Peptide compositions and methods for treating retinal diseases and disorders

Abstract

Provided are formulations and methods for treating patients having AMD, by inhibiting formation or growth of drusen, and / or reducing number and / or size of drusen, while maintaining or restoring ellipsoid zone area in a human eye.

Description

Attorney Docket No.: 87JA-403378-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 / 744,762, filed January 13, 2025, which is hereby incorporated by reference in its entirety.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’s 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.Attorney Docket No.: 87JA-403378-WOSUMMARY

[0006] The formulations and methods described herein are designed to treat drusen and / or AMD, such as intermediate AMD, wherein upon treatment the ellipsoid zone is substantially maintained, or even restored, and wherein the risk of 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 inhibiting formation or growth of drusen, and / or reducing number and / or size of one or more druse, in a human eye in need thereof, comprising administering to the eye an effective amount of a pharmaceutical formulation comprising an effective amount of a apolipoprotein A-I mimetic peptide, or salt thereof; and an aqueous pharmaceutically acceptable carrier; wherein the amount of peptide is in a range sufficient to reduce the number and / or size of one or more druse, inhibit formation or growth of one or more druse, and / or reduce or substantially eliminate the risk, occurrence, and / or severity, of lens opacity.

[0008] In some embodiments, provided herein is a method for maintaining or restoring ellipsoid zone in a human eye in need thereof, comprising administering to the eye an effective amount of a pharmaceutical formulation comprising an effective amount of an apolipoprotein A-I mimetic peptide, or salt thereof; and an aqueous pharmaceutically acceptable carrier.

[0009] In certain embodiments, the present disclosure provides methods for slowing of geographic atrophy lesion growth at an unexpectedly low dose of L4F peptide (e.g., monthly 20 pg / eye or 40 pg / eye doses).

[0010] In some embodiments, provided herein is a method of preventing geographic atrophy in a human eye in need thereof, wherein the human eye comprises at least one druse greater than about 63 pm in at least one dimension, comprising administering to the eye an effective amount of a pharmaceutical formulation comprising an effective amount of an apolipoprotein A-I mimetic peptide, or salt thereof; and an aqueous pharmaceutically acceptable carrier.

[0011] In some embodiments, the apolipoprotein A-I mimetic peptide is Ac-DWFKAFYDKVAEKFKEAF-NH2(L4F) (SEQ. ID. NO.: 13), or a salt thereof.

[0012] In some embodiments, the amount of peptide administered is about 40 pg / eye or less as a once monthly dose (e.g., once every 4 weeks), or about 10-40 pg / eye as a once monthly dose, or about 20-40 pg / eye as a once monthly dose, or about 20-30 pg / eye as a once monthly dose, or about 30-40 pg / eye as a once monthly dose. In some embodiments, the amount of peptide administered is about 40 pg / eye as a once monthly dose. In some embodiments, the amount of peptide administered is about 30Attorney Docket No.: 87JA-403378-WOpg / eye as a once monthly dose. In some embodiments, the amount of peptide administered is about 20 pg / eye as a once monthly dose. In some embodiments, the amount of peptide administered is about 10 pg / eye as a once monthly dose. In some embodiments, the amount of peptide administered is about 20 pg / eye or less, or about 20 pg / eye, or about 10 pg / eye.

[0013] In some embodiments, the amount of peptide administered is about 120-240 pg / eye within a 6 month period. In some embodiments, the amount of peptide administered is about 60 pg / eye within a 6 month period. In some embodiments, the amount of peptide administered is about 120 pg / eye within a 6 month period. In some embodiments, the amount of peptide administered is about 180 pg / eye within a 6 month period. In some embodiments, the amount of peptide administered is about 240 pg / eye within a 6 month period.BRIEF DESCRIPTION OF DRAWINGS

[0014] Fig. 1 shows large drusen decrease and photoreceptor (ellipsoid zone (EZ)) recovery after 28 weeks of treatment (10 pg / eye once every 4 weeks).

[0015] Fig. 2 shows large drusen decrease and photoreceptor (ellipsoid zone (EZ)) recovery after 16 weeks of treatment (20 pg / eye once every 4 weeks).

[0016] Fig. 3 shows drusen regression over time with peptide treatment: (dose: 10 pg / eye every 4 weeks, 7 total doses over 28 weeks; and dose: 20 pg / eye every 4 weeks, 3 total doses over 16 weeks.

[0017] Fig. 4 shows mean change in drusen volume, treatment eye vs. fellow eye.

[0018] Fig. 5A and Fig. 5B shows efficacy of inhibiting GA growth rate and impact on cataract rate in human patients (Fig. 5A shows efficacy and cataract rate / dose and Fig. 5B shows efficacy and cataract rate / patient).DETAILED DESCRIPTION

[0019] 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%. ItAttorney Docket No.: 87JA-403378-WOalso 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.

[0020] 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.

[0021] “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.

[0022] 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,Attorney Docket No.: 87JA-403378-WOthere is a gradual breakdown of the light-sensitive cells in the macula that convey visual information 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.

[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.

