 1) (monomer, dimers, and trimers), DWLKAFYDKVAEKLKE (SEQ. ID. NO. 2) (monomer, dimers, and trimers), DWFKAFYDKVAEKFKE (SEQ. ID. NO. 3) (monomer, dimers, and trimers), DWFKAFYDKVAEKFKEAF (4F) (SEQ. ID. NO. 4) (monomer, dimers, and trimers), DWLKAFYDKVAEKLKEAFPDWLKAFYDKVAEKLKEAF (SEQ. ID. NO. 5), DWLKAFYDKVAEKLKEFFPDWLKAFYDKVAEKLKEFF (SEQ. ID. NO. 6), DWFKAFYDKVAEKLKEAFPDWFKAFYDKVAEKLKEAF (SEQ. ID. NO. 7), DKLKAFYDKVFEWAKEAFPDKLKAFYDKVFEWLKEAF (SEQ. ID. NO. 8), DKWKAVYDKFAEAFKEFLPDKWKAVYDKFAEAFKEFL (SEQ. ID. NO. 9), DWFKAFYDKVAEKFKEAFPDWFKAFYDKVAEKFKEAF (4F-P-4F) (SEQ. ID. NO. 10), and the corresponding apoA-I mimetics having one or more, or all, D-amino acids (e.g., D4F having all D- amino acids) and / or the reverse order of amino acid sequence (e.g., Rev-L4F and Rev-D4F).

[0035] Non-limiting examples of apoE mimetics include AC-I1EI8A-NH2 (AEM-28) (a dual-domain [apoE and apoA-I] mimetic), Ac-[R]hE18A-NH2, AEM-28-14, mR18L, ATI-5261, COG-1410, apoE(130-149) monomer and dimers (including N-acetylated dimers), and apoE(141-155) monomer and dimers (including N-acetylated dimers). Examples of apoC-II mimetics include without limitation C-II-a.

[0036] The present disclosure encompasses the following apolipoprotein peptide mimetics:1) apo mimetics in which all of the amino acid residues have the L stereochemistry;Attorney Docket No.: 87JA-350811-WO2) apo mimetics in which one or more, or all, of the amino acid residues have the D stereochemistry;3) apo mimetics which have the reverse order of amino acid sequence and in which all of the amino acid residues have the L stereochemistry;4) apo mimetics which have the reverse order of amino acid sequence and in which one or more, or all, of the amino acid residues have the D stereochemistry; and5) multimers (including dimers and trimers) of an apo mimetic, in which two or more units of an apo mimetic are directly or indirectly attached to one another, such as via a linker or spacer group containing one or more amino acid residues or a group having multiple (e.g., two, three or more) points of attachment.

[0037] The apolipoprotein mimetics described herein can have a protecting group at the N-terminus and / or the C-terminus. In some embodiments, the apo mimetics have an N-terminal protecting group that is an unsubstituted or substituted C2-C10 acyl group (e.g., acetyl, propionyl, butanoyl, pentanoyl or hexanoyl), an unsubstituted or substituted benzoyl group, a carbobenzoxy group, or one or two unsubstituted or substituted C1-C20 or C2-C20 alkyl groups (e.g., one or two methyl, ethyl, propyl, butyl, pentyl or hexyl groups). Furthermore, the apo mimetics can have a functional group other than -CO2H at the C-terminus, such as a -C(O)NH2 or -C(O)NR1R2amide group, wherein R1and R2independently are hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, or R1and R2and the nitrogen atom to which they are connected form a heterocyclic or heteroaryl ring. An amide group at the C-terminus can be regarded as a protecting group at the C-terminus. Therefore, the disclosure encompasses apo mimetics having, e.g., both an acetyl group at the N-terminus and a -C(O)NH2 group at the C-terminus.

[0038] The disclosure also encompasses variants of the apolipoprotein mimetics described herein, wherein the variants of the apo mimetics can comprise one or more amino acid additions / insertions, deletions and / or substitutions. In other words, the disclosure encompasses variants in which one or more natural and / or unnatural amino acids are added to or inserted in, one or more amino acid residues are deleted from, or one or more natural and / or unnatural amino acids are substituted (conservative and / or non-conservative substitutions) for one or more amino acid residues of, any of the apo mimetics described herein, or any combination or all thereof. An unnatural amino acid can have the same chemical structure as the counterpart natural amino acid but have the D stereochemistry, or it can have a different chemical structure and the D or L stereochemistry. Unnatural amino acids can be utilized, e.g., to promote a-helix formation and / or increase the stability of the peptide (e.g., resist proteolytic degradation). For example, D-4F is resistant to intestinalAttorney Docket No.: 87JA-350811-WO peptidases and thus is suitable for oral use. Examples of unnatural amino acids include without limitation proline analogs (e.g., CMePro), phenylalanine analogs [e.g., Bip, Bip2EtMeO, Nal(l), Nal(2), F2Phe, Tmp, Tic, CMePhe and CNfeFPhe], tyrosine analogs (e.g., Dmt and CMeTyr), glutamine analogs (e.g., citrulline [CA]), lysine analogs (e.g., homo-lysine, ornithine [Om] and CMeLys), arginine analogs (e.g., homo-arginine [Har]), C-a-disubstituted amino acids (e.g., Aib, Ac4c, Ac5c, Ac6c and Deg), and other unnatural amino acids. One or more peptidomimetic moieties can also be used in additions / insertions and / or substitutions. The variants can have a protecting group at the N-terminus and / or the C-terminus, such as an acyl (e.g., acetyl) group at the N-terminus and / or an amide group [e.g., -C(0)NH2] at the C-terminus. In some embodiments, a biological or pharmacological activity of a variant of an apo mimetic is enhanced relative to, or substantially similar to (e.g., not diminished by more than about 10%, 20% or 30% relative to), that of the apo mimetic with a native amino acid sequence. As a non-limiting example, the disclosure encompasses a variant of 4F called 4F2, which has the sequence DWFKAFYDKV-Aib-EKFKE-Aib-F (SEQ. ID. NO. 11) in which A11and A17are substituted with a-aminoisobutyric acid (Aib). In certain embodiments, 4F2 has the structure Ac-DWFKAFYDKV-Aib-EKFKE-Aib-F-NtE (SEQ. ID. NO. 12), where all the amino acid residues have the L-form (L4F2), or one or more, or all, of the amino acid residues have the D-form.

[0039] Variants of the apolipoprotein mimetics described herein also include analogs and derivatives of the apo mimetics that have another kind of modification alternative to or in addition to an amino acid addition / insertion, deletion and / or substitution. As an example, variants of apo mimetics include fusion proteins and chimeras comprising a lipid-binding, amphipathic helical domain of an apolipoprotein or a variant thereof (e.g., 4F) which is directly or indirectly (e.g., via a linker) attached to a heterologous peptide. The heterologous peptide can impart a beneficial property, such as increased half-life. For instance, the heterologous peptide can be an Fc domain of an immunoglobulin (e.g., an IgG, such as IgGl), or a modified Fc domain of an immunoglobulin which has, e.g., one or more amino acid substitutions or mutations that alter (e.g., reduce) the effector functions of the Fc domain. An Fc domain can be modified to have reduced ability, e.g., to bind to an Fc receptor, activate the complement system, stimulate an attack by phagocytic cells, or interfere with the physiological metabolism or functioning of retinal cells, or any combination or all thereof. Inclusion of an Fc domain in a fusion protein or chimera can permit dimerization of the fusion protein or chimera (e.g., via formation of an intermolecular disulfide bond between two Fc domains), which may enhance the biological or pharmacological activity of the fusion protein or chimera.

[0040] In some embodiments, the peptide has an amino acid sequence that is less than 80 amino acids long and has 65% or more (e.g., 70% or more, 80% or more, 85% or more, 90% or more, etc.) homology to one of SEQ ID NO.: 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,Attorney Docket No.: 87JA-350811-WO25, 26, 27, 28, 29, 30, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55,56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 7, 74, 75, 76, 77, 78, 79, 80, 84, 85,86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109,110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177 or 178 as disclosed in WO2023 / 220756.

[0041] The peptides described herein can be prepared according to procedures known to those of skill in the art. As a non-limiting example, apo mimetics and salts thereof can be prepared by sequentially condensing protected amino acids on a suitable resin support and removing the protecting groups, removing the resin support, and purifying the products by methods known in the art. Solidphase synthesis of peptides and salts thereof can be facilitated through the use of, e.g., microwave, and can be automated through the use of commercially available peptide synthesizers.

[0042] In some embodiments, the concentration of peptide in the formulation is about 0.1 mg / mL to about 3.6 mg / mL. In some embodiments, the concentration of peptide in the formulation is about 0.1 mg / mL to about 1.2 mg / mL. In some embodiments, the concentration of peptide in the formulation is about 0.2 mg / mL to about 1.2 mg / mL, or 0.2 mg / mL to about 0.8 mg / mL, or 0.4 mg / mL to about 0.8 mg / mL.

[0043] In some embodiments, the concentration of peptide in the formulation is about 0.2 mg / mL to about 0.8 mg / mL. In some embodiments, the concentration of peptide in the formulation is about 0.4 mg / mL to about 0.8 mg / mL. In some embodiments, the concentration of peptide in the formulation is about 0.1 mg / mL to about 0.4 mg / mL. In some embodiments, the concentration of peptide in the formulation is about 0.2 mg / mL to about 0.4 mg / mL. In some embodiments, the concentration of peptide in the formulation is 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, or 3.6 mg / mL.

[0044] In some embodiments, the apolipoprotein A-I mimetic peptide is Ac- DWFKAFYDKVAEKFKEAF-NH2 (L4F) or a salt thereof. Accordingly, in some embodiments, provided is an injectable intraocular formulation comprising: Ac-DWFKAFYDKVAEKFKEAF-NH2 (L4F), or a salt thereof; an effective amount of at least one phospholipid; and an aqueous pharmaceutically acceptable carrier.

[0045] In some embodiments, the risk of vitreous flare is reduced or substantially eliminated. In some embodiments, the risk of lens opacity or lens haziness, e.g., cataract formation, is reduced or substantially eliminated. It has been found that the ratio of phospholipid to peptide can be attenuatedAttorney Docket No.: 87JA-350811-WO such that the occurrence and / or severity of one or both of lens haziness and / or vitreous flare is reduced or substantial ly eliminated. If the ratio of phospholipid is too low, the risk for developing a cataract is increased. However, if the ratio of phospholipid is too high, solubility limits are reached and vitreous flare is observed.

[0046] In some embodiments, the injectable intraocular formulation comprises a phospholipid in an amount that is sufficient such that the occurrence and / or severity of one or both of lens haziness and / or vitreous flare is reduced or substantially eliminated.

[0047] It is contemplated that any phospholipid, or derivative thereof, can be used in the formulations and methods described herein, including, but not limited to, natural phospholipid derivates, such as egg PC (Egg lecithin), egg PG, soy PC, hydrogenated soy PC, or sphingomyelin, and synthetic phospholipid derivates, such as phosphatidic acid (DMPA, DPPA, DSPA), phosphatidylcholine (DDPC, DLPC, DMPC, DPPC, DSPC, DOPC, POPC, DEPC), phosphatidylglycerol (DMPG, DPPG, DSPG, POPG), phosphatidylethanolamine (DMPE, DPPE, DSPE DOPE), phosphatidyl serine (DOPS), or PEG phospholipid (mPEG-phospholipid, polyglycerin-phospholipid, functionalized- phospholipid, terminal activated-phospholipid). Phospholipids include, but are not limited to, 1- hexadecanoyl-2-(9Z-octadecenoyl)-sn-glycero-3-phospho-L-serine (POPS), sphingomyelin (N- lignoceroyl-D-erythro-sphingosylphosphorylcholine), phosphatidylcholine, phosphatidyl serine, phosphatidylethanolamine, phosphatidylinositol, and phosphatidic acid.

[0048] In some embodiments, the phospholipid is selected from the table below:Attorney Docket No.: 87JA-350811-WOAttorney Docket No.: 87JA-350811-WOAttorney Docket No.: 87JA-350811-WOAttorney Docket No.: 87JA-350811-WO

[0049] In some embodiments, the phospholipid is l-hexadecanoyl-2-(9Z-octadecenoyl)-sn-glycero- 3-phospho-L-serine (POPS) or sphingomyelin.

[0050] It is contemplated that the effective amount of phospholipid may differ based on which phospholipid is implemented as certain characteristics may vary (e.g., charge, rigidity, solubility, lipophilicity, etc.) and thus the binding affinity to the apolipoprotein A-I mimetic peptide (e.g., L4F) may vary. For example, the minimum effective concentration for cell culture studies was about 2-fold higher for SM than POPS. The maximum solubility in cell culture medium was about 4-fold higher for SM than POPS. These data suggest more sphingomyelin molecules can bind to L4F as compared to POPS. The effective molar ratio of L4F:SM is therefore lower than L4F:POPS. Whereas these data can be suggestive of certain concentrations or ratios, further testing is likely required to determine effective concentrations in vivo.Attorney Docket No.: 87JA-350811-WO

[0051] In some embodiments, the phospholipid comprises a neutral headgroup. It has been found that a charged head group may cause calcium-mediated vitreous precipitation.

[0052] In some embodiments, the phospholipid comprises chain lengths less than or equal to 12 carbon atoms (per tail). In some embodiments, the phospholipid comprises chain lengths greater than 18 carbon atoms (per tail). In some embodiments, the phospholipid comprises saturated chains, i.e., does not contain a double bond. Whereas it has been found that a double bond in the fatty acid chains can increase solubility, it is contemplated that the presence of a double bond makes the phospholipid susceptible to oxidation. In some embodiments, the phospholipid comprises a neutral headgroup, chain lengths of between 12 and 18 carbon atoms (per tail), and the chains are saturated (i.e., no double bonds present in the fatty acid chains). In some embodiments, the phospholipid comprises a neutral headgroup, chain lengths of between 14 and 18 carbon atoms (per tail), and the chains are saturated (i.e., no double bonds present in the fatty acid chains). In some embodiments, the phospholipid comprises a neutral headgroup, chain lengths of between 12 and 16 carbon atoms (per tail), and the chains are saturated (i.e., no double bonds present in the fatty acid chains). In some embodiments, the phospholipid comprises a neutral headgroup, chain lengths of between 14 and 16 carbon atoms (per tail), and the chains are saturated (i.e., no double bonds present in the fatty acid chains).

