JP2020514407A - Treatment of age-related macular degeneration and other eye diseases using apolipoprotein mimetics - Google Patents

Abstract

The present disclosure provides apolipoprotein (apo) mimetics useful in the treatment of age-related macular degeneration (AMD) and other eye diseases. An apomimetic can be, for example, a peptide/polypeptide that mimics the lipid-scavenging effect of apolipoproteins (eg, Apo AI and Apo E). Apomimetics may also exhibit other beneficial effects (eg, inflammation, reduced oxidative stress and neovascularization). Using apomimetics, AMD at any stage (including early, metaphase, and advanced stages) and any phenotype of AMD (geographic atrophy (GA) (eg, non-central GA and central GA)) or new Angiogenesis (NV) (including NVs of types 1, 2, and 3) can be treated. Apomimetics used alone or in combination with other therapeutic agents (eg, complement inhibitors and/or anti-angiogenic agents) to affect AMD (eg, dry AMD and neovascular AMD) and other eye disorders Can also be treated. [Selection diagram] Figure 1

Description

BACKGROUND OF THE DISCLOSURE In the world, about 14-24% of people between the ages of 65 and 74 and about 35% of people over the age of 75 suffer from age-related macular degeneration (AMD) resulting in retinal damage. Causes vision loss or loss of vision in the center of the field of vision (the macula). AMD is a leading cause of vision loss and potentially blindness in people over the age of 50. The two major types of AMD are dry (non-exudative or "dry") AMD and neovascular (exudative or "wet") AMD. Atrophic AMD is characterized by geographic atrophy (GA) in the macular center of advanced-stage AMD, and when vision declines slowly over the years due to loss of photoreceptor cells and development of GA. There is also. Neovascular AMD is a more severe form of AMD and is characterized by neovascularization (eg, choroidal neovascularization) in advanced AMD and may lead to rapid blindness. Neovascular AMD affects over 30 million patients worldwide and is the leading cause of visual loss in people over the age of 60. Without treatment, patients are likely to lose central vision within 24 months of disease onset. About 90% of AMD patients are dry, and about 10% develop neovascular AMD. While there are no approved treatments for dry AMD in the United States, approved therapeutic agents for neovascular AMD (mainly anti-angiogenic agents) show efficacy in about 50% of neovascular AMD patients.

  The present disclosure provides apolipoprotein (apo) mimetics for the treatment of AMD and other eye diseases and disorders.

  In some embodiments, the Apo AI and / or Apo E mimetics are administered to treat AMD or other eye disease. In certain embodiments, the Apo AI mimic comprises or is L-4F or D-4F. In some embodiments, the ApoE mimetic comprises or is AEM-28-14. One or more other therapeutic agents can be administered in combination with the apomimetic to treat AMD or another eye disease. The one or more other therapeutic agents can be selected to target various underlying factors of AMD or other eye diseases. Apomimetics are optionally administered in combination with other therapeutic agents to, for example, AMD at different stages of AMD (including early, middle and advanced stages) and different phenotypes of AMD (geographic atrophy and neoplasia). Vascular AMD) can be treated and the progression of AMD to the next stage can be prevented or delayed.

In addition to apolipoprotein mimetics, other therapeutic agents that can be used to treat AMD and eye diseases and disorders include, but are not limited to:
1) antihyperlipidemic drug;
2) PPAR-α agonists, PPAR-δ agonists and PPAR-γ agonists;
3) anti-amyloid drug;
4) inhibitors of lipofuscin or its components;
5) visual / light cycle regulators and dark adaptation agents;
6) antioxidants;
7) Neuroprotective agents (neuroprotective agents);
8) apoptosis inhibitors and necrosis inhibitors;
9) C-reactive protein inhibitors;
10) inhibitors of the complement system or its components (eg proteins);
11) Inflammasome inhibitors;
12) anti-inflammatory agent;
13) immunosuppressants;
14) a matrix metalloproteinase modulator; and 15) an anti-angiogenic drug,
Is included.

  Other eye diseases and disorders treatable with AMD, in addition to apolipoprotein mimetics, and optionally, in combination with one or more other therapeutic agents include, but are not limited to, macula (Eg, age-related macular disease and diabetic macular disease), macular edema (eg, diabetic macular edema [DME] and macular edema after retinal vein occlusion [RVO]), retinopathy (eg, diabetic retinopathy [DME] Including in patients]), RVO (eg, central and branched RVO), Cotes' disease (exudative retinitis), uveitis, retinal pigment epithelial detachment, and intracellular or extracellular lipids in addition to AMD Diseases associated with increased storage or accumulation are included.

A better understanding of the features and advantages of the present disclosure may be gained by reference to the following detailed description (which describes exemplary embodiments of the present disclosure) and the accompanying drawings.
Figure 1 illustrates the role of lipid accumulation in the tissue layers involved in AMD pathology and AMD pathogenesis. OS: outer segment of photoreceptors; RPE: retinal pigment epithelium; RPE-BL: RPE basal lamina; ICL: inner collagenous layer EL: elastic layer; OCL: outer collagenous layer; ChC-BL: ChC basal lamina; ChC: choriocapillaris endothelium; BLamD: basement membrane deposition. BLinD: basal linear deposit; pre-BLinD: pre-basal linear deposit; L: lipofuscin; M: melanosome; ML: melano Lipofuscin; Mt: mitochondria; circles: lipoprotein particles. The Bruch's membrane (BrM) consists of ICL, EL and OCL. BlamD is a thickened version of RPE-BL. Basement membrane ridge is a soft drusen material within BLamD. RPE cells contain melanosomes, lipofuscin and melanolipofustin, which provide signals for, for example, fundus color photography, fundus autofluorescence and optical coherence tomography. FIG. 2 shows intra-Bruch's membrane and Bruch's membrane in the eye of the macaque injected with L-4F or placebo (scrambled L-4F) 6 times a month into the vitreous once a month and in the other non-injected eye. The neutral lipids above are stained with Oil Red O (ORO) and scored. Statistical analysis: 1) Paired t-test between the injecting and non-injecting eyes in the same group; 2) the injecting eye in the treatment (L-4F) and control (placebo) groups. There is no t-test between the two. Figure 3 shows the ester form in Bruch's membrane in the eye of the macaque injected with L-4F or placebo (scrambled L-4F) 6 times in the vitreous once a month and in the other non-injected eye. The intensity of cholesterol dyed in the Philippines is shown. Statistical analysis: 1) Paired t-test between the injecting and non-injecting eyes in the same group; 2) the injecting eye in the treatment (L-4F) and control (placebo) groups. There is no t-test between the two. Figure 4 shows Bruch's membrane and choriocapillaris in the eye of the macaque injected with L-4F or placebo (scrambled L-4F) 6 times intravitreally once a month and in the other non-injected eye. The staining intensity of the inner membrane attack complex (MAC, C5b-9) is shown. Statistical analysis: 1) Paired t-test between the injecting and non-injecting eyes in the same group; 2) the injecting eye in the treatment (L-4F) and control (placebo) groups. There is no t-test between the two. FIG. 5: Staining of complement factor D in the eyes of the macaques injected with L-4F or placebo (scrambled L-4F) 6 times intravitreally once a month and in the other non-injected eye. Shows strength. Statistical analysis: 1) Paired t-test between the injecting and non-injecting eyes in the same group; 2) the injecting eye in the treatment (L-4F) and control (placebo) groups. There is no t-test between the two. FIG. 6 shows the lateral temporal macula measured in the eye of the macaque injected with L-4F or placebo (scrambled L-4F) 6 times intravitreally once a month and in the other non-injected eye. 3 shows the thickness of the Bruch's film that has been formed. Statistical analysis: 1) Paired t-test between the injecting and non-injecting eyes in the same group; 2) the injecting eye in the treatment (L-4F) and control (placebo) groups. There is no t-test between the two.

DETAILED DESCRIPTION OF THE DISCLOSURE While various embodiments of the present disclosure are described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Many modifications and variations to the embodiments described herein, and variations and replacements thereof, will be apparent to those skilled in the art without departing from the disclosure. It is understood that in practicing the present disclosure, various alternatives to the embodiments described herein can be employed. It is also understood that all embodiments of the present disclosure are optional, but can be combined with any one or more other embodiments described herein that are consistent with the embodiments. It

  When elements are presented in list form (eg Markush groups), each possible subgroup of those elements is also disclosed, and any one or more elements can be deleted from the list or group. Is also understood.

  Also, unless stated otherwise, in any method described or claimed herein that includes more than one act, the order of the acts of the method is such that the acts of the method are described. While not necessarily limited to order, it is understood that this disclosure includes embodiments in which the order is so limited.

  Further, in general, when referring to embodiments or claims herein that include one or more features, the disclosure may consist of, or consist essentially of, such feature (s). It is understood that it also includes the embodiments included in.

  Also, any embodiment of the present disclosure, such as that found in the prior art, whether or not stated to be specifically excluded herein is claimed. It is also understood that the terms can be explicitly excluded.

  Further, the present disclosure provides, where appropriate, analogs, derivatives, prodrugs, fragments, salts, solvates, hydrates, clathrates and polymorphs of all compounds / substances disclosed herein. It is understood to include features. With respect to compounds / substances or compounds / substances in certain examples of the present disclosure, "analog", "derivative", "prodrug", "fragment", "salt", "solvate", "hydrate" , "Inclusion bodies" and "polymorphs" refer to these forms in other examples of this disclosure where the compound / substance or compound / substances are mentioned without mentioning any of these forms. It is not expected to be interpreted as the intentional omission of anything.

  Titles are included herein for reference and to help locate particular chapters. The headings are not intended to limit the scope of the embodiments or concepts described in the headinged chapters, as those embodiments and concepts are applicable to other chapters throughout this disclosure. There are cases.

  All patent documents and all non-patent documents cited herein are specifically and individually indicated to be fully incorporated by reference into each patent document or non-patent document. To the same extent, it is fully incorporated herein by reference.

I. DEFINITIONS The indefinite articles "a" and "an" and the definite article "the" used in the specification and the appended claims refer to the singular as well as plural unless otherwise stated. It may also include references to things.

  The term "exemplary" as used herein means "serving as an example, illustration, or illustration." Any embodiment characterized herein as "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments.

  The term "about" or "generally" means an acceptable error in a particular value, as determined by one of ordinary skill in the art, depending in part on how that value is measured or determined. In certain embodiments, the term “about” or “approximately” means within standard deviation. In some embodiments, the term “about” or “approximately” refers to the stated value if no particular error range (eg, standard deviation from the mean value depicted in the data chart or table) is stated. And a range included by moving the written value up or down in consideration of the significant figures. In certain embodiments, the term "about" or "generally" means within 20%, 15%, 10%, or 5% of the stated value. Whenever the term "about" or "approximately" precedes two or more consecutive numerical values or the first numerical value of two or more consecutive numerical ranges, the term "about" or "generally" means that consecutive numerical value or It applies to each number in a continuous range of numbers.

  Whenever the term "at least" or "greater than" precedes the first number in two or more consecutive numbers, the term "at least" or "greater than" means one of the numbers in the consecutive numbers. Applied to one.

  Whenever the term "less than" or "less than" precedes the first number in two or more consecutive numbers, the term "less than" or "less than" is one of the numbers in the consecutive numbers. It applies to one.

  The term "antioxidant" includes, but is not limited to, substances that inhibit the oxidation of other substances, substances that delay the deterioration of other substances by oxidation, as well as free radical species, reactive oxygen species, hydroxy radical species, and It contains scavengers of oxidized lipids and lipid peroxidation products.

  The term "apolipoprotein mimetic" includes apolipoprotein peptidomimetics and apolipoprotein mimetic peptides.

The term "conservative substitution" means the replacement of an amino acid of a polypeptide with a functionally, structurally or chemically similar natural or unnatural amino acid. In certain embodiments, the following groups each include natural amino acids that are conservative substitutions for each other:
1) glycine (G), alanine (A);
2) Aspartic acid (D), glutamic acid (E);
3) Asparagine (N), Glutamine (Q);
4) Arginine (R), Lysine (K);
5) isoleucine (I), leucine (L), methionine (M), valine (V), alanine (A);
6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W); and 7) Serine (S), Threonine (T), Cysteine (C).

In other embodiments, the amino acids may be grouped as described below:
1) Hydrophobicity: Met (M), Ala (A), Val (V), Leu (L), Ile (I), Phe (F), Trp (W);
2) Neutral hydrophilicity: Cys (C), Ser (S), Thr (T), Asn (N), Gln (Q);
3) Acidic: Asp (D), Glu (E);
4) Basicity: His (H), Lys (K), Arg (R);
5) Residues affecting the orientation of the main chain: Gly (G), Pro (P); and 6) Aromatic: Trp (W), Tyr (Y), Phe (F), His (H).

In a further embodiment, the following groups each contain natural amino acids that are conservative substitutions for each other:
1) Acidic: Asp, Glu;
2) Basic: Lys, Arg, His;
3) Uncharged polarity: Gly, Ser, Thr, Cys, Tyr, Asn, Gln;
4) Contains aliphatic hydroxyl or sulfhydryl: Ser, Thr, Cys;
5) Amide-containing: Asn, Gln;
6) Nonpolar: Ala, Val, Leu, Ile, Met, Pro, Phe, Trp;
7) Hydrophobicity: Val, Leu, Ile, Phe;
8) Aliphatic: Ala, Val, Leu, Ile;
9) Aromatic: Phe, Trp, Tyr, His; and 10) Small: Gly, Ala, Ser, Cys.

  The term “pharmaceutically acceptable” means a substance (eg, an active ingredient or excipient) suitable for use in contact with a subject's tissues or organs without undue inflammation, allergic reactions, immunogenicity and toxicity. (Form), which has an appropriately balanced benefit / risk ratio and is effective for the intended purpose. A "pharmaceutically acceptable" carrier or excipient of a pharmaceutical composition is also compatible with the other ingredients of the composition.

  The term “therapeutically effective amount”, when administered to a subject, prevents the onset of, reduces the risk of developing, delays the onset of, or delays the onset of, a medical condition during treatment (eg, age-related macular degeneration [AMD]). Refers to the amount of a substance sufficient to slow the progression or, to some extent, alleviate one or more symptoms or complications of the condition. The term "therapeutically effective amount" also refers to a substance sufficient to elicit a biological or medical response in a cell, tissue, organ, system, animal or human as identified by a researcher, veterinarian, doctor or clinician. Say the amount.

  The terms “treat”, “treating”, and “treatment” include alleviating or suppressing one or more symptoms or complications associated with a medical condition or symptoms thereof, and the condition Including alleviating or eradicating one or more causes of. Reference to "treatment" of a medical condition (eg, AMD) prevents (prevents) the onset, reduces the risk of the onset, and delays the onset of the condition or one or more symptoms or complications associated with the condition. , And delaying their progression.

  The term “subject” includes animals (eg, mammals (eg, primates (eg, human, chimpanzee, or monkey)), rodents (eg, rat, mouse, gerbil, or hamster), rabbits (eg, rabbit). ), Pig (eg, pig), horse (eg, horse), canine (eg, dog), and feline (eg, cat))). The terms “subject” and “patient” are used interchangeably herein and refer to, for example, a mammalian subject (eg, a human subject).

II. Pathogenesis and Pathophysiology of AMD Age-related changes in the retina and choroid of the eye that contribute to the development of age-related macular degeneration (AMD) include rod photoreceptor cell loss, choroid thickness reduction, and retinal pigment. Lipofuscin in the epithelium (RPE) and reportedly its components (eg A2E [N-retinylidene-N-retinyl-ethanolamine]) and RPE subbasement (sub-RPE-BL) space and Bruch's membrane (BrM; choroid). (Part of) and the accumulation of lipids in The lipoprotein particles and, reportedly, β-amyloid (Aβ) accumulate to form basement membrane-lined deposits (BLinD) on BrM. BLinD and drusen are believed to originate from the lipid wall formed on BrM. The lipid wall and the accumulation of abnormal deposits, in part due to abnormalities in the proteolytic processes that control BrM, stimulate choroidal inflammation. Abnormal aggregates of substances are associated with loss of normal extracellular matrix (ECM) maintenance function (partially mediated by a change in the ratio of matrix metalloproteinase [MMP] to tissue inhibitor of MMP [TIMP]). Combined, the resulting change in BrM results in the formation of BLinD and drusen. Drusen are extracellular deposits rich in lipids (eg, esterified cholesterol [EC] and phospholipids) and lipoprotein components (eg, apolipoprotein B [apo B] and / or apo E), RPE-BL and BrM. Formed in the RPE-BL subluminal space between the inner collagen layer and the inner collagen layer. Its formation is probably the result of RPE secretion into the basolateral part of the EC-rich very low density lipoprotein (VLDL). Ester-type cholesterol and phospholipids (in the form of lipoprotein particles with a diameter of 60-80 nm) accumulate in BrM throughout adulthood and eventually aggregate as BLinD on BrM or in the aged eye. Aggregates as soft drusen in the RPE-BL subluminal space. Soft drusen and BLinD are two types of identical lesions containing lipoprotein-derived debris (bulk and lamina, respectively). EC-rich apo B / apo E-containing lipoproteins secreted from RPE cells (eg, VLDL) are retained by BrM, which gradually thickens with age until an oil layer is formed on BrM. Oxidation of lipids and other modifications then occur, followed by fusion of individual lipoproteins over time to form BLinD. Due to inflammation and subsequent BrM changes followed by calcification and damage, accumulation of lipid-containing substances leads to neovascularization in the RPE-BL subspace and between photoreceptor cells and RPE. Invasion into the subretinal space, which is a potential space. Furthermore, lipid-rich drusen in BLinD located on the RPE-BL subluminal and BrM blocks nutrients (including vitamin A) from reaching photoreceptor cells (rods and cones) in the retina. , As a result, the cells are atrophied / degenerated and eventually die. Other extracellular lesions associated with AMD include subretinal drusenoid deposits (SDD). It differs in composition from drusen, contains non-esterified (free) cholesterol (UC) and is formed between RPE and photoreceptor cells. Its formation is probably the result of the apical secretion of UC-rich lipoproteins by RPE. The formation of SDD within the subretinal space also leads to sequelae such as inflammation and neovascularization (eg type 2 or 3).

  FIG. 1 illustrates the role of lipid accumulation in the tissue layers involved in AMD pathology and AMD pathogenesis. BrM consists of three layers: an inner collagen layer (ICL), an elastic layer (EL) and an outer collagen layer (OCL). In the healthy eye, the RPE basement membrane (RPE-BL) attaches to the BrM ICL and there is no space between the RPE-BL and ICL (RPE-BL subluminal space is the "potential" space). Throughout adulthood, RPE cells secrete basolateral lipoprotein particles (circle in FIG. 1), which are dispersed inside the BrM ICL and OCL (leftmost panel in FIG. 1). The more secreted and accumulated the lipoprotein particles over the years, the more they form pre-BLinD on BrM densely packed ICLs (second panel from the left in FIG. 1). When more lipoprotein particles are secreted and accumulated over the years, aggregation of lipoprotein particles occurs, forming BLinD (layer) and soft drusen (lump) on the ICL of BrM (2 in the middle of FIG. 1). Two panels). The formation of pre-BLinD creates a space between the RPE-BL and the ICL of BrM (RPE-BL subluminal space) which grows with the formation of BLinD and soft drusen and as the amount of these deposits increases. growing. Accumulation of lipid deposits, BLinD, and soft drusen raises RPE from BrM ICL (second panel from right in FIG. 1). If the increase (infra-RPE-BL space) is large enough, RPE-BL may be detached from the BrM ICL. For example, drusenoid pigment epithelial detachment (PED) may occur as a result of the formation of soft drusen with a diameter of about 350 microns or greater. As the drusen grow over time, the RPE cells are gradually displaced from the nutrient and oxygen sources within the choriocapillaris. Some of the RPE cells on top of the drusen migrate anteriorly to the neurosensory retina seeking the retinal vasculature, and as the RPE cells die, the RPE layer is destroyed, resulting in atrophy of the RPE layer. Furthermore, the lipid barrier created by BLinD and soft drusen blocks the exchange of influent nutrients (including vitamin A) and effluent waste between the choriocapillaris and RPE cells. This leads to atrophy of the RPE cells, which then die. RPE cell atrophy and death also results in atrophy and death of photoreceptor cells because the RPE cells can no longer shuttle nutrients to and from the photoreceptor cells. Also, BLinD on BrM and soft drusen in the RPE-BL subluminal space are good sources of lipids, which are oxidized to obtain high anti-inflammatory properties and, as a result, promote angiogenesis. To form oxidized lipids (eg, oxidized phospholipids). The biomechanically fragile dehiscence surface created by BLinD and soft drusen emanates from the choroid and across BrM in type 1 neovascularization (NV), and the RPE-BL subspace, as described below. In type 2 NV, it is vulnerable to attack by the branching of new blood vessels penetrating into the subretinal space. Leakage of fluid from the neovessels into the RPE-BL subcavities in type 1 and 2 NV further contributes to the RPE-BL subcavity volume and RPE elevation from BrM. This may cause PED.