[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 additionAttorney Docket No.: 87JA-403378-WOsalts. 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.

[0029] “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.

[0030] Apolipoprotein A-I mimetic peptides, or Apo A-I mimetic peptides, are peptides that 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. ApoA-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.

[0031] 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-403378-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.

[0032] 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.

[0033] 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).

[0034] 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.

[0035] The present disclosure encompasses the following apolipoprotein peptide mimetics:1) apo mimetics in which all of the amino acid residues have the L stereochemistry;2) 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;Attorney Docket No.: 87JA-403378-WO4) 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 mi me tic 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.

[0036] 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 R1andR2independently 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.

[0037] 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 intestinal 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), 2FPhe, Tmp, Tic, CMePhe and O feFPhe), 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 moietiesAttorney Docket No.: 87JA-403378-WOcan 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-NFE (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.

[0038] 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.

[0039] 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, 25, 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,Attorney Docket No.: 87JA-403378-WO150, 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.

[0040] The peptides described herein can be prepared according to procedures known to those of skill in the art. As a non-li mi ting 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.

[0041] 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; and an aqueous pharmaceutically acceptable carrier.Methods of Treatment

[0042] 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.

[0043] In one embodiment, provided herein is a method for inhibiting formation or growth of drusen, and / or reducing number and / or size of one or more druse, in a human eye of a patient in need thereof, comprising administering to the eye an effective amount of a pharmaceutical formulation comprising an effective amount of an apolipoprotein A-I mimetic peptide, or salt thereof; and an aqueous pharmaceutically acceptable carrier; wherein the amount of peptide is in a range sufficient to reduce the number and / or size of one or more druse, or inhibit formation and / or growth of one or more druse. In some embodiments, the risk of lens opacity or lens haziness, e.g., cataract formation, is reduced or substantially eliminated.

[0044] In some embodiments, the amount of peptide administered is about 10 to 40 pg / eye. In some embodiments, the amount of peptide administered is 10 pg / eye, 20 pg / eye, 30 pg / eye, 40 pg / eye.Attorney Docket No.: 87JA-403378-WO

[0045] In some embodiments, the amount of peptide administered is about 20 to 40 pg / eye. In some embodiments, the amount of peptide administered is 20 pg / eye, 25 pg / eye, 30 pg / eye, 35 pg / eye, 40 pg / eye.

[0046] In some embodiments, the amount of peptide administered is about 1 to 20 pg / eye. In some embodiments, the amount of peptide administered is 1 pg / eye, 2 pg / eye, 3 pg / eye, 4 pg / eye, 5 pg / eye, 6 pg / eye, 7 pg / eye, 8 pg / eye, 9 pg / eye, 10 pg / eye, 11 pg / eye, 12 pg / eye, 13 pg / eye, 14 pg / eye, 15 pg / eye, 16 pg / eye, 17 pg / eye, 18 pg / eye, 19 pg / eye, or 20 pg / eye.

[0047] In some embodiments, the amount of peptide administered is lower at the beginning of the treatment period, and then in increased thereafter (e.g., after 1, 2, 3, 4, 5, etc., months of treatment with a lower dose).

[0048] In some embodiments, the pharmaceutical formulation does not contain a phospholipid.

[0049] In one embodiment, provided herein is a method for inhibiting formation or growth of drusen, and / or reducing number and / or size of one or more druse, in a human eye of a patient in need thereof, comprising administering 20 pg or less per eye of an apolipoprotein A-I mimetic peptide, or salt thereof. In some embodiments, the risk of lens opacity or lens haziness, e.g., cataract formation, is reduced or substantially eliminated. In some embodiments, the risk of lens opacity or lens haziness, e.g., cataract formation, is associated with the administration of an apolipoprotein A-I mimetic peptide.

[0050] In some embodiments, the term drusen is used to refer to one or more druse.

[0051] Hard drusen are usually round or hemispherical, without sloped borders. Soft drusen are usually larger and nonhomogeneous, and 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). In some embodiments, the term “drusen” 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.

[0052] ‘ ‘Soft” 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 fromAttorney Docket No.: 87JA-403378-WOone 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-BL 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 a similar 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.

[0053] 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).Attorney Docket No.: 87JA-403378-WO

[0054] 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.

[0055] 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 of 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 may 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.

[0056] Ellipsoid zone (EZ) is another key measure, which corresponds to photoreceptor mitochondria. Loss of EZ area is an early sign that geographic atrophy (GA) may follow.

[0057] The disclosed methods are contemplated to resolve drusen without significant loss of ellipsoid zone (EZ), and even with the restoration or regeneration of ellipsoid zone (EZ) over the treatment period. By preventing EZ loss and / or restoring EZ area, GA can be prevented.

[0058] In some embodiments, the method comprises reduction in loss (e.g., reduction in degeneration or atrophy) of photoreceptors or ellipsoid zone area. In some embodiments, the method comprises restoration or regeneration of photoreceptors or ellipsoid zone area.

[0059] In some embodiments, the method comprises attenuation or reduction in loss of photoreceptors or attenuation or reduction in loss of ellipsoid zone integrity.