[0053] In some embodiments, the phospholipid is l-hexadecanoyl-2-(9Z-octadecenoyl)-sn-glycero- 3-phospho-L-serine (POPS), which has the structure:

[0054] In some embodiments, the concentration of POPS in the formulation is at least about 0.02 mg / mL. In some embodiments, the concentration of POPS in the formulation is at least about 0.05 mg / mL. In some embodiments, the concentration of POPS in the formulation is about 0.15 mg / mL to about 0.4 mg / mL. In some embodiments, the concentration of POPS in the formulation is about 0.2 mg / mL to about 0.3 mg / mL. In some embodiments, the concentration of POPS in the formulation is about 0.1 mg / mL. In some embodiments, the concentration of POPS in the formulation is about 0.2 mg / mL. In some embodiments, the concentration of POPS in the formulation is less than about 2 mg / mL. In some embodiments, the concentration of POPS in the formulation is 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, or 1.6 mg / mL.Attorney Docket No.: 87JA-350811-WO

[0055] In some embodiments, provided is an injectable intraocular formulation comprising: an apolipoprotein A-I mimetic peptide, or salt thereof; an effective amount of l-hexadecanoyl-2-(9Z- octadecenoyl)-sn-glycero-3-phospho-L-serine (POPS); and an aqueous pharmaceutically acceptable carrier; wherein the molar ratio of POPS to peptide is sufficient such that the occurrence and / or severity of one or both of lens opacity and / or vitreous flare is reduced or substantially eliminated; and wherein: the concentration of peptide in the formulation is about 0.1 mg / mL to about 1.2 mg / mL; and the amount of POPS in the formulation is about a 0.7 molar ratio of peptide to POPS.

[0056] In some embodiments, the molar ratio range of peptide to POPS is from about 0.25 to about 1.5. In some embodiments, the molar ratio range of peptide to POPS is from about 0.5 to about 1.

[0057] In some embodiments, provided is an injectable intraocular formulation comprising: an apolipoprotein A-I mimetic peptide, or salt thereof; an effective amount of l-hexadecanoyl-2-(9Z- octadecenoyl)-sn-glycero-3-phospho-L-serine (POPS); and an aqueous pharmaceutically acceptable carrier; wherein the molar ratio of POPS to peptide is sufficient such that the occurrence and / or severity of one or both of lens opacity and / or vitreous flare is reduced or substantially eliminated; and wherein: the concentration of peptide in the formulation is about 0.1 mg / mL to about 1.2 mg / mL; and the concentration of POPS in the formulation is from about 0.02 mg / mL to about 1.6 mg / mL.

[0058] In some embodiments, provided is an injectable intraocular formulation comprising: Ac- DWFKAFYDKVAEKFKEAF-NH2 (L4F), or a salt thereof; an effective amount of 1-hexadecanoyl- 2-(9Z-octadecenoyl)-sn-glycero-3-phospho-L-serine (POPS); and an aqueous pharmaceutically acceptable carrier; wherein the molar ratio of POPS to L4F is sufficient such that the occurrence and / or severity of one or both of lens opacity and / or vitreous flare is reduced or substantial I y eliminated; and wherein: the concentration of peptide in the formulation is about 0.1 mg / mL to about 1.2 mg / mL; and the concentration of POPS in the formulation is from about 0.02 mg / mL to 1.6 mg / mL.

[0059] In some embodiments, provided is an injectable intraocular formulation comprising: Ac- DWFKAFYDKVAEKFKEAF-NH2 (L4F), or a salt thereof; an effective amount of 1-hexadecanoyl- 2-(9Z-octadecenoyl)-sn-glycero-3-phospho-L-serine (POPS); and an aqueous pharmaceutically acceptable carrier; wherein the molar ratio of POPS to L4F is sufficient such that the occurrence and / or severity of one or both of lens opacity and / or vitreous flare is reduced or substantial I y eliminated; and wherein: the concentration of peptide in the formulation is about 0.2 mg / mL to about 0.8 mg / mL; and the concentration of POPS in the formulation is from about 0.05 mg / mL to 0.6 mg / mL.Attorney Docket No.: 87JA-350811-WO

[0060] In some embodiments, provided is an injectable intraocular formulation comprising: Ac- DWFKAFYDKVAEKFKEAF-NH2 (L4F), or a salt thereof; an effective amount of 1-hexadecanoyl- 2-(9Z-octadecenoyl)-sn-glycero-3-phospho-L-serine (POPS); and an aqueous pharmaceutically acceptable carrier; wherein the molar ratio of POPS to L4F is sufficient such that the occurrence and / or severity of one or both of lens opacity and / or vitreous flare is reduced or substantial I y eliminated; and wherein: the concentration of peptide in the formulation is about 0.4 mg / mL; and the concentration of POPS in the formulation is from about 0.05 mg / mL to 0.6 mg / mL.

[0061] In some embodiments, the molar ratio of peptide to POPS in the formulation is about 0.7, or 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.05, 1.1, 1.15, or 1.2. In some embodiments, the molar ratio of peptide to POPS in the formulation is 0.25 to 1.5. In some embodiments, the molar ratio of peptide to POPS in the formulation is 0.5-1. In some embodiments, the molar ratio of peptide to POPS in the formulation is about 0.7.

[0062] In some embodiments, provided is an injectable intraocular formulation comprising: Ac- DWFKAFYDKVAEKFKEAF-NH2 (L4F), or salt thereof; an effective amount of l-hexadecanoyl-2- (9Z-octadecenoyl)-sn-glycero-3-phospho-L-serine (POPS); and an aqueous pharmaceutically acceptable carrier; wherein the molar ratio of POPS to L4F is sufficient such that the occurrence and / or severity of one or both of lens opacity and / or vitreous flare is reduced or substantial I y eliminated; and wherein: the concentration of peptide in the formulation is about 0.4 mg / mL to about 0.8 mg / mL; the concentration of POPS in the formulation is from about 0.02 mg / mL to about 0.6 mg / mL; and the molar ratio of peptide to POPS in the formulation is about 0.7.

[0063] In some embodiments, provided is an injectable intraocular formulation comprising: Ac- DWFKAFYDKVAEKFKEAF-NH2 (L4F), or salt thereof; l-hexadecanoyl-2-(9Z-octadecenoyl)-sn- glycero-3-phospho-L-serine (POPS); and an aqueous pharmaceutically acceptable carrier; wherein: the concentration of peptide in the formulation is about 0.4 mg / mL to about 0.8 mg / mL; the concentration of POPS in the formulation is from about 0.02 mg / mL to about 0.6 mg / mL; and the molar ratio of peptide to POPS in the formulation is about 0.7.

[0064] In some embodiments, the phospholipid is sphingomyelin, which has the structure:

[0065] In some embodiments, the concentration of sphingomyelin in the formulation is 0.05 mg / mL or greater. In some embodiments, the concentration of sphingomyelin in the formulation is 1.8Attorney Docket No.: 87JA-350811-WO mg / mL, or less. In some embodiments, the concentration of sphingomyelin in the formulation is 0.05 mg / mL, or 0.1 mg / mL, or 0.15 mg / mL, or 0.2 mg / mL, or 0.25 mg / mL, or 0.3 mg / mL, or 0.35 mg / mL, or 0.4 mg / mL, or 0.45 mg / mL, or 0.5 mg / mL, or 0.55 mg / mL, or 0.6 mg / mL, or 0.65 mg / mL, or 0.7 mg / mL, or 0.75 mg / mL, or 0.8 mg / mL, or 0.85 mg / mL, or 0.9 mg / mL, or 0.95 mg / mL, or 1.0 mg / mL, or 1.1 mg / mL, or 1.2 mg / mL, or 1.3 mg / mL, or 1.4 mg / mL, or 1.5 mg / mL, or 1.6 mg / mL, or 1.7 mg / mL, or 1.8 mg / mL. In some embodiments, the concentration of sphingomyelin in the formulation is 0.05-1.8 mg / mL. In some embodiments, the concentration of sphingomyelin in the formulation is 0.12-1.5 mg / mL.

[0066] In some embodiments, provided is an injectable intraocular formulation comprising: an apolipoprotein A-I mimetic peptide, or salt thereof; an effective amount of sphingomyelin; and an aqueous pharmaceutically acceptable carrier; wherein the molar ratio of sphingomyelin to peptide is sufficient such that the occurrence and / or severity of one or both of lens opacity and / or vitreous flare is reduced or substantially eliminated; and wherein: the concentration of peptide in the formulation is about 0.1 mg / mL to about 1.2 mg / mL; and the concentration of sphingomyelin in the formulation is from about 0.05 mg / mL to 1.8 mg / mL.

[0067] In some embodiments, provided is an injectable intraocular formulation comprising: Ac- DWFKAFYDKVAEKFKEAF-NH2 (L4F), or salt thereof; an effective amount of sphingomyelin; and an aqueous pharmaceutically acceptable carrier; wherein the molar ratio of sphingomyelin to L4F is sufficient such that the occurrence and / or severity of one or both of lens opacity and / or vitreous flare is reduced or substantial ly eliminated; and wherein: the concentration of peptide in the formulation is about 0.1 mg / mL to about 1.2 mg / mL; and the concentration of sphingomyelin in the formulation is from about 0.05 mg / mL to 1.8 mg / mL.

[0068] In some embodiments, the molar ratio of peptide to sphingomyelin in the formulation is from about 0.2 to about 0.65. In some embodiments, the molar ratio of peptide to sphingomyelin in the formulation is from about 0.2 to about 0.5. In some embodiments, the molar ratio of peptide to sphingomyelin in the formulation is from about 0.2 to about 0.3. In some embodiments, the molar ratio of peptide to sphingomyelin in the formulation is 0.13. In some embodiments, the molar ratio of peptide to sphingomyelin in the formulation is 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, or 0.65.

[0069] In some embodiments, provided is an injectable intraocular formulation comprising: Ac- DWFKAFYDKVAEKFKEAF-NH2 (L4F), or salt thereof; an effective amount of sphingomyelin; and an aqueous pharmaceutically acceptable carrier; wherein the molar ratio of sphingomyelin to L4F is sufficient such that the occurrence and / or severity of one or both of lens opacity and / or vitreous flare is reduced or substantial ly eliminated; and wherein: the concentration of peptide in the formulation is about 0.4 mg / mL to about 0.8 mg / mL; the concentration of sphingomyelin in the formulation is fromAttorney Docket No.: 87JA-350811-WO about 0.12 mg / mL to 1.5 mg / mL; and the molar ratio of peptide to sphingomyelin in the formulation is about 0.25.

[0070] In some embodiments, provided is an injectable intraocular formulation comprising: Ac- DWFKAFYDKVAEKFKEAF-NH2 (L4F), or salt thereof; sphingomyelin; and an aqueous pharmaceutically acceptable carrier; wherein: the concentration of peptide in the formulation is about 0.4 mg / mL to about 0.8 mg / mL; the concentration of sphingomyelin in the formulation is from about 0.12 mg / mL to 1.5 mg / mL; and the molar ratio of peptide to sphingomyelin in the formulation is about 0.25.Methods of Treatment

[0071] In one embodiment, provided herein is a method for eliminating or reducing the number and / or size (e.g., height) of drusen, or inhibiting formation or growth of drusen, in a patient, comprising administering to the eye of a patient in need thereof, an effective amount of an injectable intraocular formulation as described herein.

[0072] In one embodiment, provided herein is a method for eliminating or reducing the number and / or size of drusen, or inhibiting formation or growth of drusen, in a patient, comprising administering to the eye of a padent in need thereof, an effective amount of pharmaceutical formulation comprising: an effective amount of an apolipoprotein A-I mimetic peptide, or salt thereof; optionally at least one phospholipid; and an aqueous pharmaceutically acceptable carrier; wherein the amount of peptide is in a range sufficient to reduce the number and / or size of drusen, inhibit formation or growth of drusen, and / or reduce or substantially eliminate the occurrence and / or severity of lens opacity.

[0073] In some embodiments, the amount of peptide is in a range sufficient to reduce the number and / or size of drusen and to inhibit formation or growth of drusen, and / or reduce or substantially

[0074] In some embodiments, the amount of peptide administered is about 0.2 to about 0.6 pg / eye. In some embodiments, the amount of peptide administered is 0.4 pg / eye.

[0075] While drusen bodies are a common finding upon standard ophthalmic exams in the aging population, they are of most concern as early signs of AMD. AMD is one of the most prevalent eye diseases in the world affecting roughly 1% to 3% of the total population. AMD is a progressive disease involving degeneration and atrophy of the portion of the retina termed the macula. This results in progressive loss of central vision and can eventually advance to blindness. Drusen bodies are classic findings in AMD, however, certain factors such as the type, number, and location of drusen bodies have prognostic value.Attorney Docket No.: 87JA-350811-WO

[0076] In some embodiments, the method further comprises reducing or eliminating the occurrence of, or lessening the risk or severity of, lens opacity (e.g., cataracts) and / or vitreous flare.