  Chronic inflammatory responses to the changes described above include complement-mediated pathways, invasion of 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 final pathway, which cleaves component 5 (C5) to C5a and C5b. The final pathway results in stepwise binding of C5b, C6, C7, C8 and polymerized C9 to form pores within the lipid bilayer of the membrane, such as RPE basement membrane, BrM or choriocapillaris endothelium. Assembly of the membrane attack complex (MAC) occurs within the cell membrane. MAC leads to dysfunction and death of RPE, BrM and / or choriocapillaris, and lateral retinal atrophy may also result. Furthermore, C5a elicits a pro-angiogenic effect, but may contribute to NV (including choroidal NV (CNV)) when combined with BrM calcification and damage.

  Early AMD (atrophic AMD) is characterized by the presence of a small number of medium-sized drusen and hyperpigmentation (eg, hyperpigmentation or hypopigmentation of RPE). Mid-stage AMD (atrophic AMD) is at least one large drusen, myriad of medium-sized drusen, hyperpigmented or hypopigmented RPE, and geographic atrophy that does not extend to the center of the macula (GA) (non-central [ Or near the center] GA). GA shows a lack of continuous pigment layer and at least some partial killing of RPE cells. The non-central GA avoids the fovea, thus preserving central vision. However, patients with non-central GA experience visual impairments, such as paracentral scotoma (impaired vision in dim light, reduced contrast sensitivity, and impaired reading). There is also. RPE-BL lower drusen elevates RPE from BrM, thereby including metamorphopsia (blindness in which objects appear distorted) through impairment of overlying photoreceptor cells and delay of rod-mediated dark adaptation. May cause mild loss of vision.

  Advanced (late) AMD, in which dry AMD remains, is characterized by the presence of drusen and GA extending to the center of the macula (central GA). Central GA contains macular atrophy. The central GA affects the fovea, thus resulting in significant loss of central vision and visual acuity. The subretinal RPE atrophies, causing vision loss through the death of photoreceptor cells. When the drusen become thicker and the RPE far away from the choriocapillaris, RPE atrophy occurs due to the increased accumulation of drusen and / or BLinD that contribute to the killing of the RPE located above it. Drusen may contain calcification in the form of hydroxyapatite and may progress to complete calcification at the stage where the RPE cells die. RPE-BL thickens in a stereotypic manner and basement membrane deposits (BLamD) are formed; RPE cells therefore reside on the thickened layer of BLamD. Usually, the connection between hexagonal RPE cells may be disturbed. Also, individual RPE cells round, overlap, and migrate anteriorly to the neurosensory retina. There, RPE cells are kept away from the supply of nutrients and oxygen within the choriocapillaris. Once the RPE cells begin to move forward, the entire RPE layer begins to atrophy.

  Advanced AMD, which becomes neovascular AMD, includes neovascularization and any of its potential sequelae (eg, (eg, plasma) leakage, plasma lipids and lipoprotein deposits, RPE-BL, subretinal and subretinal and). Retinal fluid, hemorrhage, fibrin, vascular connective tissue scarring and RPE detachment). In CNV, new blood vessels grow from the choriocapillaris and pass through BrM. This causes vision loss through the sequelae described above. There are three types of neovascularization (NV). Type 1 NV occurs in the RPE-BL subspace and new blood vessels emerge from the choroid below the macular region. Type 2 NV occurs in the subretinal space above the RPE, where new blood vessels originate from the choroid and penetrate into the subretinal space. In type 1 and type 2 NV, new blood vessels may cross BrM and branch within the proangiogenic dehiscence plane created by soft drusen and BLinD. Type 3 NV (retinal hemangioma growth) occurs predominantly in the retina (intraretinal) but can also occur in the subretinal space. The new blood vessels then emanate from the potentially anastomotic retina and extend into the choroidal circulation. Type 3 NV is the most difficult subtype of NV to diagnose, with the most serious consequences in terms of photoreceptor cell damage. However, type 3 NV responds well to treatment with anti-VEGF drugs. Neovascular AMD patients may also be a mix of NV subtypes, including, for example, type 1 + 2, type 1 + 3, and type 2 + 3. Among newly diagnosed neovascular AMD patients, the approximate incidence of various subtypes of NV is 40% in type 1, 9% in type 2, 34% in type 3, and 17% in mixed type ( The breakdown of the mixed type is 80% for type 1 + 2 type, 16% for type 1 + 3 type, and 4% for type 2 + 3 type). Another type of NV is polypoid vasculopathy, which originates in the choroid and is the most common type of NV in Asians, with generally few drusen in their eyes, It may have BLinD. The RPE may exfoliate from BrM in each subtype NV. For example, type 1 NV may cause pigment epithelium detachment when body fluid leaks from the neovascularization to the subinfrared space of RPE-BL. The new blood vessels created by NV are fragile, allowing fluid, blood, and proteins to leak under the macula. Leakage of blood into the subretinal space is particularly toxic to photoreceptor cells, and intraretinal fluid is a predictor of poor visual prognosis. Bleeding and leakage from new blood vessels, with subsequent fibrosis, can cause irreversible damage to the retina and can cause rapid loss of vision if left untreated.

  Modified lipids (including lipid peroxides) may have strong pro-inflammatory properties and thus may be pro-angiogenic. Therefore, lipid modification (including oxidation) may be an important step leading to the development of NV, including type 1 NV. For example, the modified lipids linoleic acid hydroperoxide and 7-ketocholesterol may be present in or on BrM and may stimulate NV. NV can also be considered a post-inflammatory wound healing process.

  Both eyes of AMD patients, whether dry or neovascular, are generally in a diseased state. However, it is also common for one of the eyes to be in a more diseased state than the other eye.

  See, for example, R. Jager et al., N. Engl. J. Med., 358: 2606-2617 (2008) for a description of AMD at various stages. The Age-Related Eye Disease Study (AREDS) study group has also developed a fundus photography severity scale for AMD. See, for example, M. Davis et al., Arch. Ophthalmol., 123: 1484-1498 (2005).

  Regarding the consideration of pathogenesis and pathophysiology of AMD, for example, CA Curcio et al., The oil spill in ageing Bruch membrane, Br. J. Ophthalmol., 95 (12): 1638-1645 (2011); JW Miller, Age. -Related Macular Degeneration Revisited-Piecing the Puzzle, Am. J. Ophthalmol., 155 (1): 1-35 (2013); R. Spaide et al., Choroidal neovascularization in age-related macular degeneration-what is the cause? , Retina, 23: 595-614 (2003); and S. Bressler et al., Age-Related Macular Degeneration: Non-neovascular Early AMD, Intermediate AMD, and Geographic Atrophy, in Retina, S. Ryan et al., Eds. ., pp. 1150-1182, Elsevier (London 2013).

III. Apolipoprotein Mimics As mentioned above, age-related macular degeneration (AMD) is a disease or disorder with a variety of underlying factors. The three major causes of AMD are the formation of hyperlipid deposits in the retina, subretinal space, RPE-BL subspace and BrM, inflammation and neovascularization. The formation of lipid-containing deposits is one of the primary factors contributing to sequelae (eg, chronic inflammation, non-central and / or central geographic atrophy of the retina (GA), neovascularization (including CNV) and eventual Loss of central vision or legal blindness). Lipid-capturing apolipoprotein mimetics with other beneficial properties such as anti-inflammatory properties, antioxidant properties and anti-angiogenic properties can be used to treat AMD and its complications.

  Apolipoprotein peptidomimetics can effectively reduce the accumulation of high lipid deposits in the eye. Apolipoprotein (apo) mimetics can regulate (eg, inhibit) lipoprotein (eg, VLDL) production and regulate intracellular uptake of plasma lipids (eg, cholesterol) and lipoproteins (eg, VLDL) (eg. Elimination of lipids (eg cholesterol and oxidized lipids (eg oxysterols)) and lipoproteins (eg VLDL) and its remnants (eg low density lipoprotein [LDL] and chylomicron remnants) or It can mediate capture and can also inhibit the formation of lipid-containing lesions. For example, apoE mimetics increase lipid (eg, cholesterol) excretion, mediate elimination of lipids (eg, cholesterol) and lipoproteins (eg, VLDL and chylomicrons), and reduce cholesterol and triglyceride levels. It reduces the formation of lipid-containing lesions and has antioxidant and anti-inflammatory properties. As another example, ApoA-I Mimics promote excretion of lipids (eg, cholesterol), reduce the formation of lipid-containing lesions (in the eye and intimal arteries), and have antioxidant properties. It exhibits anti-inflammatory properties. As a further example, apoA-V mimetics reduce VLDL-triglyceride (TG) production and stimulate lipoprotein lipase-mediated lipolysis of VLDL-TG. As another example, apo C-II mimics increase lipid (eg, cholesterol) excretion and activate lipoprotein lipase-mediated lipoprotein lipolysis. The beneficial effect of increased lipoprotein lipase-mediated lipoprotein lipolysis is, for example, that food-derived lipids (BrM, upstream of RPE-derived lipoproteins secreted into the RPE-BL sub- and subretinal space). Organizational availability (which may affect sources).

As an illustrative example, apo AI mimics (eg, those described herein (eg, L-4F and D-4F)) may also have accumulated extracellular and intracellular potential. Some ocular lipid deposits can be dissolved, rendered mobile, and removed. For example, L-4F and D-4F may be able to remove intracellular lipids via the LDL receptor by forming pre-βHDL particles. Lipid deposits on BrM form a lipid wall that acts as a diffusion barrier between the RPE and the choriocapillaris, promote the formation of basement membrane lined deposits (BLinD) and soft drusen, and local inflammation. And involved in oxidative stress. Apo AI mimics (eg, L-4F) can eliminate lipid deposits from BrM, thereby remodeling BrM structure to normal or more healthy state and restoring BrM function. . It includes decreased hydrodynamic resistance and increased exchange of metabolites and micronutrients between the choriocapillaris and the RPE, improving RPE health. Apo AI mimics (eg, L-4F) also eliminate lipids, lipoproteins and lipoprotein components via BrM into the choriocapillaris and systemic circulation, ultimately for their metabolism. It can be easily sent to the liver and excreted into the bile. Moreover, apo AI mimetics (eg, L-4F) may reduce local inflammation and oxidative stress by eliminating lipid deposits from, for example, BrM, BLinD and soft drusen. Furthermore, proinflammatory oxidized phospholipids (eg, Ox-PAPC (PAPC is L-α-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine), POVPC (1-palmitoyl-2- [5 -Oxovaleryl] -sn-glycero-3-phosphocholine), PGPC (1-palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine), and PEIPC (1-palmitoyl-2- [5,6-epoxyisoprostane E] ₂ ] -sn-glycero-3-phosphocholine)), for example by binding to a seed molecule necessary for the formation of apo AI mimics (eg L-4F) can prevent the oxidation of phospholipids. Apo AI mimics (eg, L-4F) also have a high affinity for pro-inflammatory oxidized lipids and mediate their clearance, thus conferring a high anti-inflammatory performance on the mimetic. Many of the AMD-related lipid deposits are extracellular and accessible to apoA-I mimics that remove lipids. Thus, apo AI mimics (eg, L-4F) can be used in AMD at any stage, including early to advanced AMD, and important upstream factors of AMD (lipid deposits (eg, on BrM). Accumulation of soft drusen) in the BLinD and RPE-BL subspace can be treated. And through removal of such deposits, AMD downstream factors (eg, local inflammation and oxidative stress) can be inhibited or reduced.

In some embodiments, the apolipoprotein mimetic comprises an amphipathic helical domain of apolipoprotein capable of binding / associating with lipids to remove / eliminate lipids. In certain embodiments, the lipid-binding amphipathic helical domain of apolipoprotein comprises
1) Amino acid (aa) about 209 to aa about 219 amino acid (aa) sequence of wild type (wt) human apo AI, aa about 220 to aa about 241 sequence, and aa about 209 to aa about 241 sequence;
2) wt human ApoA-II aa about 39 or 40 to aa about 50 sequence, aa about 51 to aa about 71 or 77 sequence, aa about 39 or 40 to aa about 71 sequence, and aa about 39 or 40. ~ Aa about 77 sequences;
3) wt human apoC-I aa about 7 to aa about 32 sequence, aa about 33 to aa about 53 sequence, and aa about 7 to aa about 53 sequence;
4) the sequence of aa about 43 to about aa 55 of wt human apo C-II;
5) the sequence of aa about 40 to about aa 67 of wt human apo C-III; and 6) the sequence of about aa 203 to aa 266 of wt human apo E.
In a further embodiment, apolipoprotein mimetics include polypeptides that include such lipid-binding amphipathic helical domains of apolipoprotein or variants thereof, including fusion proteins and chimeras.

Non-limiting examples of Apo AI mimics include 2F, 3F, 3F-1, 3F-2, 3F-14, 4F (eg L-4F and D-4F), 4F2, 5A, 5F, 6F, 7F, 18F, 37pA, 4F-P-4F, 4F-IHS-4F, ELK-2K2A2E (or ELK-2A2K2E), FAMP (Fukuoka apo AI mimetic peptide), FREL, KRES, apo J (113-122). ,
CGVLESFKASFLSALEEWTKKLQ-NH ₂ (monomer, dimer, trimer) (SEQ ID NO: 1),
DWLKAFYDKVAEKLKE (monomer, dimer, trimer) (SEQ ID NO: 2),
DWFKAFYDKVAEKFKE (monomer, dimer, trimer) (SEQ ID NO: 3),
DWFKAFYDKVAEKFKEAF (4F) (monomer, dimer, trimer) (SEQ ID NO: 4),
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 corresponding apo AI mimetics of one or more or all D amino acids (eg, D-4F of all D amino acids) and / or corresponding apo AI mimics in which the order of the amino acid sequences is reversed (eg, Rev-L-4F and Rev-D-4F).

Non-limiting examples of Apo E _{mimetic, Ac-hE18A-NH 2 (} AEM-28) ( dual-domain [apo E and apo A-I] _{mimetics), Ac- [R] hE18A-} NH 2, AEM- 28-14, mR18L, ATI-5261, COG-1410, Apo E (130-149) monomer and dimer (including N-acetylated dimer), and Apo E (141-155) monomer And dimers (including N-acetylated dimers). Examples of apo C-II mimetics include, but are not limited to, C-II-a.

The present disclosure includes the following apolipoprotein peptidomimetics:
1) an apomimetic in which all stereochemistry of amino acid residues is L-form;
2) an apomimetic in which one or more or all of the stereochemistry of amino acid residues is D-form;
3) an apomimetic in which the amino acid sequence is reversed and all stereochemistry of amino acid residues is L-form;
4) Apomimetics in which the order of amino acid sequences is reversed and one or more or all of the amino acid residues have the D-stereochemistry; and 5) multimers of apomimetics, including dimers and trimers. ), Wherein two or more units of the apomimetic are, for example, via a linker or spacer group containing one or more amino acid residues or a group having a plurality (eg, two, three or more) points of attachment, Those that are directly or indirectly linked to each other.

The apolipoprotein mimetics described herein may have N-terminal and / or C-terminal protecting groups. In some embodiments, Apo mimetic, have an N-terminal protecting group, it is unsubstituted or substituted C ₂ -C ₁₀ acyl group (e.g., acetyl, propionyl, butanoyl, pentanoyl or hexanoyl), non A substituted or substituted benzoyl group, a carbobenzoxy group, or one or two unsubstituted or substituted C ₁ -C ₂₀ or C ₂ -C ₂₀ alkyl groups (eg, one or two methyl, ethyl, propyl, butyl , Pentyl or hexyl group). Furthermore, Apo mimetics may have a functional group other than -CO ₂ H at the C-terminus, it is, for example, a is -C (O) NH ₂ or -C (O) ^NR 1 ^{R 2} amido group Wherein R ¹ and R ² are independently hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, or R ¹ and R ² and the nitrogen atom linked to them are heterocycles. Alternatively, it forms a heteroaryl ring. The C-terminal amide group may be regarded as a C-terminal protecting group. Accordingly, the present disclosure includes apomimetics that have both an N-terminal acetyl group and a C-terminal —C (O) NH ₂ group.

The disclosure also includes variants of the apolipoprotein mimetics described herein, wherein the apomimetic variants are additions / insertions, deletions, and / or substitutions of one or more amino acids. Can be included. In other words, the present disclosure provides for the addition or insertion of one or more natural and / or unnatural amino acids to one or more amino acid residues of any of the apomimetics described herein, Or a variant in which a plurality of amino acids are deleted, or one or more natural and / or unnatural amino acids are substituted (conservative and / or non-conservative substitution), or any combination thereof or all of them. It includes the variants that are carried out. The unnatural amino acid can have the same chemical structure as the corresponding natural amino acid, although the stereochemistry is D-form, or it can have a different chemical structure and the stereochemistry can be D-form or L-form. Unnatural amino acids can be utilized, for example, to promote α-helix formation and / or increase peptide stability (eg, to counter proteolysis). For example, D-4F is resistant to intestinal peptidases and is therefore suitable for oral use. Examples of unnatural amino acids include, but are not limited to, proline analogs (eg, CMePro), phenylalanine analogs [eg, Bip, Bip2EtMeO, Nal (1), Nal (2), 2FPhe, Tmp, Tic, CMePhe and CMe2FPhe], tyrosine analogues (eg Dmt and CMeTyr), glutamine analogues (eg citrulline [Cit]), lysine analogues (eg homolysine, ornithine [Orn] and CMeLys), arginine analogues (eg homoarginine). [Har]), C-α-disubstituted amino acids (eg, Aib, Ac4c, Ac5c, Ac6c and Deg), as well as other non-natural amino acids disclosed in US 2015/031630 and WO 2014/081872. One or more peptidomimetic moieties can also be used for additions / insertions and / or substitutions. The variant may have a protecting group at the N- and / or C-terminus, such as an acyl (eg, acetyl) group at the N-terminus and / or an amide group at the C-terminus [eg, —C (O) NH ₂ ]. . In some embodiments, the biological or pharmacological activity of the apomimetic variant is enhanced or is substantially similar to that of the apomimetic having the native amino acid sequence. (Eg, not reduced by more than about 10%, 20% or 30% relative to its activity). As a non-limiting example, the present disclosure has a variant of 4F designated 4F2 (sequence DWFKAFYDKV-Aib-EKFKE-Aib-F (SEQ ID NO: 11), wherein A ¹¹ and A ¹⁷ are α-. Substituted with aminoisobutyric acid (Aib)). In some embodiments, the structure of 4F2 is Ac-DWFKAFYDKV-Aib-EKFKE- Aib-F-NH 2 ( SEQ ID NO: 12), and is where all of the amino acid residues L-form (L-4F2) Or, one or more or all of the amino acid residues are in the D configuration.

  Variants of the apolipoprotein mimetics described herein include analogs and derivatives of apomimetics that have alternative modifications in addition to or in addition to amino acid additions / insertions, deletions and / or substitutions. Is also included. For example, variants of apomimetics include lipid-binding amphipathic helices of apolipoprotein or variants thereof (eg, 4F) linked directly or indirectly (eg, via a linker) to a heterologous peptide. Fusion proteins and chimeras containing domains are included. Heterologous peptides can impart advantageous properties such as increased half-life. For example, the heterologous peptide has an Fc region of an immunoglobulin (eg, IgG (eg, IgG1)) or, for example, one or more amino acid substitutions or mutations that change (eg, decrease) the action function of the Fc region. It may be a modified Fc region of immunoglobulin. By modifying the Fc region, for example, the ability to bind to the Fc receptor, activate the complement system, stimulate the attack by phagocytes, or interfere with the physiological metabolism and function of retinal cells, or any of them In some cases, all combinations or all of the capabilities may be attenuated. Inclusion of an Fc region in a fusion protein or chimera allows dimerization of the fusion protein or chimera (eg, via formation of an intermolecular disulfide bond between the two Fc regions), which fusion It may enhance the biological or pharmacological activity of the protein or chimera. The heterologous peptide that prolongs life is, for example, a carboxy-terminal peptide (CTP) derived from the β chain of human chorionic gonadotropin (eg, CTP-001, CTP-002 or CTP-003 disclosed in WO2014 / 159813). There are cases. As another example, the apo mimetic (eg, apo AI mimic (eg, L-4F) or apo E mimic (eg, AEM-28-14)) is N-terminal, C-terminal and / or A natural or synthetic polymer (eg, polyethylene glycol [PEG]) can be directly or indirectly (eg, via a linker) attached to one or more side chains. PEGylation of apomimetics (eg, using about 2-20 or 2-10 PEG units) increases protease resistance, stability and half-life, reduces aggregation, increases solubility, and apomimetics May enhance the activity of. As a further example, an apomimetic such as an Apo C-III mimetic that contains one or more sialic acid residues may be glycosylated (including a carbohydrate or sugar moiety). As a further example, the apomimetic can be phosphorylated. As another example, the apomimetic can complex with phospholipids (eg, DMPC [1,2-dimyristoyl-sn-glycero-3-phosphocholine] or POPC [1-palmitoyl-2- L-4F) complexed with oleoyl-sn-glycero-3-phosphocholine].

  In addition to, or as an alternative to, the use of an apolipoprotein mimetic, apolipoprotein (eg, apo E, apo AI, apo AV or apo C-II) is stimulated by stimulating its production. Agents that increase levels can be used. For example, an agent that increases the level of apoA-I (eg, 1,2-dimyristoyl-α-glycero-3-phosphocholine [DMPC]) may be used in addition to, or in addition to, the use of an apoA-I mimetic. Alternatively, it can be administered.