[0060] In some embodiments, the method comprises restoration or regeneration of photoreceptors or attenuation or reduction in ellipsoid zone integrityAttorney Docket No.: 87JA-403378-WO

[0061] In certain embodiments, provided is a method for maintaining or restoring ellipsoid zone area in a human eye in need thereof, comprising administering to the eye an effective amount of a pharmaceutical formulation comprising an effective amount of an apolipoprotein A-I mimetic peptide, or salt thereof; and an aqueous pharmaceutically acceptable carrier.

[0062] In certain embodiments, provided is a method of preventing geographic atrophy in a human eye, wherein the human eye comprises at least one druse greater than about 63 pm in at least one dimension, comprising administering to the eye an effective amount of a pharmaceutical formulation comprising an effective amount of an apolipoprotein A-I mimetic peptide, or salt thereof; and an aqueous pharmaceutical I y acceptable carrier.

[0063] 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.

[0064] The disclosed methods are contemplated to resolve drusen without substantial or 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.

[0065] In contrast, the methods provided herein are designed to treat patients with drusen, such as by eliminating or reducing the number and / or size of one or more druse, 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, ophcal coherence tomography (OCT), or adaptive optics scanning laser ophthalmoscope (AOSLO) allows for imaging of individual retinal pigment epithelial (RPE) cells in vivo.

[0066] 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.

[0067] 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. For example, as measured by reduction, disruption or irregularity in the RPE layerAttorney Docket No.: 87JA-403378-WO

[0068] 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.

[0069] 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 numerous drusen of small or intermediate size, or any drusen of large size (e.g., >125 microns) (early AMD has “few” small to intermediate size drusen).

[0070] In some embodiments, the AMD is geographic atrophy.

[0071] 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) may 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-403378-WOTypes of Drusen

[0072] 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. Large soft drusen are defined as larger, poorly-defined drusen with mound-like 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.

[0073] Historically, basal laminar deposits (BLamD) have been referred to as drusen. Whereas they have characteristics on OCT that look like drusen, basal laminar deposits are distinguished from soft drusen. BLamD are generally considered to be comprised of extracellular matrix proteins, sometimes in the presence of type 1 macular neovascularization that can appear as “double layer sign.”Number of Drusen

[0074] 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

[0075] 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.Attorney Docket No.: 87JA-403378-WO

[0076] In some embodiments, the majority of drusen are located between the retinal pigment epithelium (RPE) and Bruch’s membrane (BrM). “Majority” can refer to greater than 50%, such as 55% or greater, 60% or greater, 70% or greater, 80% or greater, or 90% or greater. In some embodiments, the percentage is calculated based on the number or amount of drusen. In some embodiments, the percentage is calculated based on the estimated surface area or volume of drusen.

[0077] In some embodiments, at least a portion of the drusen (i.e., one or more druse) is at least about 60 pm, 80 pm, 100 pm, 125 pm, 150 pm, 200 pm, 250 pm, 300 pm, 400 pm, or 500 pm, in one dimension (e.g., height, diameter, width, length, etc., depending on perspective or measurement).

[0078] In some embodiments, at least a portion of the drusen (i.e., one or more druse) have a width of about 63 pm or greater 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).

[0079] 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.

[0080] In some embodiments, at least a portion of the drusen (i.e., one or more druse) have an average diameter of less than about 60 pm, or 63 pm. In some embodiments, one or more druse have a height of about 60 pm, or 63 pm.

[0081] 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.

[0082] In some embodiments, at least a portion of the drusen (i.e., one or more druse) have an average diameter of greater than about 125 pm. In some embodiments, one or more druse have a height of greater than about 125 pm.

[0083] In some embodiments, at least a portion of the drusen (i.e., one or more druse) have an average diameter of from about 63 to about 125 pm. In some embodiments, one or more druse have a height of from about 63 to about 125 pm.Attorney Docket No.: 87JA-403378-WO

[0084] 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.

[0085] 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.

[0086] 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 the 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 patient 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 particular! y toxic to photoreceptors, and intraretinal fluid signifies a poor prognosis for vision. Bleeding and leaking fromAttorney Docket No.: 87JA-403378-WOthe new blood vessels, with subsequent fibrosis, can cause irreversible damage to the retina and rapid vision loss if left untreated.

[0087] 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 / or 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.

[0088] In some embodiments, the size of one or more druse is reduced by at least about 80%, or 70%, or 50%, or 25%, or 10% after about 12 weeks of treatment. In some embodiments, the size of one or more druse is reduced by at least about 80%, or 70%, or 50%, or 25%, or 10% after about 12 weeks of treatment, while the area of the ellipsoid zone is substantially increased.

[0089] In some embodiments, provided herein is a method for maintaining, restoring, or reducing the loss or attenuation of ellipsoid zone integrity in a human eye in need thereof, comprising administering to the eye an effective amount of a pharmaceutical formulation comprising an effectiveAttorney Docket No.: 87JA-403378-WOamount of an apolipoprotein A-I mimetic peptide, or salt thereof; and an aqueous pharmaceutically acceptable carrier.