[0077] In some embodiments, the concentration of peptide in the formulation is 0.1 mg / mL to 3.6 mg / mL. In some embodiments, the concentration of peptide in the formulation is about 0.1 mg / mL to about 1.2 mg / mL. In some embodiments, the concentration of peptide in the formulation is about 0.2 mg / mL to about 0.8 mg / mL. In some embodiments, the concentration of peptide in the formulation is about 0.4 mg / mL to about 0.8 mg / mL. In some embodiments, the concentration of peptide in the formulation is about 0.2 mg / mL. In some embodiments, the concentration of peptide in the formulation is about 0.4 mg / mL. In some embodiments, the concentration of peptide in the formulation is about 0.8 mg / mL.

[0078] Suitable apolipoprotein A-I mimetic peptides for use in the methods are detailed herein. In some embodiments, the apolipoprotein A-I mimetic peptide is a peptide which has an amphipathic a- helical structure that resembles the secondary structure of the native apoA-I protein, which is a tandem array of 10 class A amphipathic a-helices that mediate interactions with lipids. In some embodiments, the apolipoprotein A-I mimetic peptide is L4F or D4F. In some embodiments, the apolipoprotein A-I mimetic peptide is L4F.

[0079] In some embodiments, provided is a method for eliminating or reducing the number and / or size (e.g., height) of drusen, or inhibiting formation or growth of drusen, in a patient, comprising administering to the eye an effective amount of pharmaceutical formulation comprising: Ac- DWFKAFYDKVAEKFKEAF-NH2 (L4F), or salt thereof; at least one phospholipid; and an aqueous pharmaceutically acceptable carrier.

[0080] Suitable phospholipids for use in the methods are detailed herein. In some embodiments, the phospholipid is l-hexadecanoyl-2-(9Z-octadecenoyl)-sn-glycero-3-phospho-L-serine (POPS) or sphingomyelin.

[0081] In some embodiments, the phospholipid is l-hexadecanoyl-2-(9Z-octadecenoyl)-sn-glycero- 3-phospho-L-serine (POPS). In some embodiments, the concentration of POPS in the formulation is at least about 0.02 mg / mL. In some embodiments, the concentration of POPS in the formulation is at least about 0.05 mg / mL. In some embodiments, the concentration of POPS in the formulation is about 0.15 mg / mL to about 0.4 mg / mL. In some embodiments, the concentration of POPS in the formulation is about 0.2 mg / mL to about 0.3 mg / mL. In some embodiments, the concentration of POPS in the formulation is about 0.1 mg / mL. In some embodiments, the concentration of POPS in the formulation is about 0.2 mg / mL. In some embodiments, the concentration of POPS in the formulation is less than about 2 mg / mL. In some embodiments, the concentration of POPS in the formulation isAttorney Docket No.: 87JA-350811-WO0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, or 1.6 mg / mL.

[0082] In some embodiments, provided is a method for eliminating or reducing the number and / or size of drusen, or inhibiting formation or growth of drusen, in a patient, comprising administering to the eye an effective amount of an injectable intraocular formulation comprising: an apolipoprotein A-I mimetic peptide, or salt thereof; an effective amount of l-hexadecanoyl-2-(9Z-octadecenoyl)-sn- glycero-3-phospho-L-serine (POPS); and an aqueous pharmaceutically acceptable carrier; wherein the molar ratio of POPS to peptide is sufficient such that the occurrence and / or severity of one or both of lens opacity and / or vitreous flare is reduced or substantially eliminated; and wherein: the concentration of peptide in the formulation is about 0.1 mg / mL to about 1.2 mg / mL; and the concentration of POPS in the formulation is from about 0.02 mg / mL to about 1.6 mg / mL.

[0083] In some embodiments, provided is a method for eliminating or reducing the number and / or size of drusen, or inhibiting formation or growth of drusen, in a padent, comprising administering to the eye an effective amount of an injectable intraocular formulation comprising: an apolipoprotein A-I mimetic peptide, or salt thereof; an effective amount of l-hexadecanoyl-2-(9Z-octadecenoyl)-sn- glycero-3-phospho-L-serine (POPS); and an aqueous pharmaceutically acceptable carrier; wherein the molar ratio of POPS to peptide is sufficient such that the occurrence and / or severity of one or both of lens opacity and / or vitreous flare is reduced or substantially eliminated; and wherein: the concentration of peptide in the formulation is about 0.4 mg / mL to about 8 mg / mL; and the concentration of POPS in the formulation is from about 0.05 mg / mL to about 0.6 mg / mL.

[0084] In some embodiments, the apolipoprotein A-I mimetic peptide is Ac- DWFKAFYDKVAEKFKEAF-NH2(L4F).

[0085] In some embodiments, the molar ratio of peptide to POPS in the formulation is about 0.7, or 0.5, 0.6, 0.7, 0.8, 0.85, 0.9, 0.95, 1, 1.05, 1.1, 1.15, or 1.2. In some embodiments, the molar ratio of peptide to POPS in the formulation is 0.5-1. In some embodiments, the molar ratio of peptide to POPS in the formulation is about 0.7.

[0086] In some embodiments, provided is a method for eliminating or reducing the number and / or size of drusen, or inhibiting formation or growth of drusen, in a patient, comprising administering to the eye an effective amount of an injectable intraocular formulation comprising: Ac- DWFKAFYDKVAEKFKEAF-NH2 (L4F), or salt thereof; an effective amount of l-hexadecanoyl-2- (9Z-octadecenoyl)-sn-glycero-3-phospho-L-serine (POPS); and an aqueous pharmaceutically acceptable carrier; wherein the molar ratio of POPS to L4F is sufficient such that the occurrence and / or severity of one or both of lens opacity and / or vitreous flare is reduced or substantiallyAttorney Docket No.: 87JA-350811-WO eliminated; and wherein: the concentration of peptide in the formulation is about 0.4 mg / mL to about 0.8 mg / mL; and the concentration of POPS in the formulation is from about 0.05 mg / mL to about 0.6 mg / mL.

[0087] In some embodiments, provided is a method for eliminating or reducing the number and / or size of drusen, or inhibiting formation or growth of drusen, in a patient, comprising administering to the eye an effective amount of an injectable intraocular formulation comprising: Ac- DWFKAFYDKVAEKFKEAF-NH2 (L4F), or salt thereof; an effective amount of l-hexadecanoyl-2- (9Z-octadecenoyl)-sn-glycero-3-phospho-L-serine (POPS); and an aqueous pharmaceutically acceptable carrier; wherein the molar ratio of POPS to L4F is sufficient such that the occurrence and / or severity of one or both of lens opacity and / or vitreous flare is reduced or substantial I y eliminated; and wherein: the concentration of peptide in the formulation is about 0.4 mg / mL to about 0.8 mg / mL; the concentration of POPS in the formulation is from about 0.05 mg / mL to about 0.6 mg / mL; and the molar ratio of peptide to POPS in the formulation is about 0.7.

[0088] In some embodiments, the phospholipid is sphingomyelin. In some embodiments, the concentration of sphingomyelin in the formulation is about 0.05 mg / mL or greater. In some embodiments, the concentration of sphingomyelin in the formulation is about 1.8 mg / mL, or less. In some embodiments, the concentration of sphingomyelin in the formulation is 0.05 mg / mL, or 0.1 mg / mL, or 0.15 mg / mL, or 0.2 mg / mL, or 0.25 mg / mL, or 0.3 mg / mL, or 0.35 mg / mL, or 0.4 mg / mL, or 0.45 mg / mL, or 0.5 mg / mL, or 0.55 mg / mL, or 0.6 mg / mL, or 0.65 mg / mL, or 0.7 mg / mL, or 0.75 mg / mL, or 0.8 mg / mL, or 0.85 mg / mL, or 0.9 mg / mL, or 0.95 mg / mL, or 1.0 mg / mL, or 1.1 mg / mL, or 1.2 mg / mL, or 1.3 mg / mL, or 1.4 mg / mL, or 1.5 mg / mL, or 1.6 mg / mL, or 1.7 mg / mL, or 1.8 mg / mL. In some embodiments, the concentration of sphingomyelin in the formulation is 0.05-1.8 mg / mL. In some embodiments, the concentration of sphingomyelin in the formulation is about 0.12 mg / mL to about 1.5 mg / mL.

[0089] In some embodiments, provided is a method for eliminating or reducing the number and / or size of drusen, or inhibiting formation or growth of drusen, in a patient, comprising administering to the eye an effective amount of an injectable intraocular formulation comprising: an apolipoprotein A-I mimetic peptide, or salt thereof; an effective amount of sphingomyelin; and an aqueous pharmaceutically acceptable carrier; wherein the molar ratio of sphingomyelin to peptide is sufficient such that the occurrence and / or severity of one or both of lens opacity and / or vitreous flare is reduced or substantially eliminated; and wherein: the concentration of peptide in the formulation is about 0.1 mg / mL to about 1.2 mg / mL; and the concentration of sphingomyelin in the formulation is from about 0.05 mg / mL to about 1.8 mg / mL.Attorney Docket No.: 87JA-350811-WO

[0090] In some embodiments, provided is a method for eliminating or reducing the number and / or size of drusen, or inhibiting formation or growth of drusen, in a patient, comprising administering to the eye an effective amount of an injectable intraocular formulation comprising: Ac- DWFKAFYDKVAEKFKEAF-NH2 (L4F), or salt thereof; an effective amount of sphingomyelin; and an aqueous pharmaceutically acceptable carrier; wherein the molar ratio of sphingomyelin to L4F is sufficient such that the occurrence and / or severity of one or both of lens opacity and / or vitreous flare is reduced or substantial ly eliminated; and wherein: the concentration of peptide in the formulation is about 0.1 mg / mL to about 1.2 mg / mL; and the concentration of sphingomyelin in the formulation is from about 0.05 mg / mL to about 1.8 mg / mL.

[0091] In some embodiments, the molar ratio of peptide to sphingomyelin in the formulation is from about 0.2 to about 0.65. In some embodiments, the molar ratio of peptide to sphingomyelin in the formulation is from about 0.2 to about 0.5. In some embodiments, the molar ratio of peptide to sphingomyelin in the formulation is from about 0.2 to about 0.3. In some embodiments, the molar ratio of peptide to sphingomyelin in the formulation is 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, or 0.65.

[0092] In some embodiments, provided is a method for eliminating or reducing the number and / or size (e.g., height) of drusen, or inhibiting formation or growth of drusen, in a patient, comprising administering to the eye an effective amount of an injectable intraocular formulation comprising: Ac- DWFKAFYDKVAEKFKEAF-NH2 (L4F), or salt thereof; an effective amount of sphingomyelin; and an aqueous pharmaceutically acceptable carrier; wherein the molar ratio of sphingomyelin to L4F is sufficient such that the occurrence and / or severity of one or both of lens opacity and / or vitreous flare is reduced or substantial ly eliminated; and wherein the concentration of peptide in the formulation is about 0.4 mg / mL to about 0.8 mg / mL; the concentration of sphingomyelin in the formulation is from about 0.12 mg / mL to 1.5 mg / mL; and the molar ratio of peptide to sphingomyelin in the formulation is about 0.25.

[0093] Drusen are extracellular deposits rich in lipids (e.g., esterified cholesterol (EC) and phospholipids) and lipoprotein components (e.g., apoB and / or apoE) and form in the sub-RPE-BL space between the RPE-BL and the inner collagenous layer of the BrM, possibly as a result of RPE secretion of EC -rich lipoprotein particles, which resemble density lipoproteins (LDLs) and / or very low-density lipoproteins (VLDLs) basolaterally. “Hard” drusen are small, distinct and far away from one another, and may not cause vision problems for a long time, if at all. In contrast, “soft” drusen are large, have poorly defined edges, and cluster closer together. Soft drusen are more fragile than hard drusen, are oily upon dissection due to a high lipid constitution, and are a major risk factor for the development of advanced atrophic or neo vascular AMD. Esterified cholesterol and phospholipids (in the form of lipoprotein particles of 50-80 nm diameter) accumulate in the BrM and the sub-RPE-BLAttorney Docket No.: 87JA-350811-WO space throughout adulthood and eventually aggregate as BLinD on the BrM or soft drusen in the sub- RPE-BL space of older eyes. Soft drusen and BLinD are two forms (a lump and a thin layer, respectively) of the same lipid-rich extracellular lesion containing lipoprotein-derived debris and specific to AMD. Lipid constituents of soft drusen and BLinD interact with reactive oxygen species to form pro-inflammatory peroxidized lipids (or lipid peroxides), which inhibit paraoxonase 1 activity, activate the complement system and elicit choroidal neovascularization. Furthermore, drusen contain immunogenic complement components. EC -rich, apoB / apoE-containing lipoproteins (e.g., LDLs, and / or LDL-like particles and / or VLDLs and / or VLDL-like particles) secreted by RPE cells are retained by a BrM that progressively thickens with age, until an oily layer forms on the BrM, with oxidation of lipids or other modifications followed by fusion of individual lipoproteins over time to form BLinD. An inflammatory response to the accumulated material ensues with activation of the complement system and other components of the immune system. Moreover, by altering the BrM with subsequent calcification and fracture, the accumulation of lipid-containing material can lead to neovascularization in the sub-RPE-BL space and breakthrough to the subretinal space, the potential space between the photoreceptors and the RPE. Furthermore, the lipid-rich drusen in the sub-RPE-BL space and BLinD overlying the BrM block oxygen and nutrients (including vitamin A) from reaching the RPE cells and the photoreceptors (rods and cones) in the retina, which results in their atrophy / degeneration and eventually death.

[0094] Chronic inflammatory responses to the changes described above include complement- mediated pathways, infiltration by circulating macrophages, and activation of inflammasomes and microglia. Activation of the complement cascade leads to activation of the central component 3 (C3) and initiation of the terminal pathway with the cleavage of component 5 (C5) into C5a and C5b. The terminal pathway results in the assembly of a membrane attack complex (MAC), e.g., in the basal RPE membrane, the BrM or the choriocapillary endothelial cell membrane, by stepwise binding of C5b, C6, C7, C8 and polymerized C9 to form a pore in the lipid bilayer of the membrane. The MAC can lead to the dysfunction and death of the RPE, the BrM and / or the choriocapillary endothelium, with outer retinal atrophy ensuing. In addition, C5a elicits pro-inflammatory and pro-angiogenic effects, and combined with calcification and fracture of the BrM, can contribute to NV, including choroidal NV (CNV).