Apolipoprotein peptidomimetics or apolipoprotein mimetic peptides can be prepared according to procedures known to those of skill in the art. As a non-limiting example, apomimetics and their salts condense protected amino acids on a suitable resin support over time to remove the protecting group and remove the resin support by methods known in the art. It can be prepared by removing and purifying the product. Solid phase synthesis of peptides and their salts can be facilitated using, for example, microwaves and can be automated using commercially available peptide synthesizers. Solid phase synthesis of peptides and salts thereof is described, for example, in JM Palomo, RSC Adv., 4: 32658-32672 (2014); M. Amblard et al., Mol. Biotechnol., 33 (3): 239-254 (2006). ); And M. Stawikowski and GB Fields, Curr. Protoc. Protein Sci., Unit 18.1: Introduction to Peptide Synthesis (2012). A suitable protecting group for solid-phase synthesis of peptides and their salts are, for example, P. Wuts and T. Greene, Greene's Protective Groups in Organic Synthesis, 4 th Ed., Are described in John Wiley and Sons (New York 2006 ) . The purification method of the peptide and its salt is not limited, but includes crystallization, column (eg, silica gel) chromatography, high pressure liquid chromatography (including reverse phase HPLC), hydrophobic adsorption chromatography, silica gel adsorption chromatography, partition. Included are chromatography, supercritical fluid chromatography, countercurrent partition, ion exchange chromatography, and ion exchange using basic and acidic resins.

IV. Treatment of AMD Using Apolipoprotein Mimetics Some embodiments of the present disclosure are methods of treating age-related macular degeneration (AMD), wherein a therapeutically effective amount of apolipoprotein (Apopoprotein) is administered to a subject in need thereof. ) A method comprising the step of administering a mimetic. In some embodiments, the apomimetic is administered topically to the eye, intraocularly, in or around the eye, at a dose of about 0 per dose (eg, per injection). .1 or 0.3 mg to about 1.5 mg, or the total dose is about 0.5 or 1 mg to about 10 mg over a period of about 6 months.

  The apomimetic is used in a substantially pure form. In some embodiments, the purity of the apomimetic is at least about 90%, 95%, 96%, 97%, 98% or 99% (eg, at least about 95% or 98%). The apomimetic may be purified, that is it is substantially free of undesired chemical or biochemical components resulting from its preparation or isolation, which are unsuitable for use in pharmaceutical formulations, or The levels of such unwanted chemical or biochemical components may be low enough so that the use of the apomimetic in a pharmaceutical formulation is not hindered.

  Non-limiting examples of apolipoprotein mimetics, including Apo AI and Apo E mimetics, include those described elsewhere herein. In some embodiments, the apomimetic comprises or is an ApoE mimetic. In some embodiments, the ApoE mimetic comprises or is AEM-28-14 or a variant or salt thereof.

In a further embodiment, the apomimetic comprises or is an Apo AI mimic instead of or in addition to an Apo E mimetic (eg, AEM-28-14). In certain embodiments, the Apo AI mimetic comprises or is 4F or a variant or salt thereof (eg, acetate). In some embodiments, the stereochemistry of all amino acid residues at 4F is the L form (L-4F). In other embodiments, the stereochemistry of one or more or all amino acid residues of 4F is D (eg, D-4F is all D-amino acids). In yet another embodiment, the apomimetic has the amino acid sequence of 4F reversed in order (eg, Rev-L-4F or Rev-D-4F). The apomimetic may have a protecting group at the N- and / or C-terminus, such as an N-terminal acyl (eg, acetyl) group and / or a C-terminal amide group (eg, —C (O) NH ₂ ). it can. In some embodiments, Apo mimics the structure Ac-DWFKAFYDKVAEKFKEAF-NH ₂ (SEQ ID NO: 13) containing L-4F with, or is. When folded into the proper secondary structure, L-4F is an amphipathic α-helix, has opposite polar and hydrophobic faces, and mimics apoA-I, the major apolipoprotein of HDL. To do.

  The apo AI mimic 4F, including L-4F and D-4F, has anti-dyslipidemic properties. For example, L-4F can bind both oxidized and non-oxidized lipids with higher affinity than apoA-I itself, and also for example in the RPE-BL subluminal space and on Bruch's membrane (BrM). Reduce lipid deposits. L-4F is a potent lipid receptor and capture agent, eg, from BrM and RPE-BL subspaces to extracellular lipids (and optionally intracellular lipids) (eg, neutral lipids, esterified cholesterol and phospholipids). (Lipid) is removed. Thereby, for example, improving the BrM structure (eg reducing the thickness of BrM, normalizing its layer arrangement) and also improving BrM function (eg decreasing the hydrodynamic resistance of BrM, and , Increases the exchange of metabolites and micronutrients between the RPE and the choriocapillaris, including promoting multimolecular complexes that carry such nutrients). For example, extracellular aging-related lipid deposits at BrM form a hydrophobic diffusion barrier that causes oxidative stress and inflammation, eg, in the RPE and retina, and removal of such lipid deposits by L-4F Reduces such oxidative stress and inflammation.

  L-4F has additional beneficial attributes. For example, L-4F exhibits potent anti-inflammatory properties, which in part binds L-4F with high affinity for pro-inflammatory oxidized lipids (eg, oxidized phospholipids) and fatty acid hydroperoxides. And that L-4F eliminates such oxidized lipids. L-4F also enhances the ability of HDL-cholesterol to protect LDL-cholesterol from oxidation, thereby reducing the formation of proinflammatory oxidized lipids. Furthermore, L-4F inhibits complement activation, reducing levels of complement factor D and the membrane attack complex. This may be another reason for the antioxidant and anti-inflammatory properties of L-4F, and may also be the result of L-4F inhibiting the effects of downstream lipid deposits. . L-4F also has anti-angiogenic properties. Extracellular lipid deposits within the RPE-BL subluminal space provide a biomechanically fragile and proinflammatory environment for new blood vessels to invade and spread. It is not hindered by the binding of the RPE basement membrane to other parts of BrM. The removal of such lipid deposits by L-4F closes or substantially reduces the spacing of this pro-angiogenic dehiscence surface.

  In the following studies performed in the macaque model of human early AMD, L-4F removes neutral lipids and esterified cholesterol, restores / normalizes BrM, and downstream effects of lipid deposition (eg, complement activation and It has an effective ability to reduce local inflammation). L-4F also appears to effectively remove phospholipids, a major source of proinflammatory oxidized lipids, although phospholipid staining was not performed in this study. Results of the macaque study include all stages and morphologies of human AMD in which extracellular lipid deposits play a pathological role (including early AMD, mid-stage AMD and advanced stage AMD, as well as dry AMD and neovascular AMD). ) Is expected to have clinical application. Drusen are rich in esterified cholesterol and phospholipids, which are due to the core and surface of lipoproteins secreted by RPE, respectively. Furthermore, unlike the lipoproteins in BrM, the former is more loosely bound than the latter, because the lipoproteins (both native and modified) in drusen are not bound to structural collagen or elastin fibrils. Easier to remove. Thus, the significant reduction in ester cholesterol and lipid deposits from BrM in the macaque test indicates the ability of L-4F to effectively reduce soft drusen from BrM-containing eye tissue to remove ester cholesterol-containing lipids. It can be said that it is proven. Although proteases are activated in RPE, in this macaque test, L-4F injected intravitreally easily crossed RPE to reach BrM and effectively removed lipid deposits from BrM. .. Removal of lipid deposits from BrM by L-4F normalizes BrM structure and function. Also, the reduction of drusen volume by L-4F can reduce the rise of the RPE layer away from BrM, thereby reducing metamorphopsia and the development of non-central or central geographic atrophy. Can be blocked, delayed, or delayed in progression, thus improving vision. The reduction in drusen volume in humans can be readily quantified using spectral domain optical coherence tomography (SDOCT) and commercially available software.

  By reducing lipid deposits, L-4F can maintain or improve the integrity of RPE, thereby preventing or obviating RPE atrophy, including non-central and central geographic atrophy. . Flexible drusen and drusen-like pigment epithelial detachment (PED) increase over time because RPE cells continue to secrete lipoproteins. The RPE layer on the drusen and the drusen-like PED become coarser over time, and the RPE cells preferentially cross the apex, exit the RPE layer and move forward into the neurosensory retina. In that case, the RPE cells will be distant from the choriocapillaris and will seek oxygen from the retinal circulation. By removing native and modified lipids from drusen, L-4F can block the anterior migration of RPE cells, thereby keeping them in close proximity to the choriocapillaris. Therefore, the RPE cells are energetically and metabolically maintained in the blood circulation function and do not atrophy. Furthermore, removal of lipid deposits from BrM improves the transport of incoming micronutrients (including vitamin A) and outgoing waste between the choriocapillaris and RPE. By reducing drusen and removing lipid deposits from BrM, L-4F can maintain RPE integrity and prevent RPE atrophy. Thereby, the photoreceptor cells and visual acuity can be retained. The integrity of the RPE located on the drusen can be monitored by SDOCT of the macula.

  The reduction of lipid deposits had a downstream effect in the macaque test, which included a significant reduction in the number of membrane attack complex (MAC) present in BrM and choriocapillaris. MAC (C5b-9) is the final activation product of the complement system and accumulates in the BrM-choriocapillary plate complex throughout the life of an individual beginning in childhood. By reducing the level of MAC, L-4F improves the health of BrM and choriocapillary endothelium, thereby improving blood supply to the lateral retina and between choriocapillaris and RPE. It can improve the exchange of micronutrients of erythrocytes and facilitate the clearance of lipoprotein particles secreted by RPE into the systemic circulation.

  By removing lipids, L-4F can prevent or prevent neovascularization (NV). Basement membrane-lined deposits and soft drusen are major sources of potentially pro-inflammatory lipids in the RPE-BL subluminal space where the most common type of NV, type 1 NV, occurs. Removal of natural lipids (including esterified cholesterol in lipoprotein deposits) from ocular tissues by L-4F has been demonstrated in this macaque test, but may be subject to modifications such as peroxidation. Reduces the amount of lipids. Modified lipids (including lipid peroxides) may have strong pro-inflammatory properties and thus stimulate NV. L-4F can also remove other modified lipids formed with lipid peroxides. Furthermore, by reducing the bulk size of drusen, L-4F can prevent RPE cells from migrating away from the nutrient-transporting choriocapillaris. Therefore, it is possible to block the secretion of stress-induced VEGF, which is a strong stimulant of NV. Moreover, the normalization of BrM as a result of the removal of lipid deposits from BrM by L-4F reinforces the natural barrier between the choriocapillaris and the RPE-BL subspace, leading to choroidal NV. Suppress. Thus, through its ability to remove native lipids and modified (eg, oxidized) lipids, L-4F can block or reduce NV, including type 1 NV, and also anti-angiogenic drugs (injected intravitreally). (Including anti-VEGF drugs) can improve treatment of neovascular AMD and may reduce the burden of treatment.

  In some embodiments, an apomimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] is administered per dose. Topical administration is at a dose of about 0.1-0.5 mg, 0.5-1 mg or 1-1.5 mg (eg, per injection). In a further embodiment, an apo mimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] is administered per administration (eg, , About 0.1 to 0.3 mg, 0.3 to 0.5 mg, 0.5 to 0.75 mg, 0.75 to 1 mg, 1 to 1.25 mg or 1.25 to 1. Topical administration at a dose of 5 mg. Apomimetics are also greater than 1.5 mg per dose (eg, per injection), such as up to about 2 mg per dose (eg, per injection) or more. It can be administered locally in a dose. In certain embodiments, an apo mimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] is administered per administration (eg, , Per injection) topically at a dose of about 0.1-0.5 mg or 0.5-1 mg.

  In a further embodiment, the apo mimetic [eg, Apo AI Mimic (eg, L-4F) and / or Apo E Mimetic (eg, AEM-28-14)] is provided for about 6 months. Topical administration is at a total or cumulative dose of about 0.5 or 1-5 mg or 5-10 mg. In some embodiments, the apomimetic [eg, Apo AI Mimic (eg, L-4F) and / or Apo E Mimetic (eg, AEM-28-14)] is administered for about 6 months. Topical administration is at a total or cumulative dose of about 0.5 or 1-3 mg, 3-5 mg, 5-7.5 mg or 7.5-10 mg over time. The apomimetic can also be topically administered at a total or cumulative dose of greater than 10 mg over about 6 months, such as up to about 15 mg or more over about 6 months. In some embodiments, the apo mimetic [eg, apo AI mimetic (eg, L-4F) and / or apo E mimetic (eg, AEM-28-14)] is administered for a period of about 6 months. Topical administration is at a total or cumulative dose of about 0.5-3 mg or 3-5 mg over time.

  In yet a further embodiment, an apo mimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] is added to all or the entire treatment regimen. In contrast, the total dose or cumulative dose of about 1 or 2 to 20 mg or 5 to 15 mg is locally administered. In some embodiments, the apo mimetic [eg, Apo AI mimic (eg, L-4F) and / or Apo E mimetic (eg, AEM-28-14)] is added to the entire treatment regimen at about Topical administration is at a total or cumulative dose of 1-5 mg, 5-10 mg, 10-15 mg or 15-20 mg. In some embodiments, an apo mimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] is added to the overall treatment plan. Total dose or cumulative of about 1 to 3 mg, 3 to 5 mg, 5 to 7.5 mg, 7.5 to 10 mg, 10 to 12.5 mg, 12.5 to 15 mg, 15 to 17.5 mg or 17.5 to 20 mg. Administered locally in a dose. The apomimetic can also be topically administered at a total or cumulative dose greater than 20 mg for the entire treatment regimen, such as up to about 25 mg, 30 mg, 40 mg, 50 mg or more for the entire treatment regimen. In some embodiments, the apo mimetic [eg, Apo AI mimic (eg, L-4F) and / or Apo E mimetic (eg, AEM-28-14)] is added to the entire treatment regimen at about Topical administration is at a total or cumulative dose of 1-5 mg or 5-10 mg.

  In some embodiments, an apo mimetic [eg, Apo AI Mimic (eg, L-4F) and / or Apo E Mimic (eg, AEM-28-14)] is administered to the eye. Topical administration intraocularly, in or around the eye. In some embodiments, an apo mimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] is injected (eg, glass). Administered by intra-body, sub-conjunctival, sub-retinal or sub-Tenon injection), eye drop or transplant (eg, intravitreal, intra-aqueous, sub-retinal or sub-Tenon transplant). In certain embodiments, an apo mimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] is injected (eg, intravitreally, Subconjunctival, subretinal or sub-Tenon injection). Intravitreally injected apomimetics are readily accessible from the vitreous cavity to target sites (eg, RPE-BL subluminal and BrM). By doing so, the apomimetic can be distributed to various tissue layers of the eye (eg, neurosensory retina, BrM, and choroid). Apomimetics are long-acting (eg, at least through long-acting, eg, at least through continuous, slow re-feeding and “washout” to the various tissue layers between the inner and outer retinal layers through which the apomimetic can flow. Approximately 2, 3 or 4 weeks or more). In a further embodiment, the apomimetic [e.g., apo AI mimic (e.g. L-4F) and / or the apo E mimetic (e.g. AEM-28-14)] is administered by instillation. In another embodiment, an apomimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] is administered, eg, in the subretinal space. An aqueous humor device or material (eg, microdevice, bioabsorbable polymeric material, or bioabsorbable) that delivers an apomimetic in a controlled or sustained manner by implantation or injection into a vitreous chamber. Microparticles or nanoparticles). In another embodiment, the apo mimetic [eg, apo AI mimic (eg, L-4F) and / or the apo E mimetic (eg, AEM-28-14)] is transformed into a transgenic cell (eg, Intraocularly a virus (eg, adenovirus or lentivirus) vector containing an RPE cell containing an expression vector containing a gene encoding an apomimetic) or a gene expressing an apomimetic or an expression construct (eg, plasmid) It is administered by injection or transplant. Such delivery methods may have the advantage of requiring only a single injection or implantation in the eye of the apomimetic-encoding expression construct. The same expression construct or different expression constructs if more than one apo mimetic [eg, apo AI mimic (eg L-4F) and apo E mimic (eg AEM-28-14)] is utilized. Can express more than one apomimetic.

  An apo mimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] to the eye, intraocularly, in the eye, or In embodiments that are administered locally around the eye, the dose per administration, the total dose over a period of about 6 months, and the total dose for the entire treatment regimen are, in certain embodiments, per eye administered. And in other embodiments for both eyes. The blood system may allow some (eg, therapeutically effective) amount of apomimetic locally administered (eg, injected) into or in one eye to circulate in the other eye. .. In that case, the dose of the apomimetic can be adjusted arbitrarily (eg, increased) in view of the other eye (which may have milder symptoms of the disease). This may allow treatment of both eyes with the apomimetic at the same time without further administration (eg, injection) of the apomimetic in or into the other eye. For example, an apomimetic injected intravitreally follows natural fluid flow from the vitreous humor through the retina and RPE to the choroid, and across the blood-retinal barrier (maintained by the retinal vascular endothelium and RPE). Two target regions can be crossed across (RPE-BL subluminal and Bruch's membrane). From there, the apomimetic may enter the choriocapillaris and eventually the other non-administering eye. Without intending to be bound by theory, some amount of the apomimetic is via aqueous humor (excreted via the trabecular meshwork and Schlemm's canal to the blood system). May enter the other non-administered eye. Accordingly, some embodiments are methods of treating AMD, comprising administering to a subject in need thereof a therapeutically effective amount of an apomimetic, wherein the apomimetic is directed to one eye. , Intraocularly, topically administered in or around the eye and having a therapeutic effect on both eyes.

  In some embodiments, an apo mimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] is applied to the eye early in treatment. In contrast, it is administered locally intraocularly, in or around the eye, followed by systemic administration of the apomimetic. By way of non-limiting example, the initial dose (s) of the apomimetic (eg, the first to fifth doses) may be given by injection (eg, intravitreal, subconjunctival, subretinal or subtenon injection). ), Followed by subsequent administration (s) of the apomimetic is, for example, oral, parenteral (eg, subcutaneous, intramuscular or intravenous), or topical (eg, intranasal). Or it may be systemic (such as lungs). In other embodiments, the apomimetic is administered topically (eg, injection, eye drop or implant) only. In yet another embodiment, the apomimetic is administered systemically only.

  In some embodiments, the apo mimetic [eg, Apo AI mimic (eg, L-4F) and / or Apo E mimetic (eg, AEM-28-14)] is localized (eg, Doses of about 1, 2, 3, 4, or 5 mg / mL to about 12 or 15 mg / mL, whether by intravitreal injection) or systemic. If more than one apomimetic (eg, Apo AI and Apo E mimetics) is used, they can be administered in the same formulation or in different formulations. In certain embodiments, the apomimetic [eg, Apo AI Mimic (eg, L-4F) and / or Apo E Mimetic (eg, AEM-28-14)] is provided at about 1-4 mg / mL. Administer at a dose concentration of 4-8 mg / mL, 8-12 mg / mL, 1-5 mg / mL, 5-10 mg / mL or 10-15 mg / mL (eg, by intravitreal injection). In some embodiments, the apomimetic [eg, Apo AI mimic (eg, L-4F) and / or Apo E mimetic (eg, AEM-28-14)] is about 1-3 mg /. mL at dose concentrations of 3-5 mg / mL, 5-7.5 mg / mL, 6-8 mg / mL, 7.5-10 mg / mL, 10-12.5 mg / mL or 12.5-15 mg / mL ( (Eg, by intravitreal injection). The apomimetic is also administered at a dose concentration of greater than 15 mg / mL, such as up to about 20 mg / mL or more, whether local (eg, by intravitreal injection) or systemic. It is also possible. In certain embodiments, the apomimetic [eg, Apo AI Mimic (eg, L-4F) and / or Apo E Mimetic (eg, AEM-28-14)] is added at about 1-5 mg / mL. Administer at a dose concentration of 5-10 mg / mL or 6-8 mg / mL (eg, by intravitreal injection).

  In a further embodiment, the apomimetic [e.g., apo AI mimetic (e.g., L-4F) and / or the apo E mimetic (e.g., AEM-28-14)] is about 50-150 [mu] L or 50-. Topical administration (eg, by intravitreal injection) in a dose volume of 100 μL. In certain embodiments, the apo mimetic [eg, Apo AI mimic (eg, L-4F) and / or Apo E mimetic (eg, AEM-28-14)] is added in about 50-75 μL, 75-. Topical administration (eg, by intravitreal injection) in a dose volume of 100 μL, 100-125 μL or 125-150 μL. In some embodiments, the apo mimetic [eg, Apo AI Mimic (eg, L-4F) and / or Apo E Mimetic (eg, AEM-28-14)] is added in about 50 μL, 75 μL, Topical administration (eg, by intravitreal injection) in a dose volume of 100 μL, 125 μL or 150 μL. Unless the dose volume significantly increases intraocular pressure, the apomimetic may also be used in dose volumes greater than 150 μL, such as up to about 200 μL or more (eg, to, intraocularly, intraocularly, or intraocularly or It can also be administered topically (by injection around the eye). In certain embodiments, about 100 μL (0.1 mL) of apomimetic [eg, Apo AI Mimic (eg, L-4F) and / or Apo E Mimic (eg, AEM-28-14)]. Administered locally (eg, by intravitreal injection).