[0090] Ellipsoid zone integrity can be assessed using methods known in the art (see, e.g., Yordi, S., et al., J. Pers. Med. 2024, 14, 543). Typically, ellipsoid zone integrity is assessed as whether or not there is a full -thickness absence of EZ in a B-scan (EZ loss) or if it has been thinned below a threshold (e.g., below 20 microns thick - “partial EZ attenuation”). Other measures of EZ integrity can be evaluated for association with visual function, such as, but not limited to, mean EZ-RPE central subfield (mean thickness between the EZ and RPE within a 1 mm diameter fovea-centered circle) thickness (CST; pm), mean EZ-RPE central macular (2 mm diameter fovea-centered circle) thickness (CMT; pm), panmacular EZ-RPE volume (compartmental volume between the EZ and RPE in the entire macular cube; mm3), and partial and total EZ attenuation (percentage of macular area covered by EZ-RPE thickness <20 pm and 0 pm, respectively). EZ intensity can be measured for each a-scan, where the EZ line intensity ranges from 0 to 256 on a grayscale level. If the EZ layer was absent, the EZ intensity is labeled as 0, while maximum brightness (white) is labeled as 256. The EZ intensity value is then averaged for each a-scan across the zone of interest (panmacular, central subfield, central macula). To account for image quality variability, the EZ intensity index (or normalized EZ intensity) is calculated as the [(EZ intensity) x (EZ intensity / RPE intensity)], which standardized the EZ intensity value relative to the RPE layer brightness.

[0091] It is contemplated that the loss of ellipsoid zone is associated with the loss of photoreceptors and / or reduced health of photoreceptors, and thus may be a contributing factor to vision loss associated with AMD, and can result in the formation of geographic atrophy (GA). As such, in one embodiment, the methods provided herein can be used to halt vision loss, reduce the rate of vision loss, and / or restore vision to a patient with AMD.

[0092] In some embodiments, provided herein is a method for slowing or halting geographic atrophy in a human eye in need thereof, comprising administering to the eye an effective amount of a pharmaceutical formulation comprising an effective amount of an apolipoprotein A-I mimetic peptide, or salt thereof; and an aqueous pharmaceutically acceptable carrier; wherein the amount of peptide is in a range sufficient to reduce or substantially eliminate the occurrence and / or severity of lens opacity.

[0093] In some embodiments, no drusen are present in the eye.

[0094] In some embodiments, the eye comprises at least one druse.

[0095] In some embodiments, the eye comprises at least one druse greater than about 63 pm in at least one dimension.Attorney Docket No.: 87JA-403378-WO

[0096] In some embodiments, provided herein is a method for preventing geographic atrophy in a human eye, wherein the human eye comprises at least one druse greater than about 63 pm in at least one dimension, comprising administering to the eye an effect! ve amount of a pharmaceutical formulation comprising an effective amount of an apolipoprotein A-I mimetic peptide, or salt thereof; and an aqueous pharmaceutically acceptable carrier.

[0097] In some embodiments, provided herein is a method for treating age-related macular degeneration (AMD), such as dry AMD, in a patient in need thereof, comprising administering to the eye an effective amount of a pharmaceutical formulation comprising: an apolipoprotein A-I mimetic peptide, or salt thereof; and an aqueous pharmaceutically acceptable carrier.

[0098] 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). In some embodiments, the risk of lens opacity or lens haziness, e.g., cataract formation, is associated with the administration of an apolipoprotein A-I mimetic peptide.

[0099] It has also been surprisingly observed that improvement in deposit volume was seen in certain subjects who did not have soft drusen, but rather basal laminar deposits (BLamD). Thus is it contemplated that a pharmaceutical formulation comprising an eff'ecti ve amount of an apolipoprotein A-I mimetic peptide, or salt thereof, as disclosed herein, can be used in treating basal laminar deposits (BLamD).

[0100] 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 apo A-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. In some embodiments, the apolipoprotein A-I mimetic peptide is Ac-DWFKAFYDKVAEKFKEAF-NFL (L4F). In some embodiments, the apolipoprotein A-I mimetic peptide is Ac-DWFKAFYDKVAEKFKEAF-NH2(L4F) (SEQ. ID. NO.: 13) and is administered as the acetate salt.

[0101] In some embodiments, the apolipoprotein A-I mimetic peptide is Ac-DWFKAFYDKVAEKFKEAF-NH2 (L4F) (SEQ. ID. NO.: 13), wherein the amount of peptide administered is 10-40 pg / eye, and the peptide is administered as the acetate salt. In some embodiments, the apolipoprotein A-I mimetic peptide is Ac-DWFKAFYDKVAEKFKEAF-NFL (L4F) (SEQ. ID. NO.: 13), wherein the amount of peptide administered is 20-40 pg / eye, and the peptide is administered as the acetate salt. In some embodiments, the apolipoprotein A-I mimeticAttorney Docket No.: 87JA-403378-WOpeptide is Ac-DWFKAFYDKVAEKFKEAF-NH2(L4F) (SEQ. ID. NO.: 13), wherein the amount of peptide administered is 40 pg / eye, and the peptide is administered as the acetate salt. In some embodiments, the apolipoprotein A-I mimetic peptide is Ac-DWFKAFYDKVAEKFKEAF-NH2(L4F) (SEQ. ID. NO.: 13), wherein the amount of peptide administered is 20 pg / eye, and the peptide is administered as the acetate salt. In some embodiments, the apolipoprotein A-I mimetic peptide is AC-DWFKAFYDKVAEKFKEAF-NH2(L4F) (SEQ. ID. NO.: 13), wherein the amount of peptide administered is 10 pg / eye, and the peptide is administered as the acetate salt.