[0095] The early stage of AMD (which is atrophic AMD) is characterized by the presence of a few small to medium-size drusen and pigmentary abnormalities such as hyperpigmentation or hypopigmentation of the RPE. The intermediate stage of AMD is characterized by the presence of at least one of one large druse, multiple medium-size drusen, hyperpigmentation and / or hypopigmentation of the RPE, either without geographic atrophy (GA), or with geographic atrophy (GA) that does not extend to the center of the macula (non-foveal GA). GA represents the loss ofAttorney Docket No.: 87JA-350811-WO photoreceptor, RPE and choriocapillaris, resulting in a sharply defined atrophic lesions visually resembling geographic areas on a map. In GA, RPE below the retina atrophies, which causes vision loss through the death of photoreceptors. RPE atrophy can result from a large accumulation of drusen and / or BLinD that contributes to the death of the overlying RPE, as the drusen become thick and the RPE is far removed from the choriocapillaris. Drusen may include calcification in the form of hydroxyapatite, and may progress to complete calcification, at which stage RPE cells have died. The RPE-BL thickens in a stereotypic manner to form basal laminar deposits (BLamD); RPE cells hence reside on a thick layer of BLamD. Junctions between the normally hexagonal-shaped RPE cells may be perturbed, and individual RPE cells may round up, stack and migrate anteriorly into the neurosensory retina, at which point the RPE cells become farther removed from their supply of nutrients and oxygen in the choriocapillaris. Once RPE cells begin the anterior migration, the overall RPE layer begins to atrophy.

[0096] As intermediate AMD progresses to later stages and GA, drusen, particularly soft drusen, will often collapse or disappear. This occurs following death of RPE cells rather than healthy resolution of drusen. In regions where drusen were present and have subsequently collapsed, regions of atrophy are observed marked by loss of RPE and hyper-reflectivity underlying BrM on OCT imaging.

[0097] The disclosed formulations and methods are contemplated to resolve drusen without significant loss of RPE cells, or further significant loss if a loss of RPE cells was present at the start of treatment, unlike when drusen collapse as a result of RPE atrophy.

[0098] In contrast, the methods and formulations provided herein are designed to treat patients with drusen, such as by eliminating or reducing the number and / or size of drusen, or inhibiting formation or growth of drusen, while keeping the RPE intact. In some embodiments, “keeping the RPE intact” refers generally to preventing RPE cell loss, where there may already be a loss due to disease progression, but the formulations and methods disclosed herein prevent or slow further loss. In certain embodiments, “keeping the RPE intact” refers generally to maintaining RPE cell health. Methods for assessing RPE cell health are known in the art. For example, adaptive optics scanning laser ophthalmoscope (AOSLO) allows for imaging of individual retinal pigment epithelial (RPE) cells in vivo.

[0099] In some embodiments of the methods described herein, at least a portion of retinal pigment epithelium (RPE) cells remain intact. In some embodiments, the formulations described herein inhibit atrophy of retinal pigment epithelium (RPE) cells.

[0100] In some embodiments, greater than about 90% of RPE cells underlying and / or immediately adjacent to a druse or cluster of drusen remain intact over the course of treatment.Attorney Docket No.: 87JA-350811-WO

[0101] The formulations provided can be used to slow growth of and / or regress drusen (e.g., soft drusen), to slow growth of and / or regress drusenoid pigment epithelial detachments (PEDs), to slow and / or prevent atrophy of any or all layers of the retina (e.g., the RPE), to slow and / or prevent atrophy of one or more photoreceptors, to slow and / or prevent loss of visual function, to improve visual acuity, to prevent AMD, to slow and / or prevent progression from early AMD to intermediate AMD, to slow and / or prevent progression from intermediate AMD to Geographic Atrophy and / or to wet AMD.

[0102] In some embodiments, the drusen are associated with age-related macular degeneration (AMD). In some embodiments, the drusen are associated with dry age-related macular degeneration (dry AMD). In some embodiments, the AMD is intermediate AMD. In some embodiments, the intermediate AMD is characterized by either extensive drusen of small or intermediate size, or any drusen of large size (e.g., >125 microns).

[0103] In some embodiments, the AMD is geographic atrophy.

[0104] Age-related changes to the retina and the choroid of the eye which contribute to and comprise the development of age-related macular degeneration (AMD) include changes in Bruch’s Membrane permeability, accumulation of drusen, the loss of rod photoreceptors, the thinning of the choroid, and the accumulation of lipofuscin and reportedly components thereof (e.g., A2E (N-retinylidene-N- retinyl-ethanolamine)) in the retinal pigment epithelium (RPE) as well as lipids in the sub-RPE basal lamina (sub-RPE-BL) space and anterior to and / or within Bruch’s membrane (BrM). Cholesterol rich lipoprotein particles and other constituents accumulate, forming basal linear deposits (BLinD) and drusen on the BrM. The RPE secretes apolipoproteins including but not limited to apolipoprotein B and / or E (apoB, apoE)-containing lipoprotein particles onto BrM, where they accumulate with age and eventually form a lipid-rich layer on BrM. This lipid-rich layer is frequently referred to as BLinD and / or a druse (plural drusen). Drusen negatively impact the health and function of the RPE as they inhibit nutrient exchange with the choroid and create a hypoxic environment for the highly metabolically active RPE. As the RPE is responsible for photoreceptor maintenance, the accumulation and increased thickness of drusen lead to RPE dysfunction and death, which in turn leads to death of photoreceptors and results in blindness. While anti-VEGF therapy has proven effective for treating the neovascular or “wet” form of AMD, the more common “dry” form has limited effective therapies and is a leading cause of blindness. Drusen underlie the pathogenesis of both wet and dry AMD and are thus an important target.Attorney Docket No.: 87JA-350811-WOTypes of Drusen

[0105] There are various types of drusen bodies, each of which is associated with a different prognostic value. The types of drusen are based on the size, consistency, and histological features present. Hard drusen, also termed “small drusen” are defined as small, round, well-defined deposits with a diameter measuring less than 63 microns. Hard drusen are common and are the only type of drusen considered as normal age-associated findings. A few small drusen noted on an exam is not alarming, however, there is some thought that these drusen have the potential to enlarge and develop more worrisome characteristics as time progresses. Intermediate drusen are the hybrid form of drusen defined as a diameter between 63 microns to 125 microns. These larger drusen tend to be classified within the soft drusen category. Soft drusen are defined as larger, poorly-defined drusen with moundlike elevations and a diameter measuring greater than 125 microns. It is believed that larger drusen bodies contribute to the impediment of the exchange of nutrients and waste products between the choroidal blood vessels and the retina. The lack of metabolic exchange eventually leads to degeneration and atrophy of the retina which is the pathological process seen in AMD. Cuticular drusen are defined as small, dot-like drusen which measure between 25 microns to 75 microns. Cuticular drusen are numerous and often aggregate. Therefore, they tend to coalesce into larger drusen deposits and can carry a significant risk of AMD.Number of Drusen

[0106] The smaller the number of drusen present, the lower the risk of progression to AMD. Just as an increase in the size of drusen increases the likelihood of progression to AMD, an increase in the number of drusen increases the likelihood of progression to AMD.Location of Drusen

[0107] Drusen bodies located on the peripheral retina are less concerning than drusen bodies located within the macula or central region of the retina. Within the macula, an area called the fovea exists which is where the highest visual acuity originates. Hard drusen are typically widespread so they can be found within the peripheral or the central retina. The same can be said for cuticular drusen. Soft drusen tend to be located more within the central retina or macula which may contribute to the fact that soft drusen have a higher likelihood of progressing to AMD.

[0108] In some embodiments, the majority of drusen are located between the retinal pigment epithelium (RPE) and Bruch’s membrane (BrM).

[0109] In some embodiments, at least a portion of the drusen (i.e., one or more druse) is at least about 10 pm, 20 pm, 40 pm, 60 pm, 80 pm, 100 pm, 125 pm, 150 pm, 200 pm, 250 pm, 300 pm, 400 pm,Attorney Docket No.: 87JA-350811-WO or 500 pm, in one dimension (e.g., height, diameter, width, length, etc., depending on perspective or measurement).

[0110] In some embodiments, at least a portion of the drusen (i.e., one or more druse) have a width of greater than about 65 pm in at least one dimension. In some embodiments, at least a portion of the drusen have a width of greater than about 125 pm (or greater than about 250, or 500 pm, or 750 pm, or 1,000 pm, or 1,500 pm, or 2,000 pm). In some embodiments the drusen comprise a drusenoid pigment epithelial detachment (PED). In some embodiments two or more of the drusen may be confluent. In some embodiments one or more drusen may be subfoveal. In some embodiments one or more drusen may be at least partially within the central macula (e.g., within the central 1mm, 2mm, 3mm or 4mm diameter).

[0111] In some embodiments, at least a portion of the drusen (i.e., one or more druse) have a height of at least about 10 pm, 20 pm, 40 pm, 60 pm, 80 pm, 100 pm, 125 pm, 150 pm, 200 pm, 250 pm, 300 pm, 400 pm, or 500 pm. In some embodiments this height may be in combination with any of the aforementioned widths.

[0112] In some embodiments, at least a portion of the drusen (i.e., one or more druse) have an average diameter of less than about 125 pm. In some embodiments, one or more druse have a height of about 125 pm.

[0113] Sub-RPE-BL drusen elevate the RPE off the BrM and thereby can cause mild vision loss, including metamorphopsia (a vision defect in which objects appear to be distorted) through disturbance of overlying photoreceptors and slowing of rod-mediated dark adaptation. Non-central GA spares the fovea and thus preserves central vision. However, patients with non-central GA can experience visual disturbances due to paracentral blind spots (scotomas), which can impair vision in dim light, decrease contrast sensitivity and impair reading ability.

[0114] The most advanced stage of nonexudative AMD is characterized by GA that extends to the center of the macula (central or subfoveal GA). Central GA involves the fovea and thus results in significant loss of central vision and visual acuity.

[0115] The advanced stage of AMD that becomes neovascular or “wet” AMD is characterized by neovascularization and any of its potential sequelae, including leakage (e.g., of plasma), plasma lipid and lipoprotein deposition, sub-RPE-BL, subre tinal and intraretinal fluid, hemorrhage, fibrin, fibrovascular scars and RPE detachment. In CNV, new blood vessels grow up from the choriocapillaris and through the BrM, which causes vision loss via the aforementioned sequelae.There are three types of neovascularization (NV). Type 1 NV occurs in the sub-RPE-BL space, and new blood vessels emanate from the choroid under the macular region. Type 2 NV occurs in theAttorney Docket No.: 87JA-350811-WO subretinal space above the RPE, and new blood vessels emanate from the choroid and break through to the subretinal space. In types 1 and 2 NV, new blood vessels cross the BrM and may ramify in the pro-angiogenic cleavage plane created by soft drusen and BLinD. Type 3 NV (retinal angiomatous proliferation) occurs predominantly within the retina (intraretinal), but can also occur in the subretinal space, and new blood vessels emanate from the retina with possible anastomoses to the choroidal circulation. Type 3 NV is the most difficult subtype of NV to diagnose and has the most devastating consequences for photoreceptor health, but type 3 NV responds well to treatment with an anti-VEGF agent. A neovascular AMD padent can also have a combination of subtypes of NV, including type 1 plus type 2, type 1 plus type 3, and type 2 plus type 3. The approximate occurrence of the different subtypes of NV among newly presenting neovascular AMD patients is: 40% type 1, 9% type 2, 34% type 3, and 17% mixed (of the mixed, 80% type 1 plus type 2, 16% type 1 plus type 3, and 4% type 2 plus type 3). Another form of NV is polypoidal vasculopathy, which is of choroidal origin and is the most common form of NV among Asians, whose eyes generally have few drusen but may have BLinD. The RPE can become detached from the BrM in each subtype of NV. For instance, leakage of fluid from neovessels into the sub-RPE-BL space in type 1 NV can result in pigment epithelium detachment. The new blood vessels generated by NV are fragile, leading to leakage of fluid, blood and proteins below the macula. Leakage of blood into the subretinal space is particularly toxic to photoreceptors, and intraretinal fluid signifies a poor prognosis for vision. Bleeding and leaking from the new blood vessels, with subsequent fibrosis, can cause irreversible damage to the retina and rapid vision loss if left untreated.

[0116] In the early, intermediate and advanced stages of AMD, and in atrophic AMD and neovascular AMD, the progression and treatment of AMD can be monitored using various imaging methods known in the art (called “diagnostic” methods herein for simplicity). Such imaging methods include structural Spectral Domain Optical Coherence Tomography (SDOCT), which reveals drusen and RPE and can allow quantification of total drusen volume and monitoring the progression of the disease), color fundus photography, fundus autofluorescence (which can detect fluorophores unique to drusen and basal linear deposits), quantitative fundus autofluorescence (qAF, which relies on both blue and green autofluorescence imaging), OCT- angiography (OCT-A, which can detect the presence of sub-RPE-BL, subretinal or intraretinal fluid consistent with active neovascularization), and fluorescein angiography (which can demonstrate the types of CNV lesions). Functional measures can assess cone-mediated vision (e.g., best-corrected visual acuity [BCVA, which persists until late in the disease] on Early Treatment Diabetic Retinopathy Study (ETDRS) or Snellen charts, contrast sensitivity using a Pelli-Robson chart and other methods, low-luminance visual acuity [visual acuity measured with a neutral-density filter to reduce retinal illuminance] and rod-mediated vision (e.g., rod intercept time on dark adaptation testing, which is a sensitive measure of macular function that tracks with progression of the early disease]). For example, treatment is expected to reduce loss of and / orAttorney Docket No.: 87JA-350811-WO keep stable, and / or improve, photopic (daylight) vision mediated by cone photoreceptors and scotopic (night) vision mediated by rod photoreceptors. As another example, the loss of RPE cells can be assessed by the area of hypoautofluorescence on qAF, which can demonstrate reduced RPE area loss or stability. GA area on qAF is an FDA-approved endpoint for this stage of AMD, and has been used to monitor the progression of non-central GA or central GA and response to investigational therapies in clinical trials. The health of RPE cells can also be assessed with SDOCT. The presence of hyper- reflective foci located vertically above drusen within the retina indicates migratory RPE cells or pigmented monocytic cells and constitute a strong predictor of future atrophy of RPE cells and photoreceptors. Poor RPE health can be an indicator of poor visual outcome in both nonexudative and exudative AMD.