  In another embodiment, the apo mimetic [eg, Apo AI mimetic (eg, L-4F) and / or Apo E mimetic (eg, AEM-28-14)] is administered for 1 month (4 weeks). ) Or once every 1.5 months (6 weeks) (eg, by intravitreal injection). In another embodiment, the apo mimetic [eg, Apo AI mimic (eg, L-4F) and / or Apo E mimetic (eg, AEM-28-14)] is given for 2 months (8 weeks). ), Once every 2.5 months (10 weeks) or once every 3 months (12 weeks) (eg, by intravitreal injection). In still other embodiments, the apo mimetic [eg, apo AI mimic (eg, L-4F) and / or apo E mimetic (eg, AEM-28-14)] is added to 4, 5 or 6 Topical administration once a month (eg, by intravitreal injection or intravitreal implantation). In some embodiments, the apo mimetic [eg, Apo AI Mimic (eg, L-4F) and / or Apo E Mimetic (eg, AEM-28-14)] is added to the initial higher levels of treatment. Topically administered at a frequency and / or higher dose (eg, by intravitreal injection).

  In a further embodiment, the apomimetic [e.g., apo AI mimic (e.g., L-4F) and / or the apo E mimetic (e.g., AEM-28-14)] is added for a total of about 15 or less, 12 or less. Local administration is given at a frequency of 9 times or less, 9 times or less, 6 times or less, or 3 times or less (eg, intravitreal injection). In certain embodiments, the apo mimetic [eg, Apo AI Mimic (eg, L-4F) and / or Apo E Mimetic (eg, AEM-28-14)] is added in a total of about 3-6,6. -9, 9-12 or 12-15 times (eg, intravitreal injection) for local administration. The apomimetic can also be administered topically in a total of more than 15 administrations (eg, intravitreal injection), such as up to about 20 or more administrations (eg, intravitreal injection) in total. In some embodiments, the apo mimetic [eg, Apo AI mimetic (eg, L-4F) and / or Apo E mimetic (eg, AEM-28-14)] is added in a total of about 15,14. , 13, 12, 11 or 10 times (eg, intravitreal injection) for local administration. In another embodiment, the apo mimetic [eg, Apo AI mimic (eg, L-4F) and / or Apo E mimetic (eg, AEM-28-14)] is added in a total of about 9,8, Topical administration with 7, 6, 5, 4 or 3 doses (eg, intravitreal injection). In some embodiments, the apomimetic [eg, Apo AI Mimic (eg, L-4F) and / or Apo E Mimetic (eg, AEM-28-14)] is added in a total of about 3-6 or 7 It is administered locally by administering 10 times (eg, intravitreal injection). In embodiments in which the apomimetic is locally administered to, intraocularly, in, or around the eye, the frequency of administration and the total number of administrations (eg, injections) may be, in certain embodiments, per eye administered. Yes, in other embodiments, both eyes (because the apomimetic may also be therapeutically effective in the other non-administered eye).

  The dose per dose, total dose over a period of about 6 months, total dose for the entire treatment regimen, dosing frequency and total number of doses, duration / length of treatment with the apolipoprotein mimetic is: It can be adjusted as needed. They are then selected by the treating physician to minimize the burden of treatment and to achieve the desired prognosis (s) (eg, reduction of lipid deposits to desired levels (eg, presence of low numbers of medium-sized drusen). Alternatively, the absence of any large drusen, elimination of (non-central or central) geographic atrophy, or reduction to a desired level can be achieved.In some embodiments, apomimetics [eg, ApoA. -I mimic (eg, L-4F) and / or apoE mimic (eg, AEM-28-14)] is a treatment regimen of about 24 months or less, 18 months or less, 12 months or less, Or for up to 6 months, In further embodiments, in a further embodiment, an apo mimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14). ] For about 18 to 24 months, 12 to 18 months, or 6 to 12 months.Treatment with the apomimetic is also about 2.5 years, 3 years, 3. It may last longer than 24 months (2 years), such as up to 5 years, 4 years or more, etc. In further embodiments, apomimetics [eg, Apo AI mimics (eg, L- 4F) and / or apoE mimetics (eg, AEM-28-14)] lasts for about 24, 21, 18, 15, 12, 9, or 6 months, in some embodiments. , Apo mimetics [eg, apo AI mimics (eg, L-4F) and / or apo E mimetics (eg, AEM-28-14)] are about 6-12 or 12-. Continue for 24 months.

  In some embodiments, the apo mimetic [eg, apo AI mimic (eg, L-4F) and / or apo E mimetic (eg, AEM-28-14)] is treated with at least the progression of AMD ( It will be administered in the latter term. In certain embodiments, an apomimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] is administered at least during the advanced phase of AMD. To treat central geographic atrophy (GA) or delay its progression and / or prevent neovascular AMD or delay its onset. In a further embodiment, the apomimetic [eg, Apo AI Mimic (eg, L-4F) and / or Apo E Mimetic (eg, AEM-28-14)] is administered at least during the advanced phase of AMD. To treat or slow the progression of neovascular AMD.

  In another embodiment, an apomimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] is administered at least in the middle of AMD. To do. In certain embodiments, the apomimetic [eg, Apo AI Mimic (eg, L-4F) and / or Apo E Mimetic (eg, AEM-28-14)] is administered at least mid-stage of AMD. To treat or delay the progression of non-central GA and / or prevent or delay the onset of central GA and / or neovascular AMD. In a further embodiment, an apo mimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] is applied to at least the initial phase of metaphase AMD. Administered to prevent non-central GA or delay its onset. Metaphase AMD is characterized by a high amount of fused soft drusen, which mainly comprises ester cholesterol and phospholipids. Using apomimetics [eg, Apo AI Mimics (eg, L-4F) and / or Apo E Mimetics (eg, AEM-28-14)] to reduce fusion soft drusen in metaphase AMD. Improves the reduction ("thinning") and normalization of Bruch's membrane and the exchange of micronutrients and metabolites between the choriocapillaris and the RPE, thereby overlying the RPE cell layer Playback may occur. Reduction of fusion soft drusen can be measured by non-invasive techniques (eg, Spectral Domain Optical Coherence Tomography (SDOCT)).

  In a further embodiment, an apomimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] is administered at least early in AMD. .. Apomimetics can be administered earlier in AMD (eg, early or mid-stage) to slow or stop the progression of AMD. In some embodiments, an apo mimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] is provided at least early in AMD. Administered to prevent non-central GA or delay its onset. In some embodiments, the apomimetic is administered to the eye in the early stages of AMD, intraocularly, into or around the eye (eg, by intravitreal, subconjunctival, subretinal or subtenon injection or instillation). Administer locally. Apo mimetics [eg, Apo AI mimics (eg, L-4F) and / or Apo E mimetics (eg, AEM-28-14)] in an invasive manner (eg, intravitreal, subconjunctival) When given topically, by subretinal or sub-Tenon injection, the apomimetic is less frequent (eg, injected approximately every 3, 4, or 6 months) to minimize the burden of treatment. , Less total doses (eg, about 1, 2 or 3 injections) or higher doses per dose (eg, about 0.5-1 mg or 1-1.5 mg per injection) , Or any combination thereof or all thereof can be administered. In order to have a therapeutic or prophylactic effect for AMD, the apomimetic need not eliminate or remove all or most of the abnormal lipid deposits from the eye. When the threshold amount of abnormal lipids is eliminated from the eye, the natural transport mechanisms, including the transport between the choriocapillaris endothelium and the RPE layer, can function properly again, eliminating residual abnormal lipids from the eye. can do. Furthermore, lipids slowly accumulate in the eye over many years (however, in shorter time intervals, variations in drusen volume may be detected). Thus, less frequent administration of apomimetic (eg, about 3, 4, or 6 months intravitreal injection) and / or lesser total number of administrations (eg, about 1, 2 or 3 intravitreal injections). ) May nevertheless have a therapeutic or prophylactic effect for early AMD.

  In other embodiments, an apo mimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimic (eg, AEM-28-14)] is added early in AMD (eg, , Systemically, orally or parenterally (eg, intravenously). In order to increase the peptidase / protease resistance of the apomimetic peptide, an apomimetic variant containing one or more or all D-amino acids (eg, D-4F of all D-amino acid residues) is systemically (or ocularly). Since the surface contains peptidases / proteases, it can be administered (by eye drop). The dose of apomimetic for systemic administration may be much higher than the dose for local administration (eg, by intravitreal injection or eye drop). To do so, its systemic distribution and potential systemic anti-dyslipidemic effects (eg, arteriosclerotic plaques in the systemic vasculature (a major target (and hence absorption source) of apomimetics in the systemic circulation) This is due to the consideration of the decrease or elimination). In certain embodiments, the systemic dose of apomimetic [eg, Apo AI Mimic (eg, L-4F) and / or Apo E Mimetic (eg, AEM-28-14)] is administered locally. At least about 50, 100, 200, 300, 400, 500 or 1000 times (eg, at least about 100 or 500 times) more than the dose. In some embodiments, the systemic dose of the apomimetic [eg, Apo AI mimic (eg, D-4F) and / or Apo E mimetic (eg, AEM-28-14)] is An amount of at least about 50 mg, 100 mg, 200 mg, 300 mg, 400 mg or 500 mg per day (eg, an amount of at least about 50 mg or 100 mg per day when administered intravenously and an amount of at least about 200 or 300 mg when administered orally). Will be). In a further embodiment, the apomimetic is administered systemically (eg, oral or parenteral (eg, intravenous)) or local to the eye (eg, by eye drops) in a non-invasive manner. In the early stages of AMD for a period of time selected by the treating physician (eg, at least about 3 months, 6 months, 12 months, 18 months, 24 months or more) , Once or more than once a day, once every two days, once every three days, once a week, once every two weeks or once a month (eg once a day or two days Treatment of the disease according to selected prognostic criterion (s) (eg elimination of all or most of the soft drusen or reduction of the volume of soft drusen to a certain level). Until it succeeds.

  In some embodiments, the apo mimetic [eg, Apo AI Mimic (eg, L-4F) and / or Apo E Mimetic (eg, AEM-28-14)] is added to the AMD stage earlier. One is administered less frequently and / or at lower doses (eg, by intravitreal injection). Higher doses of apomimetic may be given earlier in the AMD stage. Stated another way, in certain embodiments, one of the apo mimetics [eg, Apo AI mimics (eg, L-4F) and / or Apo E mimetics (eg, AEM-28-14)] ( Administration (e.g., by intravitreal injection) is more frequent (the total number of doses may be higher) and / or the later in the stage of AMD or the more severe the symptoms of AMD. Higher doses (higher doses per administration and / or higher total doses throughout the treatment regimen) will be administered. By way of non-limiting example, in mid-stage and advanced stage AMD (including dry AMD and neovascular AMD), administration by apomimetic injection (eg, intravitreal, subconjunctival, subretinal or subtenon injection) May occur more frequently (eg, about once every 4-12 or 4-8 weeks for mid-stage AMD, about every 4-8 or 4-6 weeks for advanced AMD), or more Total number of injections (eg, about 4-8 or more injections for mid-stage AMD, about 8-12 or more injections for advanced-stage AMD) may be given, or higher doses per injection (eg, It may be given at up to about 1-1.5 mg per injection) or at higher total doses throughout the treatment regimen (eg up to about 10-15 mg or more for mid-stage AMD and about 10--20% for advanced AMD). 15-20 mg or more) or any combination thereof or all of them, and a higher amount of lipid deposition from the eye containing Bruch's membrane from the RPE-BL subspace. Debris (including drusen and basement membrane lined deposits) can be removed.

  In early, mid-and advanced-stage AMD, as well as dry AMD and neovascular AMD, the progression and treatment of AMD is accomplished by a variety of methods known in the art (referred to herein simply as "diagnostic" methods). Can be monitored using. Such methods include, but are not limited to, structural SDOCT (which reveals drusen and RPE, can quantify total drusen volume and monitor disease progression), hyperspectral autofluorescence (drusen and basement membrane lined). Deposit-specific fluorophore detection), fundus color photography, quantitative fundus autofluorescence (qAF) and OCT-fluorescein angiography (FA), and multiple parameters (eg, cones). Mediated visual acuity (eg best corrected visual acuity [BVCA (lasting until late stage of the disease)], visual acuity using ETDRS diagram, contrast sensitivity using Pelli-Robson diagram, low intensity visual acuity [neutral density filter to reduce retinal illumination] A visual acuity measured by using the [], and the onset of metamorphopsia) and rod-mediated visual acuity (eg, dark adaptation kinetics [a sensitive metric of macular function that tracks disease progression])). . For example, the treatment is to stabilize or improve photopic vision (day vision) mediated by cone photoreceptor cells and scotopic vision (night vision) mediated by rod photoreceptor cells. There is expected. As another example, the health of RPE cells can be assessed by qAF, and a stability or increase in qAF intensity may indicate that RPE health is stable or improved. This is because a decrease in qAF intensity may mean degeneration of RPE cells. qAF can be used to quantify the area and size of geographic atrophy and thus monitor the progression of non-central GA or central GA, and was also performed in the MAHALO Phase II trial of lampalizumab. The integrity of RPE cells can also be assessed using SDOCT, and the presence of highly reflective central points located vertically above the drusen in the retina indicates migrating RPE cells, where the RPE layer is This means that the RPE cells and the photoreceptor cells are about to be detached immediately before the atrophy. Poor RPE integrity can be an indicator of poor visual prognosis in dry AMD and neovascular AMD. As a further example, OCT-FA can detect the presence of RPE-BL, subretinal or intraretinal fluid. This means active neovascularization and leakage from the new blood vessels.

  Early, intermediate or advanced stages using one or more therapeutic agents (eg, apomimetics, anti-angiogenic agents or complement inhibitors, or any combination thereof) by employing diagnostic methods It will be possible to monitor and adjust the course of treatment of AMD or dry AMD or neovascular AMD. Examples include apo mimetics [eg, apo AI mimics (eg, L-4F) and / or apo E mimetics (eg, AEM-28-14)] are early, mid-stage or advanced AMD, Alternatively, it can be administered by injection (eg, intravitreal, subconjunctival, subretinal or subtenon injection) for the treatment of dry AMD or neovascular AMD. During the initial phase of treatment, the apomimetic can be administered at a particular injection frequency and a particular dose per injection. If one or more diagnostic methods show a substantial improvement in the disease after a significant length of treatment, or that the disease is stable (eg, SDOCT is associated with treatment of soft drusen after a significant length of treatment). Apomimetic is less injectable at lower frequency and / or lower dose per injection, or if the volume of the soft drusen is stable). Articles can be injected less frequently and at higher doses each time (thus, a substantially similar total dose is administered over a certain period of time). On the other hand, after the initial phase of treatment, one or more diagnostic methods are associated with exacerbation of the disease (especially more severe forms of the disease (eg, non-central or central geographic atrophy or neovascular AMD)), or Apomimetic is more frequent if SDOCT shows no increase in soft drusen volume or no change in soft drusen volume after the initial phase of treatment. And / or higher doses may be injected per injection. Treatment with an apomimetic may also be discontinued or discontinued if one or more diagnostic methods indicate a strong improvement in the disease (eg, if SDOCT indicates elimination of all or most of the soft drusen). However, if one or more diagnostic methods show recurrence of the disease after a period of time (eg, SDOCT shows obvious or significant amount of soft drusen), treatment with an apomimetic (eg, strong improvement). The treatment plan that caused the) may be restarted. The progress and treatment of AMD can be monitored using diagnostic methods and the treatment adjusted accordingly. Such treatment regimens may be referred to as "on-demand" or "pro-renata" regimens. An on-demand plan involves regular visits (eg, once every 4, 6 or 8 weeks) and thus one or more diagnostic methods can be implemented to monitor AMD progression and treatment. The therapeutic agent may not be administered during the visit based on the results of its diagnostic tests.

  Apomimetics [eg, apoA-I mimics (eg, L-4F) and / or apoE mimetics administered by injection (eg, intravitreal, subconjunctival, subretinal, or sub-Tenon injection) (Eg, AEM-28-14)] for treatment of early, intermediate or advanced stage AMD, or atrophic AMD or neovascular AMD, as an apomimetic during the early phase of treatment. Can be administered at a particular injection frequency (eg, once a month) and at a particular dose per injection. During the second phase of treatment, the apomimetic is less frequent (eg, once every 6 or 8 weeks) and at the same initial dose per injection as the initial dose per injection. Or can be injected at higher doses per injection, thus administering substantially the same total dose over a specified period of time. The second phase of treatment may continue for a selected period of time. During the third phase of optional treatment, apomimetics were administered at a much lower frequency (eg, once every 10 or 12 weeks) and at the same initial dose per injection as the initial dose per injection. Dose, or injectable at higher doses per injection, so that substantially similar total doses are administered over a specified period of time. The optional third phase of treatment may continue for a selected period of time. Further description will be made. Such treatment regimens are sometimes referred to as "treat-and-extend" regimens. In the initial / first phase of treatment, the second phase, the optional third phase and any additional optional phases, one or more diagnostic methods can be implemented to monitor AMD progression and treatment, and , There is also the possibility of adjusting the treatment based on the result of the diagnostic test. For example, if one or more diagnostic methods indicate aggravation of the disease (eg, SDOCT indicates an increase in the volume of soft drusen), the apomimetic is more frequent and / or higher doses per injection. Can be injected with. In contrast, if one or more diagnostic methods indicate a stable or amelioration of the disease (eg, SDOCT indicates a stable or decreased volume of soft drusen), the apomimetic is less frequent and / or once. Or apomimetic can be infused less frequently with a higher dose per injection (thus, substantially the same total dose over a certain period of time). Administered). Unlike on-demand planning, treatment and extension planning does not require regular diagnostic visits. However, the therapeutic agents are administered at regular treatment visits, the frequency of which decreases during the second and third optional phases of treatment. However, the therapeutic agent or dose administered may not be medically necessary at the time. Frequent visits (whether for monitoring and / or treatment) and frequent injections (eg, monthly) have negative consequences (eg, reduced patient compliance). , May have adverse medical effects (eg, tachyphylaxis), increased medical costs. The potential advantage of treatment and extension plans over as-needed plans is that the total number of visits for monitoring and treatment may be reduced.

  As a non-limiting example of treatment and prolongation regimens, for the treatment of neovascular AMD, anti-angiogenic agents (eg, anti-VEGF agents (eg, aflibercept, bevacizumab or ranibizumab) may be used alone or in combination with other It is used in combination with a therapeutic agent (eg, apo mimetic (eg, apo AI mimetic [eg, L-4F] or apo E mimetic [eg, AEM-28-14])) and has a maximum effect ( For example, subretinal and / or intraretinal fluid is substantially completely resolved without new retinal hemorrhage, or subretinal with OCT-FA in at least two consecutive hospital visits in the absence of new retinal hemorrhage. Fluid (and / or no further reduction in intraretinal fluid) can be injected once (eg, intravitreally) every 4, 6 or 8 weeks until an anti-angiogenic agent is achieved. Can be injected less frequently (the interval between injections can be extended, for example, about 2 or 4 weeks). If the disease is stable, the interval between injections can be extended, for example, about 2 or 4 weeks And the total extension period may be, for example, up to about 3, 4, 5 or 6 months, if the patient exhibits a relatively mild exacerbation of the disease (eg, a relatively small amount of subretinal). Fluid and / or intraretinal fluid reappears, or if its amount increases by a relatively small amount), the injection interval of the anti-angiogenic drug can be shortened, for example, by about 1 or 2 weeks. , Frequent injections of anti-angiogenic agents (eg, once every 4, 6, or 8 weeks) can be resumed.Similar principles also apply to any other type of therapeutic agent, including but not limited to, apotherapeutic agents. Mimetics (Apo AI Mimics (eg L-4F) or Apo E Mimics (eg AEM-28-14)) and Complement Inhibitors (eg Complement Factor D Inhibitors (eg Lampalizumab)) ) Is also applicable to treatment and prolongation regimens for the treatment of dry AMD or neovascular AMD.

  As an alternative to an as-needed plan or treatment and prolongation plan, for the treatment of early, intermediate or advanced AMD, or atrophic AMD or neovascular AMD, a therapeutic agent (eg, apomimetic, anti-vascular). The neoplastic agent or complement inhibitor) can be administered at substantially the same frequency of administration and at substantially the same dose per administration for substantially the entire duration of treatment selected by the treating physician, or One or more diagnostic methods can be administered until the disease indicates successful treatment according to any selected prognostic criterion (s). Such treatment plans are sometimes referred to as "fixed routine" plans.

  Apomimetics [eg, Apo AI Mimics (eg, L-4F) and / or Apo E Mimetics (eg, AEM-28-14)] are one or more pharmaceutically acceptable excipients. It can be administered as a composition containing an agent or carrier. If more than one apomimetic (eg, Apo AI and Apo E mimetics) is used, they can be administered in the same or different compositions. In some embodiments, a composition comprising an apomimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] is About 75-95% (eg, about 90%) of apomimetic (s) and about 5-25% (eg, about 10%) of the corresponding apolipoprotein by weight or molar amount relative to the total amount. (S) (eg, Apo AI and / or Apo E) or an active portion or domain thereof. In certain embodiments, a composition comprising an apo mimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] is injected (eg. , Intravitreal, subconjunctival, subretinal or subtenon injection). Examples of formulations for injection into the eye include, but are not limited to, those described elsewhere herein. In another embodiment, a composition comprising an apo mimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] is applied to eye drops. Alternatively, it is prescribed as a transplant (eg, intravitreal, subretinal or sub-Tenon transplant). By using or implanting eye drops once or twice, the potential problems associated with repeated injections can be avoided.