[0102] 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 a pharmaceutical formulation comprising: Ac-DWFKAFYDKVAEKFKEAF-NH2(L4F), or salt thereof; and an aqueous pharmaceutical I y acceptable carrier.

[0103] In some embodiments, provided is a method for treating dry age-related macular degeneration (AMD) in a patient in need thereof, comprising administering to the eye an effective amount of a pharmaceutical formulation comprising: Ac-DWFKAFYDKVAEKFKEAF-NH2(L4F), or salt thereof; and an aqueous pharmaceutical I y acceptable carrier.

[0104] In some embodiments, the amount of peptide administered is about 40 pg / eye or less as a once monthly dose (e.g., once every 4 weeks), or about 10-40 pg / eye as a once monthly dose, or about 20-40 pg / eye as a once monthly dose, or about 20-30 pg / eye as a once monthly dose, or about 30-40 pg / eye as a once monthly dose. In some embodiments, the amount of peptide administered is about 40 pg / eye as a once monthly dose. In some embodiments, the amount of peptide administered is about 30 pg / eye as a once monthly dose. In some embodiments, the amount of peptide administered is about 20 pg / eye as a once monthly dose. In some embodiments, the amount of peptide administered is about 10 pg / eye as a once monthly dose. In some embodiments, the amount of peptide administered is about 20 pg / eye or less, or about 20 pg / eye, or about 10 pg / eye as a once monthly dose.

[0105] As used herein, the phrase “once monthly dose” can refer to one dose every 4 weeks, one dose every 30 days, or one dose every calendar month, such that, for example, if a subject is treated for a 6 month period, the subject is administered 6 doses within a 6 month period.

[0106] In some embodiments, the amount of peptide administered is about 120-240 pg / eye within a 6 month period. In some embodiments, the amount of peptide administered is about 60 pg / eye within a 6 month period. In some embodiments, the amount of peptide administered is about 120 pg / eye within a 6 month period. In some embodiments, the amount of peptide administered is about 180 pg / eye within a 6 month period. In some embodiments, the amount of peptide administered is about 240 pg / eye within a 6 month period.Attorney Docket No.: 87JA-403378-WO

[0107] In some embodiments, provided is a method for inhibiting formation or growth of drusen, and / or reducing number and / or size of one or more druse, in a human eye in need thereof, comprising administering to the eye an effective amount of a peptide of formula Ac-DWFKAFYDKVAEKFKEAF-NH2(L4F) (SEQ. ID. NO.: 13), or salt thereof; and an aqueous pharmaceutically acceptable carrier; wherein the amount of peptide administered is 20-40 pg / eye.

[0108] In some embodiments, the amount of peptide administered is about 40 pg / eye as a once monthly dose. In some embodiments, the peptide (L4F) is administered as the salt (e.g., the acetate salt).

[0109] In some embodiments, the amount of peptide administered is about 120-240 pg / eye within a 6 month period, or not more than 240 pg / eye within a 6 month period.

[0110] Whereas the volume of the human vitreous varies, it averages around 4 to 5 mL. Thus, in some embodiments, the amount of peptide administered is sufficient to result in an intraocular peptide concentration of about 4 to about 9 pg / mL, or about 9 pg / mL, or about 8.9 pg / mL, or less than about 9 pg / mL.

[0111] In some embodiments, provided is a method for inhibiting formation or growth of drusen, and / or reducing number and / or size of one or more druse, in a human eye in need thereof, comprising administering to the eye an effective amount of a peptide of formula Ac-DWFKAFYDKVAEKFKEAF-NH2 (L4F) (SEQ. ID. NO.: 13), or salt thereof; and an aqueous pharmaceutically acceptable carrier; wherein the amount of peptide administered is 20 pg / eye or less.

[0112] In some embodiments, provided is a method for maintaining or restoring ellipsoid zone area in a human eye in need thereof, comprising administering to the eye an effective amount of a peptide of formula Ac-DWFKAFYDKVAEKFKEAF-NH2(L4F) (SEQ. ID. NO.: 13), or salt thereof; and an aqueous pharmaceutically acceptable carrier; wherein the amount of peptide administered is 20-40 pg / eye.

[0113] In some embodiments, provided is a method for maintaining or restoring ellipsoid zone area in a human eye in need thereof, comprising administering to the eye an effective amount of a peptide of formula Ac-DWFKAFYDKVAEKFKEAF-NH2(L4F) (SEQ. ID. NO.: 13), or salt thereof; and an aqueous pharmaceutically acceptable carrier; wherein the amount of peptide administered is 20 pg / eye or less.