[0117] Provided herein is a method for treating age-related macular degeneration (AMD) in a padent in need thereof, comprising administering to the eye an effective amount of an injectable intraocular formulation as described herein.

[0118] In some embodiments, provided herein is a method for treating age-related macular degeneration (AMD) in a patient in need thereof, comprising administering to the eye an effective amount of pharmaceutical formulation comprising: an apolipoprotein A-I mimetic peptide, or salt thereof; at least one phospholipid; and an aqueous pharmaceutically acceptable carrier.

[0119] In some embodiments, the method further comprises reducing or eliminating the occurrence of, or lessening the risk or severity of, lens opacity (e.g., cataracts) and / or vitreous flare.

[0120] In some embodiments, the concentration of peptide in the formulation is 0.1 mg / mL to 1.2 mg / mL. In some embodiments, the concentration of peptide in the formulation is about 0.2 mg / mL to about 0.8 mg / mL. In some embodiments, the concentration of peptide in the formulation is about 0.4 mg / mL to about 0.8 mg / mL.

[0121] Suitable apolipoprotein A-I mimetic peptides for use in the methods are detailed herein. In some embodiments, the apolipoprotein A-I mimetic peptide is a peptide which has an amphipathic a- helical structure that resembles the secondary structure of the native apoA-I protein, which is a tandem array of 10 class A amphipathic a-helices that mediate interactions with lipids. In some embodiments, the apolipoprotein A-I mimetic peptide is L4F or D4F. In some embodiments, the apolipoprotein A-I mimetic peptide is L4F.

[0122] In some embodiments, provided is a method for treating age-related macular degeneration (AMD) in a patient in need thereof, comprising administering to the eye an effective amount of pharmaceutical formulation comprising: Ac-DWFKAFYDKVAEKFKEAF-NH2 (L4F), or salt thereof; at least one phospholipid; and an aqueous pharmaceutically acceptable carrier.Attorney Docket No.: 87JA-350811-WO

[0123] Suitable phospholipids for use in the methods are detailed herein. In some embodiments, the phospholipid is l-hexadecanoyl-2-(9Z-octadecenoyl)-sn-glycero-3-phospho-L-serine (POPS) or sphingomyelin.

[0124] In some embodiments, the phospholipid is l-hexadecanoyl-2-(9Z-octadecenoyl)-sn-glycero- 3-phospho-L-serine (POPS). In some embodiments, the concentration of POPS in the formulation is at least about 0.02 mg / mL. In some embodiments, the concentration of POPS in the formulation is at least about 0.05 mg / mL. In some embodiments, the concentration of POPS in the formulation is about 0.15 mg / mL to about 0.4 mg / mL. In some embodiments, the concentration of POPS in the formulation is about 0.2 mg / mL to about 0.3 mg / mL. In some embodiments, the concentration of POPS in the formulation is about 0.1 mg / mL. In some embodiments, the concentration of POPS in the formulation is about 0.2 mg / mL. In some embodiments, the concentration of POPS in the formulation is less than about 2 mg / mL. In some embodiments, the concentration of POPS in the formulation is 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, or 1.6 mg / mL.

[0125] In some embodiments, provided is a method for treating age-related macular degeneration (AMD) in a patient in need thereof, comprising administering to the eye an effective amount of an injectable intraocular formulation comprising: an apolipoprotein A-I mimetic peptide, or salt thereof; an effective amount of l-hexadecanoyl-2-(9Z-octadecenoyl)-sn-glycero-3-phospho-L-serine (POPS); and an aqueous pharmaceutical I y acceptable carrier; wherein the molar ratio of POPS to peptide is sufficient such that the occurrence and / or severity of one or both of lens opacity and / or vitreous flare is reduced or substantially eliminated; and wherein: the concentration of peptide in the formulation is about 0.1 mg / mL to about 1.2 mg / mL; and the concentration of POPS in the formulation is from about 0.02 mg / mL to about 1.6 mg / mL.

[0126] In some embodiments, provided is a method for treating age-related macular degeneration (AMD) in a patient in need thereof, comprising administering to the eye an effective amount of an injectable intraocular formulation comprising: an apolipoprotein A-I mimetic peptide, or salt thereof; an effective amount of l-hexadecanoyl-2-(9Z-octadecenoyl)-sn-glycero-3-phospho-L-serine (POPS); and an aqueous pharmaceutically acceptable carrier; wherein the molar ratio of POPS to peptide is sufficient such that the occurrence and / or severity of one or both of lens opacity and / or vitreous flare is reduced or substantially eliminated; and wherein: the concentration of peptide in the formulation is about 0.2 mg / mL to about 0.8 mg / mL; and the concentration of POPS in the formulation is from about 0.5 mg / mL to about 0.6 mg / mL.

[0127] In some embodiments, provided is a method for treating age-related macular degeneration (AMD) in a patient in need thereof, comprising administering to the eye an effective amount of anAttorney Docket No.: 87JA-350811-WO injectable intraocular formulation comprising: AC-DWFKAFYDKVAEKFKEAF-NH2 (L4F), or salt thereof; an effective amount of l-hexadecanoyl-2-(9Z-octadecenoyl)-sn-glycero-3-phospho-L-serine (POPS); and an aqueous pharmaceutically acceptable carrier; wherein the molar ratio of POPS to L4F is sufficient such that the occurrence and / or severity of one or both of lens opacity and / or vitreous flare is reduced or substantially eliminated; and wherein: the concentration of peptide in the formulation is about 0.1 mg / mL to about 1.2 mg / mL; and the concentration of POPS in the formulation is from about 0.02 mg / mL to about 0.6 mg / mL.

[0128] In some embodiments, provided is a method for treating age-related macular degeneration (AMD) in a patient in need thereof, comprising administering to the eye an effective amount of an injectable intraocular formulation comprising: Ac-DWFKAFYDKVAEKFKEAF-NFL (L4F), or salt thereof; an effective amount of l-hexadecanoyl-2-(9Z-octadecenoyl)-sn-glycero-3-phospho-L-serine (POPS); and an aqueous pharmaceutically acceptable carrier; wherein the molar ratio of POPS to L4F is sufficient such that the occurrence and / or severity of one or both of lens opacity and / or vitreous flare is reduced or substantially eliminated; and wherein: the concentration of peptide in the formulation is about 0.2 mg / mL to about 0.8 mg / mL; and the concentration of POPS in the formulation is from about 0.05 mg / mL to about 0.6 mg / mL.

[0129] In some embodiments, provided is a method for treating age-related macular degeneration (AMD) in a patient in need thereof, comprising administering to the eye an effective amount of an injectable intraocular formulation comprising: Ac-DWFKAFYDKVAEKFKEAF-NIL (L4F), or salt thereof; an effective amount of l-hexadecanoyl-2-(9Z-octadecenoyl)-sn-glycero-3-phospho-L-serine (POPS); and an aqueous pharmaceutically acceptable carrier; wherein the molar ratio of POPS to L4F is sufficient such that the occurrence and / or severity of one or both of lens opacity and / or vitreous flare is reduced or substantially eliminated; and wherein: the concentration of peptide in the formulation is about 0.4 mg / mL; and the concentration of POPS in the formulation is from about 0.05 mg / mL to about 0.6 mg / mL.

[0130] In some embodiments, the molar ratio of peptide to POPS in the formulation is about 0.7, or 0.5, 0.6, 0.7, 0.8, 0.85, 0.9, 0.95, 1, 1.05, 1.1, 1.15, or 1.2. In some embodiments, the molar ratio of peptide to POPS in the formulation is 0.5-1. In some embodiments, the molar ratio of peptide to POPS in the formulation is about 0.7.

[0131] In some embodiments, provided is a method for treating age-related macular degeneration (AMD) in a padent in need thereof, comprising administering to the eye an effective amount of an injectable intraocular formulation comprising: AC-DWFKAFYDKVAEKFKEAF-NH2 (L4F), or salt thereof; an effective amount of l-hexadecanoyl-2-(9Z-octadecenoyl)-sn-glycero-3-phospho-L-serine (POPS); and an aqueous pharmaceutically acceptable carrier; wherein the molar ratio of POPS to L4FAttorney Docket No.: 87JA-350811-WO is sufficient such that the occurrence and / or severity of one or both of lens opacity and / or vitreous flare is reduced or substantially eliminated; and wherein the concentration of peptide in the formulation is about 0.2 mg / mL to about 0.8 mg / mL; the concentration of POPS in the formulation is from about 0.05 mg / mL to about 0.6 mg / mL; and the molar ratio of peptide to POPS in the formulation is about 0.7.

[0132] In some embodiments, the phospholipid is sphingomyelin. In some embodiments, the concentration of sphingomyelin in the formulation is about 0.05 mg / mL or greater. In some embodiments, the concentration of sphingomyelin in the formulation is about 1.8 mg / mL, or less. In some embodiments, the concentration of sphingomyelin in the formulation is 0.05 mg / mL, or 0.1 mg / mL, or 0.15 mg / mL, or 0.2 mg / mL, or 0.25 mg / mL, or 0.3 mg / mL, or 0.35 mg / mL, or 0.4 mg / mL, or 0.45 mg / mL, or 0.5 mg / mL, or 0.55 mg / mL, or 0.6 mg / mL, or 0.65 mg / mL, or 0.7 mg / mL, or 0.75 mg / mL, or 0.8 mg / mL, or 0.85 mg / mL, or 0.9 mg / mL, or 0.95 mg / mL, or 1.0 mg / mL, or 1.1 mg / mL, or 1.2 mg / mL, or 1.3 mg / mL, or 1.4 mg / mL, or 1.5 mg / mL, or 1.6 mg / mL, or 1.7 mg / mL, or 1.8 mg / mL. In some embodiments, the concentration of sphingomyelin in the formulation is 0.05-1.8 mg / mL. In some embodiments, the concentration of sphingomyelin in the formulation is about 0.12 mg / mL to about 1.5 mg / mL.

[0133] In some embodiments, provided is a method for treating age-related macular degeneration (AMD) in a patient in need thereof, comprising administering to the eye an effective amount of an injectable intraocular formulation comprising: an apolipoprotein A-I mimetic peptide, or salt thereof; an effective amount of sphingomyelin; and an aqueous pharmaceutically acceptable carrier; wherein the molar ratio of sphingomyelin to peptide is sufficient such that the occurrence and / or severity of one or both of lens opacity and / or vitreous flare is reduced or substantially eliminated; and wherein: the concentration of peptide in the formulation is about 0.1 mg / mL to about 1.2 mg / mL; and the concentration of sphingomyelin in the formulation is from about 0.05 mg / mL to 1.8 mg / mL.

[0134] In some embodiments, provided is a method for treating age-related macular degeneration (AMD) in a patient in need thereof, comprising administering to the eye an effective amount of an injectable intraocular formulation comprising: AC-DWFKAFYDKVAEKFKEAF-NH2 (L4F), or salt thereof; an effective amount of sphingomyelin; and an aqueous pharmaceutically acceptable carrier; wherein the molar ratio of sphingomyelin to L4F is sufficient such that the occurrence and / or severity of one or both of lens opacity and / or vitreous flare is reduced or substantially eliminated; and wherein: the concentration of peptide in the formulation is about 0.2 mg / mL to about 0.8 mg / mL; and the concentration of sphingomyelin in the formulation is from about 0.12 mg / mL to 1.5 mg / mL.

[0135] In some embodiments, the molar ratio of peptide to sphingomyelin in the formulation is from about 0.2 to about 0.65. In some embodiments, the molar ratio of peptide to sphingomyelin in theAttorney Docket No.: 87JA-350811-WO formulation is from about 0.2 to about 0.5. In some embodiments, the molar ratio of peptide to sphingomyelin in the formulation is from about 0.2 to about 0.3. In some embodiments, the molar ratio of peptide to sphingomyelin in the formulation is 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, or 0.65.

[0136] In some embodiments, provided is a method for treating age-related macular degeneration (AMD) in a patient in need thereof, comprising administering to the eye an effective amount of an injectable intraocular formulation comprising: AC-DWFKAFYDKVAEKFKEAF-NH2 (L4F), or salt thereof; an effective amount of sphingomyelin; and an aqueous pharmaceutically acceptable carrier; wherein the molar ratio of sphingomyelin to L4F is sufficient such that the occurrence and / or severity of one or both of lens opacity and / or vitreous flare is reduced or substantially eliminated; and wherein: the concentration of peptide in the formulation is about 0.4 mg / mL to about 0.8 mg / mL; the concentration of sphingomyelin in the formulation is from about 0.12 mg / mL to about 1.5 mg / mL; and the molar ratio of peptide to sphingomyelin in the formulation is about 0.25.Administration and Dosing Regimen

[0137] The formulations described herein are generally intended for intraocular administration. In some embodiments, the methods described herein comprise administering the formulation via intraocular injection.