  In a further embodiment, a composition comprising an apo mimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] is provided with sustained release. Configure for apo mimics. Non-limiting examples of sustained release compositions include those described elsewhere herein. In some embodiments, the apo mimetic [eg, Apo AI mimic (eg, L-4F) and / or Apo E mimetic (eg, AEM-28-14)] is loaded with microparticles (eg, polymer microparticles or Administered via microparticles) which predominantly comprise or consist essentially of the apomimetic. The use of sustained release compositions or such microparticles can reduce the number of times a drug is administered by performing potentially invasive methods (eg, intravitreal injection), and over a period of time. And improve the profile of the amount of drug delivered to the target site.

  In some embodiments, a composition comprising an apo mimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] comprises: Or a plurality of excipients, which inhibit peptide / protein aggregation, increase peptide / protein solubility, reduce solution viscosity, or increase peptide / protein stability, or any thereof Including all combinations or all of the above. Examples of such excipients include, but are not limited to, those described elsewhere herein. Such excipients may improve the injectability of compositions containing the apomimetic. Thus, such excipients allow the use of smaller specification (eg, <30G) needles (eg, injection needles) in the administration (eg, by intravitreal injection) of compositions containing apomimetics. And

  Since such excipients inhibit peptide / protein aggregation and increase peptide / protein solubility, for example, they may be employed to increase the concentration of the peptide or protein in the solution or suspension. You can Increasing the peptide / protein concentration has the beneficial effect of reducing the volume required to administer a given amount of peptide or protein and lowering intraocular pressure when the peptide or protein is administered by injection into the eye. May be Moreover, increasing the concentration of peptides / proteins allows higher doses of peptide or protein to be administered in a given volume. That allows the peptide or protein to be administered less frequently for a given total dose administered over a period of time. Less frequent administration of peptides or proteins (eg, by intravitreal injection) has the advantage of improving patient compliance and health, as less invasive procedures are being performed.

  Apomimetics [eg, Apo AI Mimics (eg, L-4F) and / or Apo E Mimetics (eg, AEM-28-14)], alone or in combination for treating AMD. Can be used in combination with other therapeutic agents. Examples of other therapeutic agents include, but are not limited to, those described elsewhere herein. It may be at various stages of AMD (eg, early, mid-stage or advanced stages of AMD) that the one or more other therapeutic agents are administered in combination with the apomimetic, and It may be for the treatment of AMD of various phenotypes described elsewhere (eg, geographic atrophy or neovascular AMD).

  An apolipoprotein mimetic (eg, apo AI mimetic [eg, L-4F] and / or an apo E mimetic [eg, AEM-28-14]), optionally but with one or more other therapies. It can be used in combination with a drug to treat any condition or complication associated with AMD. Examples of such symptoms and complications include, but are not limited to, accumulation of lipids (including neutral lipids and modified lipids) on BrM, thickening of BrM, accumulation of high lipid debris, RPE-BL and BrM. Deposition of high lipid debris (including basement membrane lining deposits and drusen) with the ICL, formation of a diffusion barrier between the RPE and the choriocapillaris, degeneration of photoreceptor cells, cartilaginous atrophy (non-central) And central GA), RPE atrophy, neovascularization (including NVs 1, 2, and 3), intraocular leakage, hemorrhage and scar formation, and visual impairment and loss.

  By way of non-limiting example, some embodiments of the present disclosure are methods for preventing, delaying onset, slowing progression, or reducing the extent of vision loss or loss associated with AMD that are therapeutically effective in a subject. A method comprising the step of administering an amount of an apo mimetic (eg, apo AI mimetic [eg, L-4F] and / or an apo E mimetic [eg, AEM-28-14]). One or more other therapeutic agents can optionally be administered. Visual impairment or loss may be associated with dry AMD (including non-central and / or central geographic atrophy) or neovascular AMD (including 1, 2 and / or type 3 neovascularization).

V. Other Types of Therapeutic Agents As noted above, AMD has a variety of underlying factors (eg, formation of lipid-containing deposits, formation of toxic byproducts, oxidation, inflammation, neovascularization and cell death). Multiple therapeutic agents targeting multiple underlying causes of AMD or having different mechanisms of action are available for the treatment of AMD. Therapeutic agents that may optionally be used in combination with an apolipoprotein mimetic to treat AMD include, but are not limited to,
1) antihyperlipidemic drug;
2) PPAR-α agonists, PPAR-δ agonists and PPAR-γ agonists;
3) anti-amyloid drug;
4) inhibitors of lipofuscin or its components;
5) visual / light cycle regulators and dark adaptation agents;
6) antioxidants;
7) Neuroprotective agents (neuroprotective agents);
8) apoptosis inhibitors and necrosis inhibitors;
9) C-reactive protein (CRP) inhibitors;
10) inhibitors of the complement system or its components (eg proteins);
11) Inflammasome inhibitors;
12) anti-inflammatory agent;
13) immunosuppressants;
14) modulators of matrix metalloproteinases (MMPs); and 15) anti-angiogenic agents.

  A particular therapeutic agent may exert more than one biological or pharmaceutical effect and may fall into more than one category.

  The therapeutic agent is used in a therapeutically effective amount. When used in combination with another therapeutic agent (eg, an apolipoprotein mimetic), the therapeutic agent is administered substantially simultaneously with the other therapeutic agent (eg, within about 30 or 60 minutes of each other during the same medical examination). It can be, or can be administered before or after administration of the other therapeutic agent. When co-administered with other therapeutic agents, the therapeutic agents may be administered in the same formulation as the other therapeutic agents or in separate formulations.

  The formation of high lipid deposits is an important upstream cause of AMD, leading to complications such as non-central and central geographic atrophy and neovascularization. One pleiotropic approach to prevent or minimize the accumulation of high lipid substances is to inhibit the production of lipids (eg cholesterol and fatty acids) and lipoproteins (eg VLDL) by RPE cells and plasma by RPE cells. Inhibiting the uptake of lipids (eg cholesterol and fatty acids) and lipoproteins (eg VLDL) and allowing lipids (eg cholesterol and fatty acids) into BrM, RPE-BL and subretinal space by RPE cells and Inhibiting the secretion of lipoproteins (eg VLDL) and its components (eg apo B and apo E) and from the BrM, RPE-BL and subretinal spaces to lipids (eg cholesterol and oxidized lipids) and Eliminating lipoproteins (eg VLDL) and its components (eg apo B and apo E). For example, apo B is involved in the formation of at least liver VLDL, which is at least the parent of plasma LDL. Inhibition of apo B production by RPE cells and inhibition of uptake of fatty acids available for lipid addition of apo B by RPE cells may suppress production of VLDL and thus LDL by RPE cells.

  Antidyslipidemic agents include lipids, lipoproteins and other substances that play a role in the formation of lipid-containing deposits in the retina, subretinal space, RPE-BL subspace, and choroid (eg, BrM), among others, Regulates production, uptake and elimination. One class of antidyslipidemic agents is the fibrate drugs that activate peroxisome proliferator-activated receptor alpha (PPAR-alpha). Fibrates reduce fatty acid and triglyceride production and induce lipoprotein lipolysis, but stimulate high density lipoprotein (HDL, which mediates reverse cholesterol transport) production and remove LDL from plasma. Is a lipid-lowering drug that increases cholesterol and circulates from cells and ultimately stimulates reverse cholesterol transport to the liver, where cholesterol is metabolized and excreted in bile. (Cholesterol can also be eliminated, for example, through the removal of HDL-cholesteryl esters by the gastrointestinal tract. Lecithin-cholesterol acyltransferase [LCAT] (eg, a plasma enzyme activated by apolipoprotein AI) removes free cholesterol. (Converted to cholesteryl ester, which is then sequestered into the core of HDL particles.) Examples of fibrate agents include, but are not limited to, bezafibrate, ciprofibrate, clinofibrate, clofibric acid, clofibrate, clofibrate. Included are aluminum, clofibride, etofibrate, fenofibrate, gemfibrozil, ronifibrate, synfibrate, and their analogs, derivatives and salts. Other triglyceride lowering agents include omega-3 fatty acids (eg, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)).

  Another class of antidyslipidemic agents is the HMG-CoA reductase inhibitors (statins). Statins inhibit cholesterol synthesis, decrease VLDL and LDL apo B production (or apo B containing VLDL and LDL production), reduce apo B secretion and lower plasma lipid levels. Examples of statins include, but are not limited to, atorvastatin, cerivastatin, fluvastatin, mevastatin, monacolin (eg, monacolin K [lovastatin]), pitavastatin, pravastatin, rosuvastatin, simvastatin, and analogs, derivatives and salts thereof. Be done.

Other antidyslipidemic agents include acetyl CoA carboxylase (ACC) inhibitors. ACC inhibitors inhibit fatty acid and triglyceride (TG) synthesis and decrease VLDL-TG secretion. Non-limiting examples of ACC inhibitors include anthocyanins, avenacyolides, benzodioxepins {eg, 7- (4-propyloxy-phenylethynyl) -3,3-dimethyl-3,4dihydro-2H-benzo [b]. [1,4] dioxepin}, benzothiophene [eg, N-ethyl-N ′-(3-{[4- (3,3-dimethyl-1-oxo-2-oxa-7-azaspiro [4.5] Deca-7-yl) piperidin-1-yl] -carbonyl} -1-benzothien-2-yl) urea], bis-piperidinylcarboxamide (eg, CP-640186), chloroacetylated biotin, cyclodim, diclofop, Haloxyfop, biphenyl- and 3-phenylpyridine, phenoxythiazole {eg, 5- (3-acetamidobut-1-ynyl) -2- (4-propyloxyphenoxy) thiazole}, piperazine oxadiazole, (4-piperidinyl) -Piperazine, soraphen (eg, soraphen A _1α ), spiro-piperidine, spiro-pyrazolidinedione, spiro [chroman-2,4′-piperidin] -4-one, 5- (tetradecyloxy) -2-furan Carboxylic acid (TOFA), thiazolyl phenyl ether, thiophene [eg, 1- (3-{[4- (3,3-dimethyl-1-oxo-2-oxa-7-azaspiro [4.5] deca- 7-yl) piperidin-1-yl] -carbonyl} -5- (pyridin-2-yl) -2-thienyl) -3-ethylurea] and analogs, derivatives and salts thereof.

  Acyl-CoA cholesterol acyltransferase (ACAT) inhibitors can also be used as anti-dyslipidemic agents. ACAT inhibitors inhibit cholesterol esterification and reduce the production of VLDL and LDL apoB (or the production of apoB-containing VLDL and LDL). Examples of ACAT inhibitors include, but are not limited to, avasimibe, pactimibe, peritrin, terpendole C, and analogs, derivatives and salts thereof.

  Another class of antidyslipidemic agents is the glucagon-like peptide-1 (GLP-1) receptor agonists. GLP-1 Receptor Agonists Reduce Production of Apo B and VLDL Particles, and thus VLDL-Apo B and VLDL-TG, Reduce Cellular Content of Cholesterol and Triglycerides and Reduce Lipogenesis in the Liver To reduce or reverse steatohepatitis (fatty liver). Non-limiting examples of GLP-1 receptor agonists include exendin-4, albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide, taspoglutide, CNTO736, CNTO3649, and analogs, derivatives and salts thereof. Since the endogenous ligand of the GLP-1 receptor, GLP-1, is rapidly degraded by dipeptidyl peptidase 4 (DPP-4), an anti-dyslipidemic effect similar to that of the GLP-1 receptor agonist is DPP. It can be achieved by the use of -4 inhibitors, although their potency is potentially lower. Non-limiting examples of DPP-4 inhibitors include alogliptin, anagliptin, dutogliptin, gemigliptin, linagliptin, saxagliptin, sitagliptin, teneligliptin, vildagliptin, berberine, lupeol, and analogs, derivatives and salts thereof.

  Additional antidyslipidemic agents include inhibitors of microsomal triglyceride transfer protein (MTTP) expressed in RPE cells. MTTP catalyzes the assembly of cholesterol, triglycerides and apo B into chylomicrons and VLDL. MTTP inhibitors inhibit the synthesis of apo B-containing chylomicrons and VLDL, and inhibit the secretion of these lipoproteins. Examples of MTTP inhibitors include, but are not limited to, microRNA (eg, miRNA-30c), implitapide, lomitapide, dilotapide, mitratapide, CP-346086, JTT-130, SLx-4090, and analogs and derivatives thereof. And salt are included. Systemic administration of MTTP inhibitors may result in steatohepatitis (eg, accumulation of triglycerides in the liver). However, it may be, for example, local administration of MTTP inhibitors, use of MTTP inhibitors that are not systemically absorbed (eg SLx-4090), or co-administration of GLP-1 receptor agonists, or any combination or It can be prevented by executing all of them. Another option to avoid steatohepatitis is the use of miRNA-30c. One region of the miRNA-30c sequence reduces MTTP expression and apo B secretion and another region reduces fatty acid synthesis with no adverse liver effects.

  Other types of antidyslipidemic polynucleotides include antisense polynucleotides that target apoB mRNA, including apoB48 and apoB100. Apo B is important for the formation of VLDL and subsequent LDL. Use of an antisense polynucleotide that is wholly or partially (eg, at least about 50%, 60%, 70%, 80%, 90% or 95%) complementary to apoB mRNA results in translational expression of apoB. And thus the production of VLDL and LDL. Examples of antisense polynucleotides that target apo B mRNA include, but are not limited to, mipomersene. Other antidyslipidemic antisense polynucleotides include those that target miRNA-33a and miRNA-33b. miRNA-33a and miRNA-33b suppress the expression of the ATP-binding cassette transporter ABCA1 (cholesterol efflux control protein [CERP]), which mediates efflux of cholesterol and phospholipids. Use of an antisense polynucleotide that is wholly or partially (eg, at least about 50%, 60%, 70%, 80%, 90%, or 95%) complementary to miRNA-33a and / or miRNA-33b is , Increases reverse cholesterol transport and HDL production, and decreases VLDL-TG and fatty acid production. Increased ABCA1 expression is also protective against angiogenesis in AMD.

  Furthermore, cholesteryl ester transfer protein (CETP) inhibitors can also be used as antihyperlipidemic agents. CETP transfers cholesterol from HDL to VLDL and LDL. CETP inhibitors increase levels of HDL, decrease levels of VLDL and LDL, and circulate from the cells, ultimately in the liver, where cholesterol is metabolized and excreted in the bile. Increase cholesterol transport. Examples of CETP inhibitors include, but are not limited to, anacetrapib, darcetrapib, evacetrapib, torcetrapib, AMG899 (TA-8995), and analogs, derivatives and salts thereof.

  Other antidyslipidemic agents that increase cellular lipid (eg, cholesterol) excretion include liver X receptor (LXR) agonists and retinoid X receptor (RXR) agonists. LXR forms a heterodimer with the essential partner RXR. LXR / RXR heterodimers can be activated with either LXR agonists or RXR agonists. Activation of the LXR / RXR heterodimer reduces fatty acid synthesis, circulates from cells and ultimately excretes lipids (eg, cholesterol) into the liver, where cholesterol is metabolized and excreted into bile. To increase. Non-limiting examples of LXR agonists include endogenous ligands (eg, oxysterols (eg, 22 (R) -hydroxycholesterol, 24 (S) -hydroxycholesterol, 27-hydroxycholesterol and cholestenoic acid)), and synthetic Agonists (eg, acetyl-podocalpic dimers, hypocoramides, N, N-dimethyl-3β-hydroxy-colenamide (DMHCA), GW3965, T0901317), and analogs, derivatives and salts thereof are included. Non-limiting examples of RXR agonists include endogenous ligands (eg, 9-cis-retinoic acid), and synthetic agonists (eg, bexarotene, AGN191659, AGN191701, AGN192849, BMS649, LG100268, LG100754, LGD346), and. , Analogs, derivatives and salts thereof.

  AMD can also be treated with PPAR-α and PPAR-γ agonists. The lipid lowering effect of the PPAR-α activated fibrate drug has been described above. Fibrates also reduce the expression of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2), which play a key role in the development of neovascularization including CNV. Examples of PPAR-α agonists include, but are not limited to, fibrate agents and perfluoroalkanoic acids (eg, perfluorooctanoic acid and perfluorononanoic acid). PPAR- [gamma] activated thiazolidinediones also have antihyperlipidemic effects. Like LXR, PPAR-γ forms a heterodimer with RXR. Thiazolidinediones reduce the levels of lipids (eg, fatty acids and triglycerides), increase the levels of HDL (which mediates reverse cholesterol transport), and circulate from the cells, eventually the liver (where Lipids are metabolized and excreted into bile) to increase excretion of lipids. Similar to fibrates, thiazolidinediones also inhibit VEGF-induced angiogenesis. Examples of PPAR-γ agonists include, but are not limited to, thiazolidinediones (eg, ciglitazone, robeglitazone, netoglitazone, pioglitazone, riboglitazone, rosiglitazone, troglitazone), rhodanine, berberine, honokiol, perfluorononanoic acid, and Included are analogs, derivatives and salts thereof.

  Other anti-dyslipidemic PPAR modulators include PPAR-δ agonists. PPAR-δ agonists increase HDL levels, decrease VLDL levels, and increase the expression of cholesterol efflux transporters (eg ABCA1). Non-limiting examples of PPAR- [delta] agonists include GFT505 (dual PPAR- [alpha] / [delta] agonist), GW0742, GW501516, Soderglitazar (GW677954), MBX-8025, and analogs, derivatives and salts thereof. included.

  Antidyslipidemic agents also include the apolipoprotein peptidomimetics described elsewhere herein.

  Another way to increase cholesterol excretion from cells is to increase the level of cardiolipin inside the mitochondrial membrane. Increased cardiolipin content may also prevent or reduce mitochondrial dysfunction. A non-limiting example of an agent that increases levels of cardiolipin inside the mitochondrial membrane is elamipretide (MTP-131), a cardiolipin peroxidase inhibitor and a peptide that targets the mitochondria.

  Steatohepatitis or in the blood if systemic administration of antihyperlipidemic drugs that increase lipid excretion (eg, reverse cholesterol transport) results in steatohepatitis or abnormal blood lipid levels, or the risk of doing so The abnormal lipid level may be, for example, topical administration of an anti-dyslipidemic drug to the eye, co-use of a drug that reduces or reverses steatohepatitis, co-use of a drug that reduces blood lipid level, or any of them. Can be prevented or treated by any combination or all of the above. Examples of agents that reduce or reverse steatohepatitis include, but are not limited to, hepatic adipogenic agents, such as GLP-1 receptor agonists, which are administered systemically for this purpose, eg, systemically. There are cases. A non-limiting example of a blood lipid level reducing agent is a statin, which can be administered systemically for this purpose.

  Other compounds that bind and neutralize and / or aid in the removal of lipids and toxic lipid byproducts (eg, oxidized lipids) can also be used. For example, cyclodextrin has a hydrophilic outer surface but is hydrophobic inside, thus it is capable of forming water-soluble complexes with hydrophobic molecules. Therefore, cyclodextrin (eg, α-cyclodextrin (6-membered sugar ring molecule), β-cyclodextrin (7-membered sugar ring molecule), γ-cyclodextrin (8-membered sugar ring molecule) and their derivatives (eg, methyl -Β-cyclodextrin)) is capable of forming water-soluble inclusion complexes with lipids (eg cholesterol) and toxic lipid by-products (eg oxidized lipids), thus neutralizing their action, It is possible to easily remove them.

  Another class of antidyslipidemic agents are endoplasmic reticulum (ER) modulators (including, but not limited to, azolamide) that restore proper ER function. The ER plays an important role in lipid metabolism. ER dysfunction and chronic ER stress are associated with many pathologies, including obesity and inflammation. Azolamide improves the protein folding ability of the ER and activates the chaperone ability of the ER to protect cells against ER stress.

  It has been reported that AMD is associated with extracellular deposition of apoE and amyloid β (Aβ), including drusen. Aβ deposition has been reported to be involved in the development of inflammation. Thus, anti-amyloid drugs (eg, inhibitors of Aβ formation or aggregation into plaques / deposits, and promoters of Aβ clearance) may potentially be useful in treating AMD. Examples of anti-amyloid agents (eg, anti-Aβ agents) include, but are not limited to, anti-Aβ antibodies (eg, bapinezumab, solanezumab, GSK933776, RN6G [PF4382923], AN-1792, 2H6 and deglycosylated 2H6), anti-amyloid agents. ApoE antibodies (eg HJ6.3), apoE mimetics (eg AEM-28), cystatin C, berberine, L-3-n-butylphthalide, T0901317, and analogs, derivatives, fragments and salts thereof included.

  Elevated levels of other toxic byproducts are also associated with AMD. For example, elevated levels of toxic aldehydes (eg, 4-hydroxynonenal (HNE) and malondialdehyde (MDA)) are present in patients with AMD, especially dry AMD. Agents that inhibit the formation of toxic aldehydes, bind to them, reduce their levels, or promote their degradation or elimination (eg, aldehyde trap NS2) can be used to treat AMD.