[0114] In some embodiments, the amount of peptide administered is about 40 pg / eye as a once monthly dose. In some embodiments, the peptide (L4F) is administered as the salt (e.g., the acetateAttorney Docket No.: 87JA-403378-WOsalt). In some embodiments, the amount of peptide administered is about 120-240 pg / eye within a 6 month period, or not more than 240 pg / eye within a 6 month period.

[0115] In some embodiments, provided is a method for maintaining or restoring ellipsoid zone integrity in a human eye in need thereof, comprising administering to the eye an effective amount of a peptide of formula Ac-DWFKAFYDKVAEKFKEAF-NH2(L4F) (SEQ. ID. NO.: 13), or salt thereof; and an aqueous pharmaceutical ly acceptable carrier; wherein the amount of peptide administered is 20-40 pg / eye.

[0116] In some embodiments, provided is a method for maintaining or restoring ellipsoid zone integrity in a human eye in need thereof, comprising administering to the eye an effective amount of a peptide of formula Ac-DWFKAFYDKVAEKFKEAF-NH2(E4F) (SEQ. ID. NO.: 13), or salt thereof; and an aqueous pharmaceutical ly acceptable carrier; wherein the amount of peptide administered is 20 pg / eye or less.

[0117] In some embodiments, the amount of peptide administered is about 40 pg / eye as a once monthly dose. In some embodiments, the peptide (E4F) is administered as the salt (e.g., the acetate salt). In some embodiments, the amount of peptide administered is about 120-240 pg / eye within a 6 month period, or not more than 240 pg / eye within a 6 month period.

[0118] In some embodiments, provided is a method for preventing geographic atrophy in a human eye, comprising administering to the eye an effective amount of a peptide of formula Ac-DWFKAFYDKVAEKFKEAF-NH2(E4F) (SEQ. ID. NO.: 13), or salt thereof; and an aqueous pharmaceutically acceptable carrier; wherein the amount of peptide administered is 20-40 pg / eye.

[0119] In some embodiments, prior to administering, the human eye contains at least one druse greater than about 63 pm in at least one dimension.

[0120] In some embodiments, provided is a method for preventing geographic atrophy in a human eye, wherein the human eye comprises at least one druse greater than about 63 pm in at least one dimension, comprising administering to the eye an effective amount of a peptide of formula Ac-DWFKAFYDKVAEKFKEAF-NH2(L4F) (SEQ. ID. NO.: 13), or salt thereof; and an aqueous pharmaceutically acceptable carrier; wherein the amount of peptide administered is 20-40 pg / eye.

[0121] In some embodiments, provided is a method for preventing geographic atrophy in a human eye, wherein the human eye comprises at least one druse greater than about 63 pm in at least one dimension, comprising administering to the eye an effective amount of a peptide of formula Ac-DWFKAFYDKVAEKFKEAF-NH2(L4F) (SEQ. ID. NO.: 13), or salt thereof; and an aqueous pharmaceutically acceptable carrier; wherein the amount of peptide administered is 20 pg / eye or less.Attorney Docket No.: 87JA-403378-WO

[0122] In some embodiments, the amount of peptide administered is about 40 pg / eye as a once monthly dose. In some embodiments, the peptide (L4F) is administered as the salt (e.g., the acetate salt). In some embodiments, the amount of peptide administered is about 120-240 pg / eye within a 6 month period, or not more than 240 pg / eye within a 6 month period.

[0123] In some embodiments, provided is a method for restoring or improving vision in a human padent, wherein the patient exhibits a loss of vision associated with age-related macular degeneration (AMD) having, comprising administering to the eye of a patient in need thereof, an effective amount of a peptide of formula Ac-DWFKAFYDKVAEKFKEAF-NH2(L4F) (SEQ. ID. NO.: 13), or salt thereof; and an aqueous pharmaceutically acceptable carrier; wherein the amount of peptide administered is 20-40 pg / eye.

[0124] In some embodiments, provided is a method for restoring or improving vision in a human patient, wherein the patient exhibits a loss of vision associated with age-related macular degeneration (AMD) having, comprising administering to the eye of a patient in need thereof, an effective amount of a peptide of formula Ac-DWFKAFYDKVAEKFKEAF-NH2(L4F) (SEQ. ID. NO.: 13), or salt thereof; and an aqueous pharmaceutically acceptable carrier; wherein the amount of peptide administered is 20 pg / eye or less.

[0125] In some embodiments, the amount of peptide administered is about 40 pg / eye as a once monthly dose. In some embodiments, the peptide (L4F) is administered as the salt (e.g., the acetate salt). In some embodiments, the amount of peptide administered is about 120-240 pg / eye within a 6 month period, or not more than 240 pg / eye within a 6 month period.

[0126] In some embodiments, the amount of peptide administered is between about 10 and 40 pg / eye.

[0127] In some embodiments, the amount of peptide administered is between about 20 and 40 pg / eye.

[0128] In some embodiments, the amount of peptide administered is between about 1 and 20 pg / eye.