[0138] In some embodiments, the method comprises administering the formulation via intravitreal injection. Intravitreal injection is the method of administration of drugs into the eye by injection with a needle. The medication will be directly delivered into the vitreous humor. As compared to topical administration, this method is beneficial for a more localized delivery of medications to the targeted site, as the needle can directly pass through the anatomical eye barrier (e.g., conjunctiva and sclera) and dynamic barrier (e.g., tears and vitreous humor). It could also minimize adverse drug effects on other body tissues via the systemic circulation, which could be a possible risk for intravenous injection.

[0139] The injection is usually done at the inferotemporal quadrant (i.e. the lower quadrant away from the nose) of the eye undergoing the procedure, as it is usually more accessible. However, depending on the eye’s condition, patient’s and the ophthalmologist’s preference, other regions could also be used.

[0140] Patients with aphakic (without lens due to cataract surgery), or pseudophakic eye (with implanted lens after removal of natural lens) would have the injection 3.0-3.5 mm posterior to the limbus, while injection to the phakic eye (with natural lens) is done 3.5-4.0 mm posterior to the limbus.Attorney Docket No.: 87JA-350811-WO

[0141] The administration also typically comprises application of an anesthetic to the eye and eyelid to numb the area. Common forms of anesthetic used are eye drops (e.g., tetracaine / proparacaine) or gel (e.g., lidocaine 2% or 4% jelly), which is applied topically. Other choices of anesthesia include the use of lidocaine soaked pledget (a small cotton or wool pad) and subconjunctival injection (injection under the conjunctiva) of anesthetic agents. Sometimes, for an eye with inflammation, a retrobulbar block may be given, but usually the topical or subconjunctival anesthesia is sufficient. The anesthetic takes time to show the numbing effect, ranging from 1-5 minutes, depending on the anesthetic.

[0142] The specialist then sterilizes the eye and the surrounding area, often with povidone-iodine (PVP-I) solution, to prevent any infection in the injected site. Aqueous chlorhexidine is used instead in case of adverse effects to povidone-iodine.

[0143] An eyelid speculum is placed to retract the eyelids and thus hold the eye open, which helps to prevent contamination of the needle and the injection site by the eyelid or eyelashes. Povidone-iodine solution is applied to the conjunctiva at the site of injection. Another dose of local anesthetic may be given to the conjunctival surface again (for example, by placing a cotton swab soaked with the anesthetic drug solution over the targeted region), which is followed by the reapplication of PVP-I solution.

[0144] The injection site is measured and marked with a measuring caliper or other devices. The patient is then told to look away from the injection site to show the quadrant to be injected, and the doctor inserts the needle at the target site in a single motion into the mid- vitreous cavity. Once the needle is in the vitreous cavity, the doctor pushes the plunger to release the drug into the cavity. After that, the needle is removed, and the injection site is immediately covered with a cotton swab to avoid vitreous reflux (reflux of fluid from the vitreous cavity). The excess PVP-I solution is rinsed away.

[0145] Finally, the doctor checks the patient’s vision and intraocular pressure (IOP) of the eye. The injection of certain medications, such as triamcinolone acetonide (Kenalog or Triesence), may cause a sudden increase in the IOP, and the patient should be monitored until the pressure returns to a normal level. If a large volume of drug is injected, paracentesis may be required.

[0146] In some embodiments, the formulation is administered at least in the advanced stage of AMD. In certain embodiments, the formulation is administered at least in the advanced stage of AMD to treat or slow the progression of central geographic atrophy (GA), and / or to prevent or delay the onset of neovascular AMD. In further embodiments, the formulation is administered at least in the advanced stage of AMD to treat or slow the progression of neovascular AMD (including types 1, 2 and / or 3 neovascularization) .Attorney Docket No.: 87JA-350811-WO

[0147] In additional embodiments, the formulation is administered at least in the intermediate stage of AMD. In certain embodiments, the formulation is administered at least in the intermediate stage of AMD to treat or slow the progression of non-central GA, and / or to prevent or delay the onset of central GA and / or neovascular AMD. In further embodiments, the formulation is administered at least in the early phase of intermediate AMD to prevent or delay the onset of non-central GA. The intermediate stage of AMD is characterized by the presence of at least one of one large druse, multiple medium-size drusen, hyperpigmentation and / or hypopigmentation of the RPE, either without geographic atrophy (GA), or with geographic atrophy (GA) that does not extend to the center of the macula (non-foveal GA). Reduction of confluent soft drusen in intermediate AMD using the active agent can result in decrease in the thickness and normalization of the Bruch’s membrane, as well as renewal of the overlying RPE cell layer due to improved exchange of incoming oxygen and nutrients and outgoing waste between the choriocapillaris and the RPE. Reduction of confluent soft drusen can be observed by SDOCT.

[0148] In further embodiments, the formulation is administered at least in the early stage of AMD. The formulation can be administered at an earlier stage (e.g., the early stage or the intermediate stage) of AMD to slow or stop the progression of AMD. In some embodiments, the formulation is administered at least in the early stage of AMD to prevent or delay the onset of non-central GA. The formulation does not need to eliminate or remove all or most of the abnormal lipid deposits from the eye to have a therapeutic or prophylactic effect in AMD. If a threshold amount of abnormal lipids is cleared from the eye, natural transport mechanisms, including traffic between the choriocapillaris endothelium and the RPE layer, can properly work again and can clear remaining abnormal lipids from the eye. Furthermore, lipids accumulate in the eye slowly over a period of years (although fluctuations in druse volume in a shorter time frame are detectable).

[0149] The formulation can be administered in a stage (e.g., the early, intermediate or advanced stage) of AMD for a length of time selected by the treating physician (e.g., at least about 3 months, 6 months, 12 months, 18 months, 24 months or longer) or until the disease has been successfully treated according to selected outcome measure(s) (e.g., elimination of all or most soft drusen or reduction of soft drusen volume to a certain level).

[0150] In certain embodiments, the formulation is administered at a single dose level for the duration of the treatment period. For example, in some embodiments, 100 pg of the L4F-a / phospholipid formulation is administered to the patient at one dose of L4F peptide, e.g., 0.4, 0.8, or 1.2 mg / mL L4F peptide (as the acetate salt), once per month for the duration of the treatment period (e.g., one year). In certain embodiments, the formulation is administered at a single dose level for at least two or more consecutive months before any increase in dose.Attorney Docket No.: 87JA-350811-WO

[0151] The formulations and methods provided herein can be employed for one or more of the following: 1) reduction of drusen (including soft drusen) size (e.g., diameter or volume), number or amount (e.g., by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 99%); 2) prevention or resolution of drusenoid PEDs (e.g., promotion of re-attachment of the RPE- BL to the BrM ICL, or flattening of a PED or decrease in the separation / distance between the detached RPE-BL and the BrM ICL by at least about 50%, 60%, 70%, 80%, 90%, 95% or 99%); 3) enhancement of the phagocytic function (e.g., phagocytosis of drusen and other undesired matter) of RPE cells (e.g., increase in the percentage of phagocytic RPE cells by at least about 33%, 50%, 66%, 80% or 100%); 4) prevention or curtailment of atrophy and death of RPE cells and photoreceptors (e.g., reduction of the area of non-central and / or central geographic atrophy by at least about 30%, 40%, 50%, 60%, 70%, 80% or 90%); 5) prevention or forestalling of progression to or development of intermediate atrophic AMD, advanced atrophic AMD or neovascular AMD; 6) prevention or curtailment of vision loss (e.g., reduction of loss of visual acuity to no more than about 5, 4, 3, 2 or 1 letter); and 7) improvement of visual acuity (e.g., by at least about 3, 6, 9 or 12 letters).

[0152] The formulations and methods described herein can also be used to treat other eye diseases and disorders. Non-limiting examples of other eye diseases and disorders that can be treated with one or more active agents described herein include age-related macular degeneration, macular drusen (small, intermediate, large), peripheral drusen, extramacular drusen, drusenoid pigment epithelial detachment (PED), drusenoid deposits, basal laminar deposits, basal linear deposits, Doyne honeycomb retinal dystrophy, Malattia Leventinese, familial dominant drusen (or autosomal dominant drusen), cuticular drusen, serous detachment of RPE, drupelets, RPE atrophy, geographic atrophy, ellipsoid zone (EZ) attenuation, EZ loss, incomplete retinal pigment epithelial and outer retinal atrophy (iRORA), complete retinal pigment epithelial and outer retinal atrophy (cRORA), nascent geographic atrophy, retinal flecks, fundus flavimaculatus, Best disease, adult-onset vitelliform macular dystrophy, Best vitelliform macular dystrophy, autosomal recessive bestrophinopathy, vitelliform material, pattern dystrophy, autosomal dominant vitreoretinochoroidopathy, BEST1 gene mutation disorders, retinal emboli (in retinal artery occlusion), retinal exudates, retinal exudates secondary to retinal microaneurysm, familial exudative vitreoretinopathy (FEVR), synchysis scintillans (cholesterolosis bulbi), neuronal ceroid lipofuscinosis, Batten’s Disease, retinitis pigmentosa, Bietti’s crystalline dystrophy, juvenile macular degeneration (e.g., Stargardt’s disease), macular telangiectasia, maculopathy (e.g., age-related maculopathy (ARM) and diabetic maculopathy (DMP) (including partial ischemic DMP)), macular edema (e.g., diabetic macular edema (DME) (including clinically significant DME, focal DME and diffuse DME), Irvine-Gass Syndrome (postoperative macular edema), and macular edema following RVO (including central RVO and branch RVO)), retinopathy (e.g., diabetic retinopathy (including in patients with DME), Purtscher’s retinopathy and radiation retinopathy), retinal artery occlusion (RAO) (e.g., central and branch RAO),Attorney Docket No.: 87JA-350811-WO retinal vein occlusion (RVO) (e.g., central RVO (including central RVO with cystoid macular edema (CME)) and branch RVO (including branch RVO with CME)), glaucoma (including low-tension, normal-tension and high-tension glaucoma), ocular hypertension, retinitis (e.g., Coats’ disease (exudative retinitis) or retinitis pigmentosa), chorioretinitis, choroiditis (e.g., serpiginous choroiditis), uveitis (including anterior uveitis, intermediate uveitis, posterior uveitis with or without CME, and pan-uveitis), retinal detachment (e.g., in von Hippel-Lindau disease), retinal pigment epithelium (RPE) detachment, bestrophinopathy, Doyne honeycomb / dominant drusen, and diseases associated with increased intra- or extracellular lipid storage or accumulation in addition to AMD.

[0153] The formulations and methods provided herein can provide prevention of loss or improvement in one or more of the following: metamorphopsia on Amsler grid (resolve; no distortion in straight lines from previous distortion); metamorphopsia on ForeSee Home, notal vision device (resolve; line with no distortion viewed on the device, from previous line with distortion. The trend score no longer exceeds the test score change threshold); best corrected visual acuity (BCVA) or prevention of loss of BCVA (0-100 ETDRS letters); color vision (cone contrast test 0-100% of normal, 100% being normal. Farnsworth or Lanthony D-15: confusion index 1-3, with 1 being normal and 3 abnormal, total error score 11-40, 11 being normal and 40 abnormal); visual field testing (per eye: maximum is 160° in horizontal plane and 135° in the vertical plane); scotoma / visual field loss (0 to 160° horizontal, 0 to 135°); macular sensitivity on microperimetry testing (MAIA MP: 0-36 dB, Nidek MP: 0-20 dB); retinal sensitivity on virtual perimetry, dark adaptation (rod intercept time RIT from 0 to >20 min or 30 min; normal RIT is considered <6.5 min, abnormal > 6.5 min); change in reading speed from baseline under standard and low luminance conditions (0-38 words / minute); contrast sensitivity (MARS chart has log scale abnormal 0 to 1.92 normal, Pelli Robson 0 abnormal to 2 normal); ellipsoid zone (EZ) improvement or prevention of EZ attenuation (0-20 um) or EZ loss (0 um) (size 0 to 30 mm2); full field electro-retinogram (ERG): a-wave implicit times (normal 15-16.5 Hz, abnormal >16.5 (to 19 Hz), flicker peak times (normal 29-30.5 Hz, abnormal 30.5 to 35 Hz); multifocal ERG testing: response amplitude normal 27-30 nV, abnormal <27 nV, implicit time normal < 29 ms, abnormal 29-33 ms; electro-oculogram (EOG) testing (Arden ratio: abnormal 0 to 1.8, 1.8 to 2 borderline, >2 normal); Size of window defects on fluorescein angiogram (GA) (0 to 17.5 mm2); NEI-VFQ (worst 0 worst to 100 best); low luminance questionnaire (worst 0 to 100 best, abnormal < 80); and functional reading independence (FRI; score 1-4).

[0154] The formulations and methods provided herein can be employed to achieve one or more of the following: decrease in number of hyper-reflective foci (1- infinity, typically 5-20 per OCT 6x6 mm volume); decrease or prevention of increase in vitelliform material height / volume (height 0-1200 mm, typically around 200-250 mm and volume 0.5 mm3); decrease or prevention of increase in drusen volume (0 to 0.03 mm3normal, over 0.03 mm3at high risk of late AMD; range 0- 0.5 mm3; decreasedAttorney Docket No.: 87JA-350811-WO unesterified cholesterol in the RPE; normalization of distribution of the esterified cholesterol from the Bruch’s membrane to the photoreceptor outer segments; decreased levels of 4-hydroxy-2-nonenal (HNE) adducts (lipid peroxidation by-products) in the retina; prevention of or regression of retraction of apical microvilli of RPE cells; prevention of pseudohyopyon (clinical assessment); decrease in or prevention of increase of yellows dots / flecks, punctate white opacities (typically 0 to 100); prevention of retinal arteriolar narrowing (narrow artery < 50 mm); prevention of optic nerve pallor (pallor scale 0 to 4); prevention or regression of thickening of cone outer segments (0 to 2.5 mm); decrease in hyperautofluorescent lesions (0 -100); prevention or decrease of sub-RPE fibrosis; prevention of RPE atrophy (0 to 28.3 mm2, measured on qAF imaging); prevention of pigment epithelial detachment (serous, vascular or drusenoid); prevention of geographic atrophy (0 to 17.5 mm2, measured on qAF imaging); prevention of choroidal neovascularization (as defined on FA by CNV and OCT by subretinal / intraretinal fluid); prevention of macular holes; decrease in or prevention of subretinal hemorrhage, subretinal fluid, intraretinal fluid; decrease in or prevention of macular edema (intraretinal cysts 0 to 200); prevention of iRORA, cRORA (by case definitions), treatment of neovascular AMD, prevention of neovascular AMD, slowed progression of neovascular AMD, prevention of progression of disease, slowing progression of disease, improved visual acuity, stabilization of visual acuity, improvement of visual field as measured using Amsler grid, reduction of drusen size, reduction of drusen volume, reduction in number of drusen, elimination of drusen, improvement in ocular coherence tomography metrics, reduction and / or elimination of basal laminar deposits, reduction of anti-VEGF treatments, reduction of complement-related treatments, prevention of geographic atrophy, prevention of drusen formation, and reduction in rate of GA growth.