  It has also been reported that with age, lipofuscin and its components (eg A2E) accumulate in the RPE as a byproduct of the visual cycle. Lipofuscin bisretinoid A2E inhibits the lysosomal degradation function and cholesterol metabolism in RPE, induces the complement system, mediates blue light-induced apoptosis, and is thus reported to be associated with RPE cell atrophy and cell death. ing. Thus, inhibitors of lipofuscin or components thereof (eg A2E) (inhibitors of their formation or accumulation and promoters of their degradation or elimination) may potentially be useful for treating AMD. .. Examples of inhibitors of lipofuscin or components thereof (eg, A2E) include, but are not limited to, isotretinoin, which inhibits the formation of A2E and the accumulation of lipofuscin pigments; soraprazan, which promotes the release of lipofuscin from RPE cells; and Included are retinol binding protein 4 (RBP4) antagonists (eg, A1120 and compound 43 [cyclopentyl fused pyrrolidine]) that inhibit the formation of lipofuscin bisretinoids such as A2E.

  Another possible way to prevent or reduce the accumulation of lipofuscin bisretinoids (eg A2E) is to interfere with the visual / light cycle in photoreceptor cells. For example, the visual / photocycle modulator fenretinide reduces serum levels of retinol and RBP4 and inhibits retinol binding to RBP4. Thereby, the level of retinoids in the photocycle is reduced, stopping the accumulation of lipofuscin bisretinoids (eg A2E). Other visual / photocycle modulating agents include, but are not limited to, trans to trans-to-cis-retinol isomerase RPE65 (eg, emixstat [ACU-4429] and retinylamine), which are all By inhibiting the conversion of all-trans retinol into 11-cis retinol within the RPE, the amount of retinol available and its downstream byproduct A2E are reduced. Treatment with a light cycle modifier may slow the rate of rod-mediated dark adaptation in the patient. Dark-adapted drugs may be administered to accelerate the rate of dark adaptation. Non-limiting examples of dark-adapted drugs include carotenoids (eg, carotene such as β-carotene), retinoids (eg, all-trans-retinol [vitamin A], 11-cis-retinol, all-trans-retinal [vitamin A aldehyde], 11- Cis-retinal, all-trans retinoic acid [tretinoin] and its ester, 9-cis-retinoic acid [aritretinoin] and its ester, 11-cis retinoic acid and its ester, 13-cis-retinoic acid [isotretinoin] and its ester , Etretinate, acitretin, adapalene, bexarotene and tazarotene), and analogs, derivatives and salts thereof.

Oxidative events play an important role in the pathogenesis of AMD. For example, lipid peroxide accumulation can lead to inflammation and neovascularization. Antioxidants may be administered to prevent AMD, delay its onset, or delay its progression. Antioxidants also exert neuroprotective effects by preventing or reducing toxicity within the retina and interfering with cell death pathways. For example, the mitochondrial-targeted electron trapping agent XJB-5-131 inhibits cardiolipin (mitochondria-specific polyunsaturated phospholipid) oxidation, thereby reducing cell death, including in the brain. In another example, the carotenoids found in saffron, crocin and crocetin, protect cells from apoptosis. In yet another example, xanthophyll (eg, lutein and zeaxanthin) can prevent development of RPE drusen-like lesions, loss of macular pigment, and light-induced photoreceptor cell apoptosis. In yet another example, carnosic acid, a benzenediol abietane diterpene found in rosemary and sage, upregulates antioxidant enzymes, protects retinal cells from the toxicity of hydrogen peroxide, and the outer granular layer. Increase the thickness of. In a further example, curcuminoids found in turmeric (eg, curcumin) can upregulate heme oxygenase-1 and thereby protect RPE cells from hydrogen peroxide-induced apoptosis. As a further example, zinc increases the activity of catalase and glutathione peroxidase, thereby protecting RPE cells and photoreceptor cells from hydrogen peroxide and tert-butyl hydroperoxide, and Protects other retinal cells from caspase-mediated cell death. In a still further example, the cyclopentenone prostaglandin (eg, cyclopentenone 15-deoxy-Δ-prostaglandin J ₂ [15d-PGJ ₂ ]; a ligand for PPAR-γ) is, for example, an antioxidant. Upregulation of glutathione synthesis may protect RPE cells from oxidative damage. Cyclopentenone prostaglandins also retain anti-inflammatory properties.

Non-limiting examples of antioxidants include anthocyanins, apolipoprotein mimetics (eg, Apo AI mimics and Apo E mimetics), benzenediol abietane diterpenes (eg, carnosic acid), carnosine, carotenoids (eg, Carotene [eg, β-carotene], xanthophyll [eg, lutein, zeaxanthin and meso-zeaxanthin], and saffron carotenoids [eg, crocin and crocetin]), curcuminoids (eg, curcumin), cyclopentenone prostaglandins (eg. , _15d-PGJ 2), flavonoids flavonoids (eg, ginkgo-biloba (ginkgo) [example, myricetin and quercetin]), prenylflavonoids (eg, isoxanthohumol), retinoids, stilbenoids (e.g., resveratrol) Uric acid, vitamin A, vitamin B ₁ (thiamin), vitamin B ₂ (riboflavin), vitamin B ₃ (niacin), vitamin B ₆ (eg, pyridoxal, pyridoxamine, 4-pyridoxic acid and pyridoxine), vitamin B ₉ (folic acid) , Vitamin B ₁₂ (cobalamin), vitamin C, vitamin E (eg tocopherol and tocotrienol), selenium, zinc (eg zinc monocysteine), inhibitors and scavengers of lipid peroxidation and its by-products (eg vitamin E [ [Alpha.-tocopherol], tirirazad, NXY-059 and XJB-5-131), an activator of nuclear factor (erythrocyte-derived 2) -like 2 (NFE2L2 or NRF2) (eg, OT-551), superoxide dismutase (eg, OT-551). SOD) mimetics (eg, OT-551) and analogs, derivatives and salts thereof.

Antioxidants can be provided, for example, by food supplements (eg, AREDS or AREDS2 formulations, ICAPS® formulations, Ocuvité® formulations, Saffron2020 ™ or Phototrop®). Copper (eg, cupric oxide or cupric sulfate), but optionally high zinc intake, if the supplement contains relatively high amounts of zinc (eg, zinc acetate, zinc oxide or zinc sulfate) It may be co-administered with zinc to prevent copper deficiency anemia associated with. Saffron 2020 ™ contains saffron, resveratrol, lutein, zeaxanthin, vitamins A, B ₂ , C and E, zinc, and copper. Phototrop® contains acetyl-L-carnitine, omega-3 fatty acids and coenzyme Q ₁₀ . An exemplary aging eye disease test (AREDS) formulation includes β-carotene, vitamin C, vitamin E, zinc (eg, zinc oxide) and copper (eg, cupric oxide).
An exemplary AREDS2 formulation is
1) β-carotene, vitamin C, vitamin E and zinc; or
2) Vitamin C, vitamin E, zinc and copper; or
3) vitamin C, vitamin E and zinc; or
4) β-carotene, vitamin C, vitamin E, omega-3 fatty acids, zinc and copper; or
5) β-carotene, vitamin C, vitamin E, lutein, zeaxanthin, zinc and copper; or
6) Contains β-carotene, vitamin C, vitamin E, lutein, zeaxanthin, omega-3 fatty acids, zinc and copper.
An exemplary ICAPS® formulation is
1) vitamin A, vitamin C, vitamin E, zinc and copper; or
2) Contains vitamin A, vitamin B ₂ , vitamin C, vitamin E, lutein, zeaxanthin, zinc, copper and selenium.
An exemplary Ocuvite® formulation is:
1) vitamin C, vitamin E, lutein, zeaxanthin, zinc and copper; or
2) vitamin C, vitamin E, lutein, zeaxanthin, omega-3 fatty acids, zinc and copper; or
3) Contains vitamin A, vitamin C, vitamin E, lutein, zeaxanthin, zinc, copper and selenium.

Instead of, or in addition to, antioxidants, other neuroprotective agents (neuroprotective agents) may be administered for the treatment of AMD. Neuroprotective agents can be used, for example, to promote the health and / or growth of cells in the retina and / or prevent cell death regardless of initiation event. For example, ciliary neurotrophic factor (CNTF) can rescue photoreceptor cells from degeneration. In another example, glatiramer acetate reduces retinal microglial cytotoxicity (and inflammation). Examples of neuroprotective agents include, but are not limited to, berberine, glatiramer acetate, alpha ₂ - adrenergic receptor agonists (e.g., apraclonidine and brimonidine), serotonin _{5-HT 1A} receptor agonists (e.g., AL-8309B And azapyrone [eg, buspirone, gepirone and tandospirone]), neuroprotectin (eg, neuroprotectin A, B and D1), an endogenous neuroprotective agent (eg, carnosine, CNTF, glial cell derived neurotrophic factor (GDNF)). Family (eg, GDNF, Artemin, Neurturin and Percephine), and Neurotrophin (eg, Brain-Derived Neurotrophic Factor [BDNF]), Nerve Growth Factor [NGF], Neurotrophin-3 [NT-3] and Neurotro. Fin-4 [NT-4])}, prostaglandin analogs (eg, unoprostone isopropyl [UF-021]), and analogs, derivatives, fragments and salts thereof.

  Furthermore, other neuroprotective agents that can be used to treat AMD include retinal associated cells (eg, RPE cells and light) due to apoptosis (programmed cell death) and / or necrosis (characterized by cell swelling and rupture). Receptor cells) are included to prevent the death of the cells. For example, the nucleoside reverse transcriptase inhibitor (NRTI) blocks death of RPE cells through inhibition of P2X7-mediated NLRP3 inflammasome activation of caspase-1, reducing geographic atrophy and CNV. As apoptosis decreases (eg, by inhibition of caspases), necrosis may increase to compensate for the decrease in apoptosis, so an effective strategy to prevent or reduce death of retinal associated cells is to reduce apoptosis and necrosis. It is good to block both. Non-limiting examples of apoptosis inhibitors include caspases (eg, caspase family [eg, Q-VD (OMe) -OPh (SEQ ID NO: 14), Boc-D-FMK (SEQ ID NO: 15), Z-VAD ( SEQ ID NO: 16) and Z-VAD-FMK (SEQ ID NO: 17)], caspase-1 [eg, Z-YVAD-FMK (SEQ ID NO: 18)], caspase-2 [eg, Z-VDVAD-FMK ( SEQ ID NO: 19)], Caspase-3 [eg, Q-DEVD-OPh (SEQ ID NO: 20), Z-DEVD-FMK (SEQ ID NO: 21) and Z-DQMD-FMK (SEQ ID NO: 22)], Caspase-4 [eg, Z-LEVD-FMK (SEQ ID NO: 23)], caspase-5 [eg, Z-WEHD-FMK (SEQ ID NO: 24)], caspase-6 [eg, Z-VEID-FMK ( SEQ ID NO: 25)], caspase-8 [eg, Q-IETD-OPh (SEQ ID NO: 26) and Z-IETD-FMK (SEQ ID NO: 27)], caspase-9 [eg, Q-LEHD-OPh ( SEQ ID NO: 28) and Z-LEHD-FMK (SEQ ID NO: 29)], caspase-10 [eg, AEVD-FMK (SEQ ID NO: 30)], caspase-12 [eg, Z-ATAD-FMK (SEQ ID NO: SEQ ID NO: 28). : 31)] and an inhibitor of caspase-13 [eg, LEED-FMK (SEQ ID NO: 32)]), an inhibitor of inflammasome, an inhibitor of P2X7-mediated NLRP3 activation of caspase 1 (eg, NRTI). (Eg, abacavir [ABC], lamivudine [3TC], stavudine [d4T], me-d4T and zidovudine [AZT])), neuroprotectin, and analogs, derivatives and salts thereof. Examples of necrosis inhibitors include, but are not limited to, caspase inhibitors, inhibitors of receptor interacting protein (RIP) kinases (eg, necrostatins such as necrostatin 1, 5 and 7), necrox compounds (eg. , Neckox-2 and Neckox-5), Nec-1s, and analogs, derivatives and salts thereof.

  Elevated levels of C-reactive protein (CRP) have been found in the blood and eyes of AMD patients. Elevated CRP levels may increase VEGF production, which may lead to neovascularization. CRP is also involved in the development of inflammation and inhibits cholesterol efflux via down-regulation of cholesterol efflux proteins ABCA1 and ABCG1. Moreover, monomeric CRP binds to complement protein C1q and subsequently activates the classical complement pathway. And in concert with the alternative complement pathway, it leads to the formation of the membrane attack complex (MAC) and ultimately to cell lysis. Thus, CRP inhibitors that decrease the level of CRP (eg, via decreasing its production or increasing degradation or elimination) or activity can be used to treat AMD. Examples of CRP inhibitors include, but are not limited to, DPP-4 inhibitors, thiazolidinediones, stilbenoids, statins, epigallocatechin-3-gallate (EGCG), CRP-i2, and analogs, derivatives and salts thereof. Is included.

  The complement system of the innate immune system is involved in the pathogenesis of AMD. For example, variants of the CFH gene that cause a deficiency or deficiency in complement factor H (CFH) are strongly associated with risk of AMD. In addition, the alternative complement pathway may be activated by the accumulation of apolipoprotein (eg, apoE) and lipofuscin or its components (eg, A2E). The membrane attack complex (MAC, C5b-9) has also been demonstrated to be on choroidal vessels, Bruch's membrane (BrM) and RPE, and is associated with abnormal RPE cells. That suggests that complement-mediated cytolysis may accelerate RPE dysfunction and death in AMD. Moreover, there is a significant accumulation of MAC in BrM of the age-related macular and choriocapillaris endothelium. The complement system also plays an important role in inflammatory and oxidative events. As an example, the anaphylatoxins C3a, C4a and C5a mediate inflammation and the production of cytotoxic oxygen radicals. For example, binding of C3a and C5a to the C3a and C5a receptors, respectively, triggers an inflammatory response by, for example, stimulating mast cell-mediated inflammation via histamine release. Activation of the complement cascade and local inflammation are involved, for example, in drusen formation, a hallmark of dry AMD, which can lead to neovascular AMD. The complement system is also involved in neovascularization, including CNV. For example, activation of the complement system can lead to the formation of MAC in the choriocapillary endothelium and degradation by MAC can lead to hypoxia and thus CNV. Furthermore, some complement components (eg C5a) exhibit pro-angiogenic properties. For example, the C5a receptor mediates increased VEGF secretion in RPE cells. Moreover, MACs release pro-angiogenic molecules (eg PDGF and VEGF).

  Alternative to, or in addition to, inhibition of the alternative complement pathway, inhibition of the lectin complement pathway (and / or classical complement pathway) is beneficial for the treatment of atrophic AMD and / or neovascular AMD May be. Inhibition of mannan-binding lectin serine protease (or mannose-related serine protease [MASP]) (eg, MASP-1, -2 or 3) using, for example, an antibody or fragment thereof (eg, OMS721; anti-MASP-2 antibody) Attenuates amplification of complement activation and its sequelae (eg, inflammation). In the lectin pathway, MASP cleaves C2 and C4 to form C2 convertase C2aC4b. At the boundary between the lectin pathway and the alternative pathway, C3 convertase cleaves C3 into C3a and C3b. C3b binds to C2aC4b to form C5-convertase, which cleaves C5 into C5a and C5b. C5b, C6, C7, C8 and C9 together form a membrane attack complex (MAC), which may result in cell lysis via cell swelling and rupture. Complement factors H and I inactivate C3b and downregulate the alternative pathway, thereby suppressing, for example, inflammation. By inhibiting the formation of the C3 convertase C2aC4b, MASP inhibitors may be useful in treating dry AMD and / or neovascular AMD.

Thus, AMD is the complement system or its components (eg proteins, factors) (eg CFB, CFD, C2, C2a, C2b, C4, C4a, C4b, C3 convertase [eg, C2aC4b and C3bBb], C3, C3a. , C3b, C3a receptor, C3 [H ₂ O], C3 [H ₂ O] Bb, C5-convertase [eg, C2aC3bC4b and C3bBbC3b], C5, C5a, C5b, C5a receptor, C6, C7, C8, It can be treated with inhibitors of C9 and MAC [C5b-9]). Illustratively, Lampalizumab is an antigen-binding fragment (F _ab ) of a humanized monoclonal antibody that targets complement factor D (CFD), the rate-limiting enzyme involved in activation of the alternative complement pathway (ACP). CFD cleaves CFB into a proteolytically active factor Bb. Bb spontaneously binds to hydrolyzed C3 [C3 (H ₂ O)], leading to the formation of C5 convertase C3bBbC3b. ACP hyperactivity is involved in the development of AMD, including geographic atrophy (GA). Lampalizumab can be used to inhibit complement activation and inflammation to treat or slow the progression of AMD, including GA. Atrophic AMD patients with mutations in complement factor I (CFI) appear to have a more positive response to lampalizumab treatment. In the MAHALO Phase II study, patients receiving intravitreal injections of 10 mg lampalizumab once a month for 18 months compared to placebo-treated patients showed fundus autofluorescence measurements in the eye of the injection side compared to placebo-treated patients. The area of geographic atrophy was reduced by about 20%. The subgroup of patients who were positive for the CFI biomarker and who received 10 mg of lampalizumab once a month for 18 months had a strong reduction in the area of geographic atrophy of about 44%. CFI, a C3b / C4b inactivator, regulates complement activation by cleaving C3b and C4b in cell-bound or liquid phases.

  Non-limiting examples of inhibitors of the complement system or components thereof include sCR1 (soluble complement receptor 1 [CR1] that promotes C3bBb degradation and inhibits the classical and alternative complement pathways), TT30 ( A fusion protein containing a complement receptor 2 [CR2] and a CFH domain that inhibits the alternative pathway), an anti-CFB antibody and a fragment thereof (eg TA106), an anti-CFD antibody and a fragment thereof (eg Lampalizumab [FCFD4514S]) , Compstatin and its derivatives (eg POT-4 [AL-78898A]) (inhibits C3 and MAC formation), mycophenolic acid-glucosamine conjugate (down regulator of C3), soluble form as C3 inhibitor Proteins or fragments thereof (eg CR1, decay accelerating factor [DAF] and membrane cofactor proteins [MCP or CD46]), 3E7 (anti-C3b / iC3b monoclonal antibody), anti-C5 antibodies and fragments thereof (eg eculizumab [C5] And LFG316), an anti-C5 aptamer (eg, ARC1905 [Zimura (registered trademark)], an inhibitor of C5 cleavage), another C5 inhibitor (eg, Coversin), C5a receptor Body antagonists (eg, JPE-1375, JSM-7717, PMX-025, Ac-F [OPdChaWR] {PMX-53}, and anti-C5aR antibodies and fragments thereof [eg, neutradimab]), Apo AI Mimetics (eg, L-4F, an inhibitor of complement activation), CD59 and modified CD59 with glycolipid anchors (inhibitors of MAC), tandospirone (to reduce complement deposition), zinc (complement) Inhibitors of activation and MAC deposition), and analogs, derivatives, fragments and salts thereof.

  Inflammation is also an important contributor to the pathogenesis of AMD. For example, the inflammatory response may be involved in drusen formation and upregulate the expression of VEGF and other pro-angiogenic factors that give rise to neovascularization, including CNV. Inflammation may be mediated by the cellular immune system (eg, dendritic cells) and / or the humoral immune system (eg, complement system). Inflammation may also be mediated by inflammasome, a component of the innate immune system. For example, accumulation of substances within BrM (eg lipoprotein-like particles, lipids, and in some cases lipofuscin or its components [eg A2E]) can activate the NLRP3 inflammasome, resulting in a chronic inflammatory response. cause. Also, the assembly of inflammasomes (eg, NLRP3) in response to cellular stress signals activates caspases (eg, caspase-1), thereby mediated by inflammation (eg, proinflammatory interleukin-1β production). And finally cell death (eg, of RPE cells) occurs.

  Many substances described in this disclosure have anti-inflammatory properties in addition to the property (s) described for them. Other anti-inflammatory drugs include, but are not limited to, hydroxychloroquine, corticosteroids (eg, fluocinolone acetonide and triamcinolone acetonide), steroids with little glucocorticoid activity (eg, anecortab [anecortab acetate]), Non-steroidal anti-inflammatory drugs (eg, non-selective cyclooxygenase [COX] 1 / COX-2 inhibitors [eg, aspirin] and COX-2 selective inhibitors [eg, coxib]), mast cell stabilizers, and infrastructure Includes masome inhibitors. Examples of inhibitors of inflammasomes (eg, inhibitors of their assembly or function) include, but are not limited to, NLRP3 (NALP3) inhibitors (eg, interleukin 4 [IL-4], omega-3 fatty acids). , Anthraquinone [eg, chrysophanol], sesquiterpene lactone [eg, partenolide], sulfonylurea [eg, glyburide], triterpenoid [eg, asiatic acid] and vinyl sulfone [eg, Bay11-7082]), NLRP3 / AIM2 inhibition Agent (eg, diarylsulfonylurea [eg, CP-456,773]), NLRP1 inhibitor (eg, Bcl-2, Bcl-2 loop region, and Bcl-X [L]), NLRP1B inhibitor (eg, Auranofin), and analogs, derivatives, fragments and salts thereof.