[0129] In some embodiments, the method comprises administering the formulation via intraocular injection.

[0130] In some embodiments, the method comprises administering the formulation via intravitreal injection.

[0131] In some embodiments, the peptide is administered once every 4 weeks.Attorney Docket No.: 87JA-403378-WOAdministration and Dosing Regimen

[0132] The formulations described herein are generally intended for intraocular administration. In some embodiments, the methods described herein comprise administering the formulation via intraocular injection.

[0133] 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.

[0134] 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, padent’s and the ophthalmologist’s preference, other regions could also be used.

[0135] 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.

[0136] 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.

[0137] 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.

[0138] 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-iodineAttorney Docket No.: 87JA-403378-WOsolution 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.

[0139] The injection site is measured and marked with a measuring caliper or other devices. The padent 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.

[0140] 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.

[0141] 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) .

[0142] 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.Attorney Docket No.: 87JA-403378-WO

[0143] 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).

[0144] 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).

[0145] 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 resoludon 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).

[0146] 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 dominantAttorney Docket No.: 87JA-403378-WOdrusen), 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 vitreoreti nochoroidopathy, 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), 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.

[0147] 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 inAttorney Docket No.: 87JA-403378-WOreading 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).

[0148] 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; decreased 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.Attorney Docket No.: 87JA-403378-WO

[0149] 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 scintillans (cholesterolosis bulbi), neuronal ceroid lipofuscinosis, Batten’s Disease, retinitis pigmentosa, and Bietti’s crystalline dystrophy.

[0150] In some embodiments, the treatment period is 1-30 days, 4-52 weeks, 1-12 months, or 1-5 years.

[0151] In some embodiments, the peptide is administered once every 4 weeks. In some embodiments, the treatment period is 4 weeks, 8 weeks, 12 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 weeks, or 52 weeks, or more.

[0152] The methods provided herein can comprise administering the peptide to the patient 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

[0153] In each of the following examples and associated figures, Ac-DWFKAFYDKVAEKFKEAF-NH2 acetate salt (L4F-a) was used. However, amounts of peptide (e.g., 40 ug, 20 ug, 10 ug) refer to the amount L4F peptide alone, not including the acetate counterion.Attorney Docket No.: 87JA-403378-WOExample 1

[0154] A sterile solution of L4F peptide formulated for intravitreal (IVT) administration at concentrations of up to 1.2 mg / mL was prepared. Subjects received an IVT injection in their study eye every 4 weeks (at 20 pg / eye or 10 pg / eye) during the treatment period. Drusen size and ellipsoid zone (EZ) area were assessed.

[0155] Drusen Volume Measurements: The open-source EyeSeg Python package (Morelle et al., 2023) was employed to segment the outer retinal layers and quantify drusen in OCT volumes. This software extends the convolutional neural network (CNN)-based drusen segmentation approach described by Schulz and colleagues, wherein the neural network directly predicts one-pixel-thick layers (e.g., Bruch’s membrane (BM), retinal pigment epithelium (RPE), and the ellipsoid zone (EZ)) while enforcing correct anatomical ordering. By integrating sub-pixel accuracy for layer boundaries, this approach obviates the need for post-processing with shortest-path algorithms and ensures robust delineation of RPE elevations. Drusen were then computed based on the separation (height difference) between the RPE and BM layers, using EyeSeg’ s default threshold of 2 pixels to exclude small artifacts. All volumes in the study were processed at baseline and at the specified follow-up time point (e.g., 20 weeks), and drusen burden was summarized as total area or volume within the macular region of interest.

[0156] Drusen volume in the untreated fellow eye did not change from baseline through 12 week follow-up. The treatment eye showed a trend toward reduced drusen volume over this same time period (FIG. 1, FIG. 2, FIG. 3, and FIG. 4).

[0157] Ellipsoid zone (EZ) intensity was measured for each a-scan, where the EZ line intensity ranged from 0 to 256 on a grayscale level. If the EZ layer was absent, the EZ intensity was labeled as 0, while maximum brightness (white) was labeled as 256. The EZ intensity value was then averaged for each a-scan across the zone of interest (panmacular, central subfield, central macula). To account for image quality variability, the EZ intensity index (or normalized EZ intensity) was calculated as the [(EZ intensity) x (EZ intensity / RPE intensity)], which standardized the EZ intensity value relative to the RPE layer brightness. For detailed methods, see e.g., Yordi, S.; et al., Ellipsoid Zone Integrity and Visual Function in Dry Age-Related Macular Degeneration, J. Pers. Med. 2024, 14, 543.

[0158] FIG. 1 and FIG. 2 show recovery of EZ area over the treatment period.Example 2

[0159] 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 peptide formulated in DPBS. TheAttorney Docket No.: 87JA-403378-WOhighest 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 at higher concentrations.Example 3

[0160] A 52 week human clinical study was conducted to investigate the safety and efficacy of L4F in patients with geographic atrophy of any size and vision of 20 / 100 or worse. Patients were administered 10 pg / eye, 20 pg / eye, or 40 pg / eye via intravitreal injection of L4F peptide formulated in DPBS once every 4 weeks.2Phakic: have a natural lens, and therefore have potential for cataract formation.3Number of doses administered in an eye with a natural lens. Includes all doses up to and including a dose which resulted in a cataract. Excludes doses after cataract formation.