[0155] The formulations and methods provided herein can be employed to treat or prevent one or more of the following indications (e.g., retinal diseases and disorders): age-related macular degeneration, macular drusen (small, intermediate, large), peripheral drusen, extramacular drusen, drusenoid pigment epithelial detachment (PED), drusenoid deposits, basal laminar deposits, basal linear deposits, Doyne honeycomb retinal dystrophy (Malattia Leventinese, familial dominant drusen or autosomal dominant drusen), cuticular drusen, serous detachment of RPE, drupelets, RPE atrophy, geographic atrophy, total and partial ellipsoid zone (EZ) attenuation, EZ loss, incomplete retinal pigment epithelial and outer retinal atrophy (iRORA), complete retinal pigment epithelial and outer retinal atrophy (cRORA), nascent geographic atrophy, Stargardt’s disease, retinal flecks, fundus flavimaculatus, Best disease, bestrophinopathy, adult-onset vitelliform macular dystrophy, Best vitelliform macular dystrophy, autosomal recessive bestrophinopathy, vitelliform material, pattern dystrophy, autosomal dominant vitreoretinochoroidopathy, BEST1 gene mutation disorders, retinal emboli (in retinal artery occlusion), retinal exudates, Coat’s disease, retinal exudates secondary to retinal microaneurysm, familial exudative vitreoretinopathy (FEVR), synchysis scintillansAttorney Docket No.: 87JA-350811-WO(cholesterolosis bulbi), neuronal ceroid lipofuscinosis, Batten’s Disease, retinitis pigmentosa, and Bietti’s crystalline dystrophy.

[0156] In some embodiments, the treatment period is 1-30 days, 4-52 weeks, 1-12 months, or 1-5 years.

[0157] The methods provided herein can comprise administering formulation as disclosed herein to the padent once weekly, once every two weeks, once every four weeks, once every six weeks, once every two months, once every three months, once every four months, once every five months, once every six months, once every seven months, once every eight months, once every nine months, once every ten months, once every eleven months, once every twelve months, once every eighteen months, once every two years, once every three years, once every four years, once every five years, once every six years, once every seven years, once every eight years, once every nine years, once every ten years, or a number or a range between any two of the values.Examples

[0158] In each of the following examples and associated figures, Ac-DWFKAFYDKVAEKFKEAF- NH2 acetate salt (L4F-a) was used although molar equivalents were calculated based on L4F alone, not including acetate - the counterion.Example 1: In Vitro Model, Solubility and RPE Viability Studies

[0159] RPE cells were used as a surrogate cell type for lens fiber cells and cell viability was used as a measure of membrane disruption caused by L4F peptide. Varying concentrations of L4F peptide with phospholipid (POPS or sphingomyelin) were incubated with RPE cells and cell viability was determined by RealTime-Glo™ MT Cell Viability Assay (Promega G6080).Solubility Evaluation of L4F-a-POPS in XVIVO Culture Media:

[0160] Varying amounts of L4F-a and POPS were weighed into 50 mL conical tubes in an analytical balance and dissolved by serum-free XVIVO culture media. The mixture was then shaken at 150 rpm at 37°C overnight. After the overnight incubation, solubility of POPS was evaluated by visual observation of precipitates. The XVIVO culture medium was used as a fully soluble control.Short-term Toxicity Evaluation of L4F-a-POPS in the RPE Model:

[0161] Retinal Pigmented Epithelium Cell Culture: Human induced pluripotent stem-cell-derived retinal pigmented epithelium (hiPSC-RPE) cells were cultured on a 96-well black polystyrene plate with a clear bottom for at least 4 weeks in a serum-free XVIVO culture medium. Maturation ofAttorney Docket No.: 87JA-350811-WO hiPSC-RPE was confirmed by observing polygonal and pigmented monolayers under phase contrast and bright-field microscopy.

[0162] Real-time Cell Viability Assay: The L4F-a-POPS solutions were prepared as described above. The solutions are equivalent to 37°C before conducting the viability assay (triplicates per sample). The cell viability assay was performed following the instruction of a commercial kit, RealTime- GloTM MT Cell Viability Assay, purchased from Promega (Catalog number G9711). The reagents were thawed at room temperature and equivalent to 37°C. The reagents, MT Cell Viability Substrate and NanoLuc® Enzyme, were diluted 1000X directly in the L4F-a-POPS solutions. The medium from the cell culture plate was exchanged with the prepared solutions. To reduce the processing time that may affect the result, the prepared solutions were first dispensed to a separate 96-well plate and then transferred to the cell culture plate. Cells treated with 0.2% Triton-X-100 served as negative controls and cells without any treatment were the positive controls. The empty wells with L4F-POPS or X- VI VO culture medium alone were measured to correct the background signal at each concentration. After changing the medium, the plate was immediately shaken for 5 seconds, and the luminescence was continuously measured every 72 seconds for 2 hours using the BioTek Cytation 5 Cell Imaging Multimode Reader (Agilent).

[0163] Data Analysis and Graph Preparation: The data was exported as an Excel file from the microplate reader. All the values were subtracted from the average of the background value. The results at each time point in the first 30 minutes were plotted to represent the distribution of cell viability over time. The value of slope was calculated by the linear regression of each sample in the first 30 minutes to represent the rate of the cells in consuming the substrate. The results were presented as mean ± SEM and graphed using Graph Pad PRISM vlO.

[0164] In Figure 1, cell viability was assessed by calculating the slope of the accumulation of luminescence (RLU) over time (30 minutes). A higher accumulation of luminescence over time indicates that the cells are viable, whereas a low or no accumulation of luminescence over time indicates that the cells are not viable. As shown in Figure 1, cell viability was preserved with the POPS formulated peptide.

[0165] As shown in Table 1, RPE cells had an acute toxic effect on RPE cells at concentrations 0.4 mg / mL and greater. Formulations with the phospholipid POPS protected cells from the toxic effect of E4F when the phospholipid concentration was above a threshold that was dependent on the peptide concentration. An upper limit of phospholipid concentration was also found, in which the peptide + phospholipid formulation was not soluble. Table 1 summarizes these data.Attorney Docket No.: 87JA-350811-WOTable 1: In Vitro L4F + POPS or Sphingomyelin (SM) RPE Viability and Solubility Ranges1Solubility in cell culture medium is lower than in solutions such as DPBS, which are used for formulation in drug product2Viability in the low concentration 0.4 mg / mL was only tested at 24 hours while all other data points measured acute toxicity within the first 15 min of culture; in the acute 15 min viability assay, a lower POPS concentration is expected to be effective3Maximum solubility was not determined, concentrations listed here were not soluble in cell culture mediumExample 2: Preparation of L4F / POPS DPBS Formulation

[0166] ApoA-I mimetic peptide, L4F acetate salt (L4F-a) was formulated as a sterile solution for injection with a phospholipid l-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine sodium salt (POPS) in Dulbecco’s phosphate buffered saline (DPBS).

[0167] For example, about 6 mg of L4F-a and 2 mg of POPS was weighed into a vial. To this vial, 5 mL of DPBS was added. The mixture was stirred on a shaker at ambient temperature for ~ 15 mins to give a clear solution. The above solution was filtered through 0.22 micron syringe filter to give a clear, sterile formulation of L4F-a (1.2 mg / mL) with POPS (0.4 mg / mL). Formulations were subsequently used for Rabbit studies.Example 3: Solubility Evaluation of L4F-a and Phospholipids in DPBS

[0168] Appropriate amounts of phospholipid powders were weighed into 7 mL clear glass vials to test solubility with AC-DWFKAFYDKVAEKFKEAF-NH2 acetate salt (L4F-a). The amount of each phospholipid was calculated to achieve the specified molar ratios (Table 2) relative to 1.2 mg / mL of peptide.Attorney Docket No.: 87JA-350811-WOTable 2: Molar ratios of phospholipid to L4F tested for solubility.

[0169] L4F-a (1.2 mg / mL) was dissolved in Dulbecco’s phosphate-buffered saline (DPBS), and this solution was used to solubilize the weighed phospholipid powders. Vials were shaken at 450 rpm at 37°C overnight. After incubation, solutions were visually inspected for clarity; only those without precipitation or turbidity were considered soluble. Clear solutions were sterilized using 0.22 pm PVDF syringe filters (Millipore) and sterile Air-Tite syringes, then aliquoted into sterile 1.5 mL Eppendorf tubes and stored at 4°C for further analysis.Acute Toxicity and Rescue Effect Evaluation of L4F-a Phospholipid formulation in ARPE19 ModelHuman Retinal Pigment Epithelium Cell Culture (ARPE-19)

[0170] Human retinal pigment epithelial cells (ARPE-19; ATCC, CRL-21302) were cultured in black, polystyrene 96-well tissue culture plates. Cells were seeded at a density of 0.05 x 106cells per well in DMEM / F-12 medium (Gibco, Cat# 11320033) supplemented with 10% fetal bovine serum (FBS) and Normocin® (InvivoGen, Cat# ant-nr-1). Cultures were maintained at 37°C in 5% CO2 for 7 days to allow monolayer formation before treatment.Real-time Cell Viability Assay

[0171] Cell viability was assessed using the RealTime-Glo™ MT Cell Viability Assay (Promega, Cat# G9711). MT Cell Viability Substrate and NanoLuc® Enzyme were added (1:1000 each) directly to the peptide-phospholipid formulation and equilibrated to 37°C. The enzyme / substrate-containing solutions were pre-dispensed into sterile 96-well plates, then quickly transferred to the cell culture plates to minimize kinetic loss. Plates were shaken for 5 seconds, and luminescence was recorded every 54 seconds for 2 hours using a Biotek Synergy Hl Multimode Reader (Agilent), preequilibrated to 37°C. Controls were as follows: cell treated with 0.2% Triton X-100 served as theAttorney Docket No.: 87JA-350811-WO negative control; cell treated with 10% DPBS in medium served as the vehicle control; untreated cells served as positive control; and well without cells but containing viability reagent served as the background control.Data Analysis and Graph Preparation

[0172] Raw luminescence values were exported to Excel. Background signal was subtracted, and data over 2 hours were plotted to show viability trends. Final time point values were normalized to untreated controls and plotted as bar graphs. Results were presented as mean ± SEM using GraphPad Prism vlO.Functional Activity and Cell Viability Rescue Effect Evaluation of L4F-a Phospholipid formulation in ARPE19 ModelAssay Treatment Preparation

[0173] Formulations that passed acute toxicity screening were selected. The oxidized phospholipid, POVPC (l-palmitoyl-2-(5’-oxo-valeroyl)-sn-glycero-3-phosphocholine; Avanti, Cat# 870606), was used as a stressor. A 10 mg / mL stock solution of POVPC was prepared in DMSO. L4F-a- phospholipid formulations at 1.33:1 molar ratio were serially diluted 3-fold in DPBS from a 1.2 mg / mL stock. For treatment, final working solutions were prepared in culture medium (1% FBS) containing: 75 pg / mL POVPC and respective peptide formulations diluted 80-fold from intermediate solution. Treatments solution was equilibrated to 37 °C and then directly dispensed to respective cell culture wells. It was incubated for 24 hours under standard conditions. Controls were as followed: The vehicle control consisted of 75 pg / mL POPVC and 1.25% DPBS; a treatment baseline consisting of 0.75% DMSO and 1.2% DPBS; untreated cells served as the positive control; and wells without cells but containing assay reagents served as the background control.24-hour Cell Viability Assay

[0174] Performed using the same RealTime-Glo™ MT Cell Viability Assay as in the Data Analysis and Graph Preparation above. Reagents were diluted (1:1000) to cell culture medium with 1%FBS, equilibrated to 37 °C, and added directly to treatment wells. After a 1-hour incubation, plates were shaken for 5 seconds, and end-point luminescence was measured at 0 and 24 hours.

[0175] Figs. 2A-2G show cell viability assay for L4F peptide formulations with and without phospholipid.Data Analysis and Graph Preparation

[0176] Raw luminescence values were exported to Excel. Background-corrected luminescence data were normalized to untreated controls. 24-hour values were further normalized to their correspondingAttorney Docket No.: 87JA-350811-WOO-hour values to evaluate relative change. ECso values were calculated, and data were presented as mean ± SEM using GraphPad Prism vlO.Table 3SynSM = synthetic sphingomyelin; scL4F = Ac-DWFAKDYFKKAFVEEFAK-NH2(SEQ. ID. NO.: 14)Table 4Attorney Docket No.: 87JA-350811-WO

[0177] Lens opacity was observed for naked L4F at high concentrations in vivo (120 pg / eye). POPS and synthetic sphingomyelin were shown to protect from lens opacity in vivo; although in rabbit, a vitreous precipitate formed at high concentrations with POPS. In vitro, DOPG showed dosedependent calcium mediated precipitate.