  Non-limiting examples of corticosteroids (without mineralocorticoids) include hydrocortisone forms (eg, cortisone, hydrocortisone [cortisol], prednisolone, methylprednisolone, prednisone and thixocortol), betamethasone forms (eg, betamethasone, dexamethasone and Fluocortron), halogenated steroids (eg, alclomethasone, beclomethasone, clobetasol, clobetasone, desoxymethasone, diflorazone, diflucortron, flupredoneden, fluticasone, halobetasol [urobetasol], halometasone and mometasone), acetonide and related substances (eg. , Amcinonide, budesonide, ciclesonide, desonide, fluocinonide, fluocinolone acetonide, flulandlenolide [fludroxycyclotide], halcinonide, triamcinolone acetonide and triamcinolone), carbonates (eg, prednivalvert), and the like. Body, derivatives and salts are included.

Examples of non-steroidal anti-inflammatory drugs (NSAIDs) include, but are not limited to
Acetic acid derivatives (eg aceclofenac, bromfenac, diclofenac, etodolac, indomethacin, ketorolac, nabumetone, sulindac, sulindac sulfide, sulindac sulfone and tolmethine);
Anthranilic acid derivatives (phenamate) (eg, flufenamic acid, meclofenamic acid, mefenamic acid and tolfenamic acid);
Enolic acid derivatives (oxicam) (eg, droxicam, isoxicam, lornoxicam, meloxicam, piroxicam and tenoxicam);
Propionic acid derivatives (eg, fenoprofen, flurbiprofen, ibuprofen, dexbuprofen, ketoprofen, dexketoprofen, loxoprofen, naproxen and oxaprozin);
Salicylates (eg, diflunisal, salicylic acid, acetylsalicylic acid (aspirin), choline magnesium trisalicylate and salsalate);
COX-2 selective inhibitors (eg, apricoxib, celecoxib, etoricoxib, firocoxib, fluorocoxibs (eg, fluorocoxibs AC), lumiracoxib, mabacoxib, parecoxib, rofecoxib, tilmacoxib (JTE-522), valdecoxib, 4 -O-methylhonokiol, niflumic acid, DuP-697, CG100649, GW406381, NS-398, SC-58125, benzothieno [3,2-d] pyrimidin-4-onesulfonamidethio derivative, and Tribrus terrestris ( A COX-2 inhibitor derived from Tribulus terrestris));
Dual inhibitors of other types of NSAIDs (eg, anilinopyridinecarboxylic acid (eg, clonixin), sulfonanilide (eg, nimesulide), and lipoxygenase (eg, 5-LOX) and cyclooxygenase (eg, COX-2) (Eg, kebragic acid, lycoferon, 2- (3,4,5-trimethoxyphenyl) -4- (N-methylindol-3-yl) thiophene, and di-tert-butylphenol-based compound [eg, DTPBHZ, DTPINH , DTPNHZ and DTPSAL])); and,
Included are analogs, derivatives and salts thereof.

In noncentral and central geographic atrophy, mast cells degranulate in the choroid, releasing histamine and other inflammatory mediators. The mast cell stabilizer stabilizes mast cells by blocking calcium channels essential for mast cell degranulation. It blocks the release of histamine and other inflammatory mediators. Examples of mast cell stabilizers include, but are not limited to, beta ₂ - adrenergic receptor agonists, chromo glycinate, ketotifen, methylxanthines, nedocromil, olopatadine, omalizumab, pemirolast, quercetin, tranilast and its analogs , Derivatives and salts are included. Examples of short-acting β ₂ -adrenergic agonists include, but are not limited to, bitolterol, fenoterol, isoprenaline (isoproterenol), levosalbutamol (levalbuterol), orciprenaline (metaproterenol), pirbuterol, procaterol, Includes ritodrine, salbutamol (albuterol), terbutaline, and their analogs, derivatives, and salts. Non-limiting examples of long-acting β ₂ -adrenergic agonists include alformoterol, bambuterol, clenbuterol, formoterol, salmeterol, and analogs, derivatives and salts thereof. Examples of ultralong-acting β ₂ -adrenergic agonists include, but are not limited to, carmoterol, indacaterol, milveterol, olodaterol, vilanterol, and their analogs, derivatives and salts.

  In summary, examples of anti-inflammatory agents include, but are not limited to, hydroxychloroquine, anti-amyloid agents, antioxidants, apolipoprotein mimetics (eg, apo AI mimetics and apo E mimetics), C-reactive. Protein inhibitors, complement inhibitors, inflammasome inhibitors, neuroprotective agents (eg glatiramer acetate), corticosteroids, steroids with little glucocorticoid activity (eg anecortab), non-steroidal anti-inflammatory drugs (NSAIDs) ), Mast cell stabilizers, cyclopentenone prostaglandins, anti-angiogenic agents (eg, anti-VEGF / VEGFR agents), and immunosuppressive agents.

  Other therapeutic agents that can be used to treat dry AMD and / or neovascular AMD include immunosuppressive agents. Immunosuppressive agents may have anti-inflammatory properties. Examples of immunosuppressive agents include, but are not limited to, inhibitors of interleukin-2 (IL-2) signaling, production or secretion (eg, antagonists of the IL-2 receptor α subunit [eg, basiliximab and Daclizumab], mTOR inhibitors [eg rapamycin (sirolimus), deforolimus (ridaforolimus), everolimus, temsirolimus, umirolimus (biolimus A9) and zotarolimus] and calcineurin inhibitors [eg, cyclosporine, pimecrolimus], tacrolimus]. Inhibitors of necrosis factor (eg TNF-α) (eg adalimumab, certolizumab pegol, etanercept, golimumab and infliximab) are included. As a non-limiting example of the potential benefit of the use of immunosuppressive agents, immunosuppressive agents may be used in the treatment of neovascular AMD to determine the frequency or frequency of administration of anti-angiogenic agents (eg, frequency of injection of anti-VEGF / VEGFR agents or Frequency) can be reduced.

  Matrix metalloproteinases (MMPs) degrade extracellular matrix (ECM) proteins and play important roles in cell migration (dispersion and adhesion), cell proliferation, cell differentiation, angiogenesis and apoptosis. For example, as AMD progresses to advanced stages, elevated levels of MMPs may cause degradation of Bruch's membrane (BrM), ECM, and some of the choroid. Endothelial cells migrate along the ECM to the site of injury, proliferate, form endothelial tubules, and mature into new blood vessels that arise from capillaries in the choroid and grow through damaged BrM. Furthermore, breakage of BrM may cause endothelial cells to migrate into the RPE-BL subspace, forming leaky, tortuous, immature blood vessels, which may spread into the subretinal space. The end result is neovascularization (including CNV) and development of neovascular AMD. MMPs also cleave peptide bonds at cell surface receptors, releasing pro-apoptotic ligands (eg FAS). MMP inhibitors can be used, for example, to inhibit angiogenesis and apoptosis, and include neovascular AMD (including neovascularization of types 1, 2 and / or 3) or (non-central and / or central) Atrophic AMD (including geographic atrophy) can be treated. For example, doxycycline reduces photoreceptor cell loss. Non-limiting examples of MMP inhibitors include tissue inhibitors of metalloproteinases (eg, TIMP 1, 2, 3 and 4), tetracyclines (eg, doxycycline, incyclinide and minocycline), dichloromethylene diphosphonic acid, batimastat, cipemasat. , Ilomastat, Marimasterat, Purinomasterat, Levimasterat, Tanomatastat, ABT-770, MMI-166, MMI-270, Ro28-2653, RS-130830, CAS Registration Number: (CRN) 239796-97-5, CRN420121 -84-2, CRN544678-85-5, CRN5560530-30-3, CRN582311-81-7, CRN848773-43-3, CRN868368-30-3, and analogs, derivatives, fragments and salts thereof.

  Other types of cell migration inhibitors can be used in place of or in addition to MMP inhibitors. For example, rho kinase (ROCK) inhibitors, including ROCK1 and ROCK2 inhibitors, block cell migration, including endothelial cell migration, early in neovascularization. Examples of ROCK inhibitors include, but are not limited to, fasudil, netarsudil, lipasudil, GSK-429286A, RKI-1447, Y-27632 and Y-30141.

  In some situations, it may be desirable to use MMP activators rather than MMP inhibitors. In BrM, there is a steady turnover mediated by MMPs and TIMPs. BrM thickens progressively with aging. This is also due in part to increased TIMP levels and consequently reduced ECM turnover. The thickening of ECM in BrM with aging may result in the lipoproteins secreted by RPE being retained in BrM, ultimately leading to the formation of BLinD and drusen. Deposition of high lipid BLinD and basement membrane deposits (BlamD; excess extracellular matrix in thickened RPE-BL) prolongs the diffusion distance between the choriocapillaris and RPE. The use of MMP activators allows for greater BrM turnover and thinner BrM thicknesses, but BrM is so susceptible to degradation that new blood vessels do not grow through BrM. Examples of MMP activators include, but are not limited to, basigin (extracellular matrix metalloproteinase inducer [EMMPRIN] or CD147), concanavalin A, cytochalasin D, and analogs, derivatives, fragments and salts thereof. Be done. Similarly, matrix metalloproteinases may be employed to reduce the thickness of BLamD on BrM.

  Angiogenesis is the underlying mechanism of neovascularization (including types 1, 2 and 3) and occurs in the advanced stages of AMD and, if left untreated, results in neovascular AMD and severe visual loss. cause. Neovascular AMD is characterized by vascular growth and fluid leakage in the choroid, sub-RPE-BL space, subretinal space and neural retina. Leakage from blood vessels may be responsible for the loss of vision associated with neovascular AMD rather than the growth of new blood vessels. Vascular endothelial growth factor (VEGF) is very important in the pathogenesis of neovascular AMD. VEGF is a potent secretory endothelial mitogen that stimulates endothelial cell migration and proliferation, increasing the permeability of new blood vessels. As a result, body fluids, blood and proteins leak from the blood vessels. VEGF also increases the level of MMPs, which further degrades the ECM. Moreover, VEGF enhances the inflammatory response. However, VEGF or its receptor is not the only potential target for anti-angiogenic drugs. For example, by using an integrin inhibitor (eg, ALG-1001) to target integrin that binds to a receptor tyrosine kinase, the production and growth of new blood vessels is inhibited, and the permeability (leakage) of blood vessels is increased. Decrease. Angiogenesis can also be inhibited through inhibiting other targets, including, but not limited to, kinases (eg, tyrosine kinases such as receptor tyrosine kinases) and phosphatases (eg, receptor tyrosine phosphatases). Such as tyrosine phosphatase).

Anti-angiogenic agents can be used to block or reduce neovascularization (including types 1, 2 and 3) and reduce vascular permeability / leakage. For example, interleukin-18 (IL-18) removes VEGF from the eye, thereby inhibiting the formation of injured blood vessels behind the retina. Non-limiting examples of anti-angiogenic agents include inhibitors of VEGF (eg, squalamine, PAN-90806, anti-VEGF antibodies and fragments thereof (eg, bevacizumab [AVASTIN®]), ranibizumab [LUCENTIS®]]. ), ESBA1008 and ESBA903, anti-VEGF aptamer (eg, pegaptanib [MACUGEN®]), anti-VEGF-designed ankyrin repeat protein [DARPin] (eg, Avisipearl pegol [AGN-150998 or MP0112]), soluble VEGFR. [Eg, VEGFR1], and a soluble fusion protein comprising one or more extracellular domains of one or more VEGFRs [eg, VEGFR1 and VEGFR2] (eg, Aflibercept [EYLEA®] and Convertate)) , VEGF receptor (VEGFR) inhibitors (eg, axitinib, pazopanib, sorafenib, sunitinib, X-82, PF-337210, isoxanthohumol, and anti-VEGFR antibodies and fragments thereof), platelet-derived growth factor (PDGF) (Eg, squalamine, anti-PDGF aptamer (eg, E10030 [FOVISTA (registered trademark)]), anti-PDGF antibody and fragments thereof, and soluble PDGFR) or its receptor (PDGFR) inhibitor (eg, axitinib, Pazopanib, sorafenib, sunitinib, X-82, and anti-PDGFR antibodies and fragments thereof [eg REGN2176-3]), inhibitors of fibroblast growth factor (FGF) (eg squalamine, anti-FGF antibodies and fragments thereof, anti- FGF aptamer and soluble FGFR) or its receptor (FGFR) inhibitor (eg, anti-FGFR antibody and fragment thereof), angiopoietin inhibitor (eg, anti-angiopoietin antibody and fragment thereof (eg, Nesbacumab [REGN910] and REGN910-). 3), and soluble angiopoietin receptor) or its receptor inhibitor (eg, antibody to angiopoietin receptor and fragments thereof), integrin inhibitor (eg, ALG-1001, JSM-6427, and anti-integrin antibody and its) Fragment), anecortab (anecortab acetate), angiostatin (eg, angiostatin K1-3), α _V β ₃ inhibitor (eg, etaracizumab), apo AI mimic (eg, L-4F and L-5F). , Berberine, bleomycin, borrelidin, carboxamidotriazole, cartilage-derived angiogenesis inhibitor (eg , Chondromodulin I and troponin I), castanospermine, CM101, inhibitors of the complement system, cyclopropene fatty acids (eg, sterculic acid), α-difluoromethylornithine, endostatin, everolimus, fumagillin, genistein, interferon-α. , Interleukin-12, interleukin-18, itraconazole, linomid, MMP inhibitor, 2-methoxyestradiol, pigment epithelium-derived factor (PEDF), platelet factor-4, PPAR-α agonist (eg, fibrate drug), PPAR-γ agonist (eg, thiazolidinedione), prolactin, anti-angiogenic siRNA, sphingosine-1-phosphate inhibitor (eg, sonepcizumab), squalene, staurosporine, angiogenesis-suppressing steroid (eg, tetrahydrocortisol), and Heparin, stilbenoids, suramin, SU5416, tasquinimod, tecogalane, tetrathiomolybdate, thalidomide and its derivatives (eg lenalidomide and pomalidomide), thiabendazole, thrombospondin (eg thrombospondin 1), TNP-470, tranilast, withaferin. A, and analogs, derivatives, fragments and salts thereof.

  One or more anti-angiogenic agents may be administered at appropriate times to prevent or reduce the risk of developing a condition that may lead to severe loss of vision. In certain embodiments, one or more anti-angiogenic agents are administered in sufficient amount before scarring (fibrosis) occurs.

  The anti-angiogenic agents described herein may have other beneficial properties. For example, the anti-PDGF aptamer E10030 may also have anti-fibrotic effects by reducing subretinal fibrosis, which may lead to central vision loss in about 10-15% of neovascular AMD patients.

  In some embodiments, two or more anti-angiogenic agents that target different mechanisms of angiogenesis are used to inhibit neovascularization (including types 1, 2, and 3) and to increase vascular permeability. / Reduce leakage and treat neovascular AMD. In certain embodiments, the two or more anti-angiogenic agents include anti-VEGF / VEGFR agents (eg, aflibercept, bevacizumab or ranibizumab) and agents that target different mechanisms of angiogenesis. In some embodiments, the two or more anti-angiogenic agents include an anti-VEGF / VEGFR agent and an anti-PDGF / PDGFR agent (eg, bevacizumab or ranibizumab and E10030, or aflibercept and REGN2176-3). E10030 blocks PDGF-B from binding to the pericyte's natural receptors, causing pericytes to be shed from newly formed abnormal blood vessels. In the unprotected state, endothelial cells are very sensitive to the action of anti-VEGF drugs. Due to this ability to shed pericytes, E10030 may have effects on both immature and more mature blood vessels shortly later in the disease process. In a further embodiment, the two or more anti-angiogenic agents include an anti-VEGF / VEGFR agent and an anti-angiopoietin / angiopoietin receptor agent (eg, aflibercept and Nesbacumab or REGN910-3).

  Alternatively, one anti-angiogenic drug that targets different mechanisms of angiogenesis may be employed to treat, for example, neovascular AMD. For example, a bispecific antibody or DARPin that targets VEGF / VEGFR and PDGF / PDGFR, or a bispecific antibody or DARPin that targets VEGF / VEGFR and angiopoietin / angiopoietin receptors can be used.

AMD can also be treated with other types of therapy (eg, laser photocoagulation therapy (LPT), photodynamic therapy (PDT), radiation therapy (RT)). LPT can use, for example, an Argon (Ar) laser, a micropulse laser or a nanosecond laser, or any combination thereof, and reduce or eliminate drusen in patients with dry AMD or neovascular AMD. .. Laser surgery can also be used to destroy the abnormal blood vessels in the eye, but if the abnormal blood vessels do not grow too wide and the abnormal blood vessels are not too close to the fovea, laser surgery is generally suitable. There is. PDT utilizes a laser in combination with a compound (eg, verteporfin) that is activated by specific wavelengths of light to damage target cells rather than normal cells. Optionally, the steroid may be administered in PDT. PDT is often used to treat polypoid neovascularization, the most common type of neovascularization in Asians. Examples of RT include, but are not limited to, external beam irradiation, focal radiation emission (eg, via intravitreal, transvitreal or transpupillary delivery) (eg, strontium 90 [ ⁹⁰ Sr] at a dose of 15 Gy or 24 Gy). X-rays delivered via the vitreous) and irradiation combined with anti-VEGF / VEGFR drugs (eg, ⁹⁰ Sr X-rays at a single dose of 24 Gy combined with bevacizumab, or 16 Gy X-rays combined with ranibizumab delivered transvitreally). Is included. PDT or RT can be provided to reduce neovascularization (eg, CNV) in neovascular AMD patients and limit visual loss or improve visual acuity. In some embodiments, neovascular AMD patients who do not respond sufficiently to treatment with LPT, PDT or RT, or any combination or all thereof, with an anti-angiogenic drug (eg, anti-VEGF / VEGFR drug). To provide.

  Furthermore, cell replacement therapies and stem cell-based therapies (eg, stem cell derived retinal pigment epithelium (RPE) cells) can be employed to treat AMD. As an illustrative example, apolipoprotein mimetics [eg, apo AI mimics (eg, L-4F) and / or apo E mimetics (eg, AEM-28-14)] in combination with RPE cell replacement It can be used, for example, to treat advanced AMD, including central geographic atrophy and neovascular AMD. RPE cells may atrophy and die as a result of lipid deposition spreading in the RPE-BL subspace and on BrM. Removal of lipid deposits from the RPE-BL subluminal space and BrM normalizes BrM structure and function, and inflows micronutrients (including vitamin A) and outflow waste between the choriocapillaris and RPE. Transport of goods is improved, thereby improving the health of RPE cells. Accordingly, advanced AMD patients are first treated with apo mimetics [eg, Apo AI mimics (eg, L-4F) and / or Apo E mimetics (eg, AEM-28-14)]. And then undergo RPE cell replacement (eg, via one or more injections or transplants into the subretinal space, for example). RPE cells are, for example, RPE cells derived from stem cells (eg, human embryonic stem cells [hESC], human neural stem cells [hNSC], bone marrow stem cells and induced pluripotent stem cells [iPSC] (including autologous stem cells)) or complete cells. It may be RPE cells obtained by migrating a retina of various thickness. Removal of ocular lipid deposits by apomimetics can lead to beneficial effects (eg, reduced local inflammation, oxidative stress and complement activation), which prevents atrophy and death of RPE cells or May help prevent.

  As an example of RPE cell replacement therapy, RPE cells can be introduced as a sheet on a polymer or other suitable carrier material, which allows the cells to combine with the rest of the photoreceptor cells, among other functions. Important phagocytosis and vitamin A transport function can be resumed. Lipid-exclusion apomimetics [eg, apo AI mimics (eg, L-4F) and / or apo E mimetics (eg, AEM-28-14)] flow out with nutrients flowing in across BrM. Improves waste transport, thereby improving cellular health in the surrounding area. Optionally, in combination with agents that reduce the thickness of basement membrane deposits (BLamD) on BrM (eg, matrix metalloproteinases), apomimetics allow the elimination pathway from the choriocapillaris to the transplant matrix. Useful for the preparation of transplant beds suitable for RPE cell sheets that benefit from

  Another example of RPE cell replacement therapy is the introduction of cells into the eye by non-surgical methods. Bone marrow cells can be reprogrammed by populating them on the RPE layer or by being brought to a place surrounded by native RPE cells. The apo mimetic [eg, Apo AI Mimic (eg, L-4F) and / or Apo E Mimetic (eg, AEM-28-14)] is optionally, but not limited to the thickness of BLamD on BrM. In combination with a reducing agent (eg matrix metalloproteinases), it increases the transport of nutrients flowing in and outflowing wastes across BrM, thereby improving the integrity of cells in the RPE layer.

  RPE rejuvenation is also possible. For example, free floating cells (eg, umbilical cord cells) can be injected to provide trophic support to preexisting cells (eg, nerve cells and RPE cells). Lipid-exclusion apomimetics [eg, apo AI mimics (eg, L-4F) and / or apo E mimetics (eg, AEM-28-14)] flow out with nutrients flowing in across BrM. Improves waste transport, thereby improving the integrity of cells in the choroid basin. Optionally, in combination with agents that reduce the thickness of BLamD on BrM (eg, matrix metalloproteinases), apomimetics help to prepare a diffusion bed suitable for infused cells.

  AMD can also be treated by cell replacement therapy for the choriocapillaris. For example, the choriocapillaris endothelium can be replaced with stem cell-derived choriocapillaris endothelial cells.