[0161] As shown in FIG. 5A and FIG. 5B, administering L4F in humans in an amount provided herein is effective in inhibiting GA growth rate with minimal impact on cataract rate in human patients.* * *

[0162] 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 theAttorney Docket No.: 87JA-403378-WOdisclosure. 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.

[0163] 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-403378-WOWhat is claimed is:

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

2. The method of claim 1, wherein the amount of peptide administered is 20-40 pg / eye.

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

4. The method of any one of claims 1-3, wherein the drusen are associated with dry age-related macular degeneration (dry AMD).

5. The method of claim 4, wherein the AMD is intermediate AMD.

6. The method of any one of clams 1-5, wherein at least one druse is greater than about 63 pm in at least one dimension.

7. The method of claim 1 , wherein the method comprises attenuation or reduction in loss of photoreceptors or attenuation or reduction in ellipsoid zone integrity.

8. The method of claim 1, wherein the method comprises restoration or regeneration of photoreceptors or attenuation or reduction in ellipsoid zone integrity.

9. A method for maintaining or restoring ellipsoid zone area in a human eye in need thereof, comprising administering to the eye an effective amount of a pharmaceutical formulation comprising an effective amount of an apolipoprotein A-I mimetic peptide, or salt thereof; and an aqueous pharmaceutically acceptable carrier.

10. A method of preventing geographic atrophy in a human eye, wherein the human eye comprises at least one druse greater than about 63 pm in at least one dimension, comprising administering to the eye an effective amount of a pharmaceutical formulation comprising an effective amount of an apolipoprotein A-I mimetic peptide, or salt thereof; and an aqueous pharmaceutically acceptable carrier.Attorney Docket No.: 87JA-403378-WO11. A method for slowing or halting geographic atrophy in a human eye in need thereof, comprising administering to the eye an effective amount of a pharmaceutical formulation comprising an effective amount of an apolipoprotein A-I mimetic peptide, or salt thereof; and an aqueous pharmaceutically acceptable carrier; wherein the amount of peptide is in a range sufficient to reduce or substantially eliminate the occurrence and / or severity of lens opacity.

12. The method of any one of claims 9-11, wherein the eye comprises at least one druse.

13. The method of any one of claims 9-11, wherein the eye comprises at least one druse greater than about 63 pm in at least one dimension.

14. The method of any one of claims 9-11, wherein no drusen are present in the eye.

15. The method of any one of claims 9-11, wherein the amount of peptide administered is 20-40 pg / eye.

16. The method of any one of clams 1-15, wherein the apolipoprotein A-I mimetic peptide is a peptide of formula Ac-DWFKAFYDKVAEKFKEAF-NH2(L4F) (SEQ. ID. NO.: 13) or a salt thereof.

17. A method for inhibiting formation or growth of drusen, and / or reducing number and / or size of one or more druse, in a human eye in need thereof, comprising administering to the eye an effective amount of a peptide of formula Ac-DWFKAFYDKVAEKFKEAF-NFE (L4F) (SEQ. ID. NO.: 13), or salt thereof; and an aqueous pharmaceutically acceptable carrier; wherein the amount of peptide administered is 20-40 pg / eye.

18. A method for maintaining or restoring ellipsoid zone integrity in a human eye in need thereof, comprising administering to the eye an effective amount of a peptide of formula Ac-DWFKAFYDKVAEKFKEAF-NH2 (L4F) (SEQ. ID. NO.: 13), or salt thereof; and an aqueous pharmaceutically acceptable carrier; wherein the amount of peptide administered is 20-40 pg / eye.

19. The method of claim 17 or 18, wherein prior to administering, the human eye contains at least one druse greater than about 63 pm in at least one dimension.

20. A method of preventing geographic atrophy in a human eye, wherein the human eye comprises at least one druse greater than about 63 pm in at least one dimension, comprising administering to the eye an effective amount of a peptide of formula Ac-DWFKAFYDKVAEKFKEAF-NH2 (L4F) (SEQ. ID. NO.: 13), or salt thereof; and an aqueous pharmaceutically acceptable carrier; wherein the amount of peptide administered is 20-40 pg / eye.Attorney Docket No.: 87JA-403378-WO21. The method of any preceding claim, wherein the amount of peptide administered is 40 pg / eye.

22. The method of any preceding claim, wherein the apolipoprotein A-I mimetic peptide is a peptide of formula Ac-DWFKAFYDKVAEKFKEAF-NH2 (L4F) (SEQ. ID. NO.: 13) and is administered as the acetate salt.

23. The method of any preceding claim, wherein the method comprises administering the formulation via intraocular injection.

24. The method of any preceding claim, wherein the method comprises administering the formulation via intravitreal injection.

25. The method of any preceding claim, wherein the peptide is administered once every 4 weeks.

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