[0178] Based on these studies, chain length plays a role in protective ability of the phospholipid. It has been found that chain length greater than 15 or 16 Angstroms resulted in a protective effect. If the carbon chain of the phospholipid is saturated, a chain length below 18 carbons, or 21 or 22 Angstroms, is beneficial, above which, solubility became an issue. Table 5 summarizes the findings.Table 5Attorney Docket No.: 87JA-350811-WO* SM has two different carbon chains. As listed in the table, the projected length is specific to the referenced carbon chain, either 16:0 or 18:1. The prefix "d" is dihydroxy.Example 4: Rabbit Lens Observations Study #1

[0179] The purpose of the in vivo rabbit lens study is to investigate toxicity of intravitreal injection of peptide at various concentrations and formulations. L4F formulations were administered by intravitreal injection into rabbit eyes and lens opacity was measured as an indication of cataract formation. Lens opacity changes were observed within the first week of administration. POPS formulations protected from lens opacity formation with a minimum threshold concentration, dependent on peptide concentration. An upper POPS concentration limit was also found, in which vitreous flare was observed. Vitreous flare was believed to result from precipitation of either L4F or POPS in the formulation in the presence of vitreous fluid.

[0180] New Zealand White male rabbits approximately 22-28 weeks old and weighing 2-4 kg were used for the study in accordance with local bioethical regulations. Animals were anesthetized prior to dosing via intramuscular injection of 0.5 mL / kg body weight soludon containing ketamine and xylazine. While anesthetized, animal condition were monitored to verify animal health condition. AnyAttorney Docket No.: 87JA-350811-WO abnormal conditions (e.g., irregular respiration, cold to touch, etc.) observed while animals are under the effects of anesthesia were recorded.

[0181] Experimental details are as follows. Dose Route: Both eyes via intravitreal injection; dose administration was done using a 1-cc syringe and 30-gauge needle. A new needle and syringe will be used for each injection. Dose Frequency: Once (Study Day 1 is defined as the first day of dosing for each cohort). Dose Volume: 100 .L / eye total (administered as a single injection for each eye). Dose Site: Vehicle control or test article was administered to each animal via intravitreal injection to the left eye first. Test article was administered via intravitreal injection to the right eye after completion of dosing the left eye. The dosing completion time for each eye was recorded following each injection (e.g., dose left eye, record time for left eye, dose right eye, record time for right eye). Dose Site Preparation: Prior to injections and following anesthesia administration, a topical anesthetic (e.g., proparacaine) was instilled in each eye. A wire speculum was used to retract eyelids. Each eye was cleaned with a dilute povidone iodine solution or equivalent and rinsed with sterile saline prior to injection. Dosing Procedure: The needle was inserted 2 mm away from the limbus in the superotemporal quadrant and advanced into the vitreous body. Once inserted accordingly, the material was injected into the vitreous body. The needle was left in place for approximately 3 to 5 seconds and then removed slowly to reduce potential back flow from the injection track. Shortly after the needle is removed the eye was rinsed with balanced salt solution (BSS). Additional Procedures: A topical antibiotic (e.g., Neo-Poly-Bac or appropriate substitute) was instilled in each eye following completion of each dosing (to be administered as the animal recovers from anesthesia).

[0182] All surviving animals had ophthalmic examinations conducted for each eye at least once during the acclimation period and once (prior to dosing on days of dosing as applicable) on Study Days 3, 5, 10, 12, 15, 22, and 29.

[0183] Animals were examined with a slit-lamp biomicroscope and indirect ophthalmoscope. The adnexa and anterior portions of each eye were examined with the slit-lamp biomicroscope. The ocular fundus of both eyes were observed (when able) using an indirect ophthalmoscope. Prior to examination with an indirect ophthalmoscope, pupils were dilated with an appropriate mydriatic agent (e.g., 1% tropicamide).

[0184] Eyes were macroscopically examined and graded using a modified Hackett-McDonald Scoring System. All eye abnormalities observed or an indication of normal were recorded for each eye of each animal. Data for certain formulations are shown in the Table 6and Table 7 below.Attorney Docket No.: 87JA-350811-WOTable 6: Summary of POPS Formulations on Rabbit SafetyTable 7: Summary of Sphingomyelin Formulations on Rabbit SafetyExample 5: Rabbit Study #2Study Design

[0185] New Zealand white or black Rabbits (n=3 per group) received a single intravitreal injection dose of vehicle to the left eye or different formulations of test article to the right eye on Day 1. The formulations were comprised of L4F with different phospholipids, with a dose volume of 100 pL per eye to each animal. The animals were monitored for 7 or 28 days and sacrificed on Day 29.Measurements:

[0186] Ophthalmic examinations were conducted by a study ophthalmologist at predose and on Study Days 1 (1-2 hr postdose), 2, 3, (or 5), 8, or 12, 15, 22, or 29. Ocular findings including lens opacity were examined with a slit-lamp biomicroscope and indirect ophthalmoscope. The adnexa and anterior portions of each eye were examined with the slit-lamp biomicroscope. The ocular fundus of both eyes were observed using an indirect ophthalmoscope. All eyes were macroscopically examinedAttorney Docket No.: 87JA-350811-WO and graded using a modified Hackett-McDonald Scoring System. The lens were graded as either normal or abnormal. The presence of lenticular opacities and % Area of lens opacity were described, and the location was noted.

[0187] Results are shown in Tables 8 and 9.Table 8Attorney Docket No.: 87JA-350811-WO* No TA-related findings for any.Table 9Attorney Docket No.: 87JA-350811-WOAttorney Docket No.: 87JA-350811-WOExample 6: Clinical Findings with L4F

[0188] A human clinical study was conducted to investigate the safety and efficacy of L4F in AMD. Patients were administered 100 pL intravitreal injection of L4F acetate (L4F-a) peptide formulated in DPBS. The highest dose tested was 0.4 mg / mL L4F. A cataract formed within the first week of administration of L4F at this high dose in 1 of 3 patients who had intact lenses. These results demonstrate the risk of L4F causing cataracts and the need to formulate with phospholipid to address this risk.

[0189] Based on the studies disclosed herein, a charged head group was shown to cause calcium- mediated vitreous precipitation. Further, a chain length less than or equal to 12 carbon atoms showed little to no protective effects, and a chain length greater than 18 carbons which is also saturated has little to no solubility. A double bond in the fatty acid chain aids in solubility; however, it is contemplated that the presence of a double bond would make the phospholipid susceptible to oxidation.* * *

[0190] The present disclosure is not to be limited in scope by the specific embodiments described which are intended as single illustrations of individual aspects of the disclosure, and any compositions or methods which are functionally equivalent are within the scope of this disclosure. It will be apparent to those skilled in the art that various modifications and variations can be made in the methods and compositions of the present disclosure without departing from the spirit or scope of the disclosure. Thus, it is intended that the present disclosure cover the modifications and variations of this disclosure provided they come within the scope of the appended claims and their equivalents.

[0191] All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

Claims

Attorney Docket No.: 87JA-350811-WOWhat is claimed is:

1. A method for inhibiting formation or growth of drusen, and / or reducing number and / or size of drusen, in a patient in need thereof, comprising administering to the eye an effective amount of pharmaceutical formulation comprising: an effective amount of a apolipoprotein A-I mimetic peptide, or salt thereof; optionally at least one phospholipid; and an aqueous pharmaceutically acceptable carrier; wherein the amount of peptide is in a range sufficient to reduce the number and / or size of drusen, inhibit formation or growth of drusen, and / or reduce or substantially eliminate the occurrence and / or severity of lens opacity.

2. The method of claim 1 , wherein a portion of retinal pigment epithelium (RPE) cells remain intact.

3. The method of claim 1, wherein the drusen are associated with age-related macular degeneration (AMD).

4. The method of claim 1 or 2, wherein the drusen are associated with dry age-related macular degeneration (dry AMD).

5. The method of claim 3, wherein the AMD is intermediate AMD.

6. The method of claim 3, wherein the AMD is geographic atrophy.

7. The method of claim any one of clams 1-6, wherein the majority of drusen are located between the retinal pigment epithelium (RPE) and Bruch’s membrane (BrM).

8. The method of any one of clams 1-7, wherein at least one druse is greater than about 10 pm in at least one dimension.

9. A method for treating age-related macular degeneration (AMD) in a patient in need thereof, comprising administering to the eye an effective amount of pharmaceutical formulation comprising: an apolipoprotein A-I mimetic peptide, or salt thereof; at least one phospholipid; and an aqueous pharmaceutically acceptable carrier.Attorney Docket No.: 87JA-350811-WO10. The method of any one of clams 1-9, wherein the apolipoprotein A-I mimetic peptide is AC-DWFKAFYDKVAEKFKEAF-NH2(L4F) (SEQ. ID. NO.: 13) or a salt thereof.

11. The method of any one of clams 1-10, wherein the method further comprises reducing or eliminating the occurrence of, or lessening the risk or severity of, lens opacity and / or vitreous flare.

12. The method of any one of clams 1-11, wherein the concentration of peptide in the formulation is 0.1 mg / mL to 1.2 mg / mL.

13. The method of any one of claims 1-12, wherein the amount of peptide administered is 40-120 pg / eye, or 40 pg / eye, 80 pg / eye, or 120 pg / eye.

14. The method of any one of claims 1-13, wherein the phospholipid is selected from 1- hexadecanoyl-2-(9Z-octadecenoyl)-sn-glycero-3-phospho-L-serine (POPS) and sphingomyelin.

15. The method of claim 14, wherein the concentration of peptide in the formulation is about 0.4 mg / mL to about 0.8 mg / mL.

16. The method of claim 14 or 15, wherein the concentration of POPS in the formulation is about 0.05 mg / mL to about 0.6 mg / mL.

17. The method of claim 16, wherein the molar ratio of peptide to POPS in the formulation is about 0.7.

18. The method of claim 14 or 15, wherein the concentration of sphingomyelin in the formulation is from about 0.12 to about 1.5 mg / mL.

19. The method of claim 18, wherein the molar ratio of peptide to sphingomyelin in the formulation is from about 0.25.

20. The method of any one of claims 1-19, wherein the method comprises administering the formulation via intraocular injection.

21. The method of any one of claims 1-20, wherein the method comprises administering the formulation via intravitreal injection.

22. An injectable intraocular formulation comprising: an apolipoprotein A-I mimetic peptide, or salt thereof; an effective amount of at least one phospholipid; and an aqueous pharmaceutically acceptable carrier;Attorney Docket No.: 87JA-350811-WO wherein the molar ratio of phospholipid to peptide is sufficient such that the occurrence and / or severity of one or both of lens opacity and / or vitreous flare is reduced or substantially eliminated.

23. The injectable intraocular formulation of claim 19, wherein the apolipoprotein A-I mimetic peptide is Ac-DWFKAFYDKVAEKFKEAF-NH2(L4F) (SEQ. ID. NO.: 13) or salt thereof.

24. An injectable intraocular formulation comprising:AC-DWFKAFYDKVAEKFKEAF-NH2(L4F), or salt thereof; an effective amount of at least one phospholipid; and an aqueous pharmaceutically acceptable carrier.

25. The injectable intraocular formulation of claim 24, wherein the molar ratio of phospholipid to peptide is sufficient such that the occurrence and / or severity of one or both of lens haziness and / or vitreous flare is reduced or substantially eliminated.

26. The injectable intraocular formulation of any one of claims 22-22, wherein the molar ratio of phospholipid to peptide is sufficient to substantially slow or prevent peptide-induced 7kCh- mediated cell death in vitro.

27. The injectable intraocular formulation of any one of claims 22-26, wherein the concentration of peptide in the formulation is 0.1 mg / mL to 1.2 mg / mL.

28. The injectable intraocular formulation of any one of claims 22-27, wherein the phospholipid is selected from l-hexadecanoyl-2-(9Z-octadecenoyl)-sn-glycero-3-phospho-L-serine (POPS) and sphingomyelin.

29. The injectable intraocular formulation of claim 28, wherein the concentration of peptide in the formulation is about 0.4 mg / mL to about 0.8 mg / mL.

30. The injectable intraocular formulation of claim 28 or 29, wherein the concentration of POPS in the formulation is about 0.05 mg / mL to about 0.6 mg / mL.

31. The injectable intraocular formulation of claim 30, wherein the molar ratio of peptide to POPS in the formulation is about 0.7.

32. The injectable intraocular formulation of claim 28 or 29, wherein the concentration of sphingomyelin in the formulation is from about 0.12 to about 1.5 mg / mL.Attorney Docket No.: 87JA-350811-WO33. The injectable intraocular formulation of claim 32, wherein the molar ratio of peptide to sphingomyelin in the formulation is from about 0.25.

34. An injectable intraocular formulation comprising: Ac-DWFKAFYDKVAEKFKEAF- NH2 (L4F) (SEQ. ID. NO.: 13), or salt thereof; l-hexadecanoyl-2-(9Z-octadecenoyl)-sn-glycero-3- phospho-L-serine (POPS); and an aqueous pharmaceutically acceptable carrier; wherein: the concentration of peptide in the formulation is about 0.4 mg / mL to about 0.8 mg / mL; the concentration of POPS in the formulation is from about 0.02 mg / mL to about 0.6 mg / mL; and the molar ratio of peptide to POPS in the formulation is about 0.7.

35. An injectable intraocular formulation comprising: Ac-DWFKAFYDKVAEKFKEAF- NH2 (L4F) (SEQ. ID. NO.: 13), or salt thereof; sphingomyelin; and an aqueous pharmaceutically acceptable carrier; wherein: the concentration of peptide in the formulation is about 0.4 mg / mL to about 0.8 mg / mL; the concentration of sphingomyelin in the formulation is from about 0.12 mg / mL to 1.5 mg / mL; and the molar ratio of peptide to sphingomyelin in the formulation is about 0.25.

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