  Loss / disappearance of blood vessels in the choriocapillaris and diminished choroidal blood flow may occur early in the onset of AMD. In early AMD, choriocapillaris vascular density is inversely correlated with the density of RPE-BL sub-deposits (eg, drusen and BLinD), and the number of "ghost" vessels (remains of previously healthy capillaries). Is positively correlated with the density of RPE-BL sub-deposits. Loss of vascular endothelial cells may be caused by activation of the complement system or MAC formation in the choriocapillaris, and by using complement inhibitors (eg inhibitors of MAC formation, deposition or function) It can be inhibited. The causes of endothelial dysfunction may be: 1) due to a high level of nitric oxide, which is a high level of dimethylarginine, which interferes with L-arginine-stimulated nitric oxide synthesis. Can be corrected by the use of agents that increase nitrogen levels (eg, nitric oxide synthesis stimulants or dimethylarginine formation inhibitors); 2) Increased reactive oxygen species, which can impair nitric oxide synthesis and activity. And can be inhibited by the use of antioxidants (eg, reactive oxygen species scavengers); and 3) the onset of inflammation (which is an agent that inhibits the development of endothelial inflammation (eg, apo AI mimics (eg, Rev-D-4F))). Decreased choroidal blood flow (CBF) may be due to agents that increase CBF (eg, CBF enhancers (eg, MC-1101) or vasodilators (eg, hyperpolarization-mediated [calcium channel blockers (eg, adenosine)]). , CAMP-mediated [eg, prostacyclin], cGMP-mediated [eg, nitric oxide], inhibitors of phosphodiesterase [PDE] [eg, moxaverin or sildenafil {PDE5 inhibitors}], or complement poly that causes contraction of smooth muscle It may be ameliorated by the use of peptides [eg inhibitors of C3a, C4a and C5a] .Increasing CBF can prevent BrM rupture.To treat vascular loss and / or CBF reduction. In addition, one or more therapeutic agents (including the therapeutic agents described herein) that maintain or improve endothelial health and / or blood flow in the vasculature of the eye can be administered at least at initial AMD. is there.

  In some embodiments, an apolipoprotein mimetic (eg, apo AI mimetic [eg, L-4F] and / or an apo E mimetic [eg, AEM-28-14]) treats AMD. For use in combination with one or more additional therapeutic agents. In certain embodiments, the apomimetic and the one or more additional therapeutic agents have a synergistic effect.

VI. Treatment of AMD with Apolipoprotein Mimetics and Anti-Angiogenic Agents Some embodiments of the present disclosure are methods of treating AMD, wherein a therapeutically effective amount of an apolipoprotein (apo) mimetic is administered to a subject in need thereof. And a therapeutically effective amount of an anti-angiogenic agent, wherein the apomimetic is from about 0.1 or 0.3 mg to about 1.5 mg per administration (eg, per injection). A dose may be administered topically to the eye, intraocularly, in or around the eye in a total dose of about 0.5 or 1 mg to about 10 mg over a period of about 6 months. It may or may not be about the method. All embodiments relating to the treatment of AMD with an apolipoprotein mimetic, described in Chapter IV and elsewhere herein, also relate to the treatment of AMD with an apomimetic and an anti-angiogenic agent. Is also applied.

Examples of apolipoprotein mimetics, including Apo AI mimics and Apo E mimetics, include, but are not limited to, those described elsewhere herein. In some embodiments, the apomimetic comprises, or is an Apo AI mimic. In some embodiments, the Apo AI mimetic comprises or is 4F or a variant or salt thereof (eg, acetate). In some embodiments, all amino acid residues in 4F are in the L form (L-4F). In other embodiments, one or more or all amino acid residues of 4F are in D form (eg, D-4F where all amino acid residues are in D form). 4F may have a protecting group (eg, an acyl group (eg, acetyl group)) at the N-terminus and / or a protecting group (eg, an amide group (eg, —C (O) NH ₂ )) at the C-terminus. Good. In some embodiments, Apo A-I mimetic structure Ac-DWFKAFYDKVAEKFKEAF-NH ₂ (SEQ ID NO: 13) containing L-4F with, or is. In a further embodiment, the apo mimetic comprises or is an apo E mimetic. In some embodiments, the ApoE mimetic comprises or is AEM-28-14 or a variant or salt thereof.

  Examples of anti-angiogenic agents include, but are not limited to, those described elsewhere herein. In some embodiments, the anti-angiogenic agent inhibits the action of vascular endothelial growth factor, including, but not limited to, VEGF-A, VEGF-B and placental growth factor (PGF). Or a drug that does (anti-VEGF drug). Non-limiting examples of anti-VEGF agents include those described elsewhere herein. In certain embodiments, the anti-VEGF agent comprises aflibercept (EYLEA®), bevacizumab (AVASTIN®) or ranibizumab (LUCENTIS®), or any combination or all thereof, Or, In a further embodiment, the anti-angiogenic agent includes platelet-derived growth factor including, but not limited to, PDGF-A, PDGF-B, PDGF-C, PDGF-D and PDGF-A / B. Or a drug (anti-PDGF drug) that inhibits the action of 1). Non-limiting examples of anti-PDGF agents include those described elsewhere herein. In certain embodiments, the anti-PDGF agent comprises or is E10030 (FOVISTA®).

  In some embodiments, in the absence of treatment with an apomimetic [eg, apo AI mimic (eg, L-4F) and / or apo E mimetic (eg, AEM-28-14)]. Of anti-angiogenic agents (eg, anti-VEGF agents) at a lower frequency than conventional or recommended dosing of anti-angiogenic agents and / or at lower doses than conventional or recommended doses To do. At that time, the apomimetic is administered at a dose of about 0.1 or 0.3 mg to about 1.5 mg per administration (eg, per injection) or over a period of about 6 months. It may or may not be administered topically at a total dose of 0.5 or 1 mg to about 10 mg. In some embodiments, in the absence of treatment with an apomimetic [eg, apo AI mimic (eg, L-4F) and / or apo E mimetic (eg, AEM-28-14)]. At least about 1.5, 2, 3, 4, 5, or 6 (eg, at least about 2) times less frequently (eg, by intravitreal injection) than the conventional or recommended dosing frequency of anti-angiogenic agents in Administer an anti-angiogenic drug (eg, anti-VEGF drug). In certain embodiments, an anti-angiogenic agent (eg, an anti-VEGF agent) is administered intraocularly, intraocularly, to the eye (eg, by intravitreal injection) once every 2, 3, 4, 5 or 6 months. Or locally around the eye. In a further embodiment, treatment with an apomimetic [eg, Apo AI Mimic (eg, L-4F) and / or Apo E Mimetic (eg, AEM-28-14)] is an anti-angiogenic agent. Decrease the total number of times (eg, anti-VEGF drug) is administered (eg, total number of injections). In certain embodiments, the anti-angiogenic agent (eg, anti-VEGF agent) is administered no more than about 20, 18, 15, 12, or 10 times (eg, by intravitreal injection). In another embodiment, in the absence of treatment with an apomimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)]. At least about 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% (eg, at least about 20%) of a conventional or recommended dose of the anti-angiogenic agent of The anti-angiogenic agent (eg, anti-VEGF agent) is administered at a dose about 10-30%, 30-50%, or 50-70% lower (eg, by intravitreal injection).

  An apo mimetic [eg, apo AI mimetic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] and an anti-angiogenic drug (eg, anti-VEGF drug) The AMD treatment used may have a synergistic effect. For example, treatment with apomimetics (eg, Apo AI and / or Apo E mimetics) can potentiate the efficacy of anti-angiogenic agents and vice versa. As an example, L-4F significantly reduces lipid deposits from Bruch's membrane (BrM) and structurally remodels BrM to a normal or more healthy state, thereby leading to neovascularization of types 1 and 2 ( In NV), BrM is less susceptible to invasion of new blood vessels that grow from the choroid through BrM into the RPE-BL and subretinal spaces. In another example, an anti-angiogenic agent is the ability of L-4F to reduce the key NV stimulus, inflammation (eg, through inhibition of activation of the complement system and formation of pro-inflammatory oxidative lipids). It is possible to reduce the required frequency and / or dose of (eg, by injection). The synergism between an apomimetic (eg, Apo AI and / or Apo E mimetic) and an anti-angiogenic agent is due to the apo mimetic (eg, Apo AI and / or Apo E). Less than conventional or recommended dosing frequency of an anti-angiogenic agent in the absence of treatment with a mimetic) and / or at a lower than conventional or recommended dose, for example: Allows administration of anti-angiogenic agents but is not required.

  Administration of lower doses of anti-angiogenic agents may have benefits (eg, better safety profile due to fewer side effects). Less frequent administration of anti-angiogenic agents (eg, by intravitreal injection) also results in greater / good patient comfort, convenience, and compliance due to less invasive procedures being performed. There may be benefits such as health. Frequent dosing can be burdensome for both health care providers and patients because of frequent visits for testing, monitoring, and treatment. Furthermore, anti-angiogenic agents (eg, anti-VEGF agents) may become less effective with repeated use (a phenomenon known as tachyphylaxis). In addition, the risks of intravitreal injections include elevated intraocular pressure, bacterial and sterile endophthalmitis, cataract formation, hemorrhage and retinal detachment, and repeated injections thin the retina and cause map-like atrophy. May occur.

  In certain embodiments, the anti-angiogenic agent comprises or is aflibercept (EYLEA®), and an apo mimetic [eg, Apo AI mimic (eg, L-4F) and / Or ApoE mimetics (eg, AEM-28-14)] in the absence of treatment with a 2 mg dose once a month for the first 3 months followed by an intravitreal injection once every two months. When compared to the conventional or recommended dose and dosing frequency of 2 mg aflibercept, which is optional, once a month for the first 1, 2 or 3 months, or the first 1. After administration at a dose of about 1-1.5 mg or 1.5-2 mg once every 6 weeks for 5 or 3 months, then about 1-1.5 mg or 1 once every 3, 4, 5 or 6 months. Administer aflibercept at a dose of 0.5-2 mg (eg, by intravitreal injection). The intravitreal half-life of aflibercept is estimated to be approximately 9.0 days.

  In other embodiments, the anti-angiogenic agent comprises or is aflibercept, and is an apo mimetic [eg, apo AI mimic (eg, L-4F) and / or apo E mimetic. (Eg, AEM-28-14)] at about 1 to 1.25 mg substantially similar to or at a conventional or recommended dosing frequency of aflibercept in the absence of treatment with , 1.25-1.5 mg or 1.5-1.75 mg (eg, by intravitreal injection).

  In a further embodiment, the anti-angiogenic agent comprises or is ranibizumab (LUCENTIS®), and is an apo mimetic [eg, apo AI mimic (eg, L-4F) and / or Conventional or recommended dose and dosing frequency of 0.5 mg ranibizumab administered by intravitreal injection once a month in the absence of treatment with an ApoE mimetic (eg, AEM-28-14). By comparison with, optionally, about 0.2 to 0 once a month for the first 1, 2 or 3 months, or once every 6 weeks for the first 1.5 or 3 months. About 0.2-0.3 mg, 0.3 once every 2, 3, 4, 5 or 6 months after administration at a dose of 3 mg, 0.3-0.4 mg or 0.4-0.5 mg. Ranibizumab is administered at a dose of ~ 0.4 mg or 0.4-0.5 mg (eg, by intravitreal injection). The intravitreal half-life of ranibizumab is estimated to be about 7.1 days.

  In other embodiments, the anti-angiogenic agent comprises, or is ranibizumab, and at a dose of about 0.2-0.3 mg or 0.3-0.4 mg once a month (eg, glass. Administer ranibizumab (by internal injection).

  In another embodiment, the anti-angiogenic agent comprises or is bevacizumab (AVASTIN®), and an apo mimetic [eg, apo AI mimic (eg, L-4F) and / or Or about 1.25 mg of AMD therapeutic bevacizumab administered by intravitreal injection once a month in the absence of treatment with an ApoE mimetic (eg, AEM-28-14)]. Compared to the dose and frequency of administration, it is optional, but once a month for the first 1, 2 or 3 months, or once every 6 weeks for the first 1.5 or 3 months. Approximately 0.5 to 0.75 mg, once every 2, 3, 4, 5 or 6 months after administration at a dose of 0.5 to 0.75 mg, 0.75 to 1 mg or 1 to 1.25 mg. Bevacizumab is administered at a dose of 75-1 mg or 1-1.25 mg (eg, by intravitreal injection). The intravitreal half-life of bevacizumab is estimated to be about 9.8 days.

  In other embodiments, the anti-angiogenic agent comprises or is bevacizumab, and at a dose of about 0.5-0.75 mg or 0.75-1 mg once a month (eg, intravitreal injection). Bevacizumab).

  In some embodiments, the duration / length of treatment with the anti-angiogenic drug (eg, anti-VEGF drug) is within about 36, 30, 24, 18 or 12 months. In certain embodiments, the length of treatment with the anti-angiogenic drug (eg, anti-VEGF drug) is within about 24, 18 or 12 months. In a further embodiment, the length of treatment with the anti-angiogenic drug (eg, anti-VEGF drug) is about 6-12, 12-18 or 18-24 months.

  In some embodiments, an anti-angiogenic drug (eg, an anti-VEGF drug) is administered to include neovascularization (NV) type 1, 2 and 3 and there are signs of neovascularization activation. Treatment of neovascular AMD (wet type), or delaying its progression. The presence of fluid under RPE-BL, under the retina or in the retina (meaning activation of neovascularization and fluid leakage from new blood vessels) can be detected by techniques such as OCT fluorescein angiography. In certain embodiments, an anti-angiogenic agent (eg, an anti-VEGF agent) is administered when the presence of fluid is detected under or within the retina. Anti-angiogenic drugs (eg, anti-VEGF drugs) can also be used when RPE-BL semen is detected. However, pigment epithelium detachment caused by RPE-BL semen may remain stable for a relatively long period of time and may not require anti-angiogenic therapy. In a further embodiment, an anti-angiogenic drug (eg, an anti-VEGF drug) is administered at least during the advanced stages of AMD to prevent, delay its onset, or delay its progression. In certain embodiments, anti-angiogenic agents (eg, anti-VEGF agents) are administered less frequently and / or at lower doses (eg, by intravitreal injection) to treat or treat neovascular AMD. Rather than slowing its progression, it prevents neovascular AMD, delays its onset, or slows its progression.

  With respect to the apomimetic, in some embodiments, the apomimetic [eg, apo AI mimic (eg, L-4F) and / or apo E mimetic (eg, AEM-28-14)] is given once. Per administration (eg, per injection) about 0.1 or 0.3-1.5 mg, 0.1-0.5 mg, 0.5-1 mg, 1-1.5 mg, 0.1-0 .3 mg, 0.3 to 0.5 mg, 0.5 to 0.75 mg, 0.75 to 1 mg, 1 to 1.25 mg or 1.25 to 1.5 mg (eg, about 0.1 to 0.5 mg or 0.5-1 mg) is administered topically to the eye (eg, by intravitreal injection), intraocularly, into the eye, or around the eye. The apomimetic can also be topically administered at a dose of greater than 1.5 mg per dose, such as up to about 2 mg per dose (eg, per injection) or more. In a further embodiment, the apo mimetic [eg, Apo AI mimic (eg, L-4F) and / or Apo E mimetic (eg, AEM-28-14)] is administered for a period of about 6 months. About 0.5 or 1-10 mg over time (where the duration / length of treatment with the apomimetic may be, for example, about 6-12, 12-18 or 18-24 months or more) , 0.5 or 1 to 5 mg, 5 to 10 mg, 0.5 or 1 to 3 mg, 3 to 5 mg, 5 to 7.5 mg or 7.5 to 10 mg (eg, about 0.5 to 3 mg or 3 to 5 mg) Locally (eg, by intravitreal injection or via a sustained release composition). The apomimetic can also be topically administered at a total dose of greater than 10 mg over about 6 months, such as up to about 15 mg or more over about 6 months. In a further embodiment, an apomimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] is used to treat the apo mimetic. About 1 or 2 to 20 mg, 5 to 15 mg, 1 to 5 mg, 5 to 10 mg, 10 to 15 mg, 15 to 20 mg, 1 to 3 mg, 3 to 5 mg, 5 to 7.5 mg and 7. Topically administered in a total dose of 5-10 mg, 10-12.5 mg, 12.5-15 mg, 15-17.5 mg, or 17.5-20 mg (eg, about 1-5 mg or 5-10 mg). The apomimetic can also be administered locally in a total dose greater than 20 mg for the entire treatment regimen, such as up to about 25 mg, 30 mg, 40 mg, 50 mg or more for the entire treatment regimen.

  An apo mimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] to the eye, intraocularly, in the eye, or In embodiments that are administered locally around the eye, the dose per administration, the total dose over a period of about 6 months, and the total dose for the entire treatment regimen are, in certain embodiments, per eye administered. And in other embodiments for both eyes. The blood system may allow some (eg, therapeutically effective) amount of apomimetic locally administered (eg, injected) into or in one eye to circulate in the other eye. .. In that case, the dose of the apomimetic can be adjusted arbitrarily (eg, increased) in view of the other eye (which may have milder symptoms of the disease). This may allow treatment of both eyes with the apomimetic at the same time without further administration (eg, injection) of the apomimetic in or into the other eye. For example, intravitreally injected apomimetics can cross the blood-retinal barrier and reach two target regions (RPE-BL subluminal and Bruch's membrane). From there, the apomimetic may enter the choriocapillaris and eventually the other non-administering eye. While not intending to be bound by theory, some amount of the apomimetic is mediated by aqueous humor (exhausted through the trabecular meshwork and Schlemm's canal into the blood system). May enter the other non-administered eye. Accordingly, some embodiments include a method of treating AMD comprising administering to a subject in need thereof a therapeutically effective amount of an apomimetic and a therapeutically effective amount of an anti-angiogenic agent, The invention relates to a method wherein an apomimetic is topically administered to one eye, intraocularly, in or around the eye, to have a therapeutic effect on both eyes.

  In another embodiment, the apo mimetic [eg, Apo AI mimetic (eg, L-4F) and / or Apo E mimetic (eg, AEM-28-14)] is administered for 1 month (4 weeks). ) Or once every 1.5 months (6 weeks) (eg, by intravitreal injection). In another embodiment, the apo mimetic [eg, Apo AI mimic (eg, L-4F) and / or Apo E mimetic (eg, AEM-28-14)] is given for 2 months (8 weeks). ), Once every 2.5 months (10 weeks) or once every 3 months (12 weeks) (eg, by intravitreal injection). In still other embodiments, the apo mimetic [eg, apo AI mimic (eg, L-4F) and / or apo E mimetic (eg, AEM-28-14)] is added to 4, 5 or 6 Topical administration once a month (eg, by intravitreal injection or via a sustained release composition). In a further embodiment, the apomimetic [e.g., apo AI mimic (e.g., L-4F) and / or the apo E mimetic (e.g., AEM-28-14)] is added for a total of about 15 or less, 12 or less. Local administration is performed by administration (eg, injection) less than 9 times, less than 9 times, less than 6 times or less than 3 times (eg, 3 to 6 times or 7 to 10 times). The apomimetic can also be administered topically in a total of more than 15 administrations (eg, injections), such as up to about 20 or more administrations (eg, injections) in total. In embodiments in which the apomimetic is locally administered to, intraocularly, in, or around the eye, the frequency of administration and the total number of administrations (eg, injections) may be, in certain embodiments, per eye administered. Yes, in other embodiments, both eyes (because the apomimetic may also be therapeutically effective in the other non-administered eye).

  In some embodiments, the apomimetic [eg, Apo AI mimic (eg, L-4F) and / or Apo E mimetic (eg, AEM-28-14)] is added to at least the advanced stage of AMD. To treat or slow the progression of neovascular AMD, including NVs 1, 2, and 3. In a further embodiment, the apomimetic [eg, Apo AI Mimic (eg, L-4F) and / or Apo E Mimetic (eg, AEM-28-14)] is administered at least during the advanced phase of AMD. To treat central geographic atrophy (GA) or delay its progression and / or prevent neovascular AMD or delay its onset. In another embodiment, an apomimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] is administered at least mid-stage of AMD. To treat or delay the progression of non-central GA and / or prevent or delay the onset of central GA and / or neovascular AMD.

  In some embodiments, an apo mimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] and / or anti-vascular Newborn drugs (eg, anti-VEGF drugs) are administered topically to, intraocularly, in, or around the eye. Possible routes, sites and means of topical administration are described elsewhere in this specification. In some embodiments, an apo mimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] and / or anti-vascular Administration of new drug (eg, anti-VEGF drug) by injection (eg, intravitreal, subconjunctival, subretinal or subtenon injection), eye drop or transplant (eg, intravitreal, subretinal or subtenon transplant) . In certain embodiments, an apomimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] and an anti-angiogenic agent (eg, anti-angiogenic agent). VEGF drug) and is administered by injection (eg, intravitreal, subconjunctival, subretinal or subtenon injection). In a further embodiment, an apomimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] and / or an anti-angiogenic agent (Eg, anti-VEGF drug) is administered via a sustained release composition. Non-limiting examples of sustained release compositions include those described elsewhere herein.

  In some embodiments, an apo mimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] is applied to the eye early in treatment. In contrast, topical administration is intraocularly, in or around the eye, followed by systemic administration of the apomimetic. By way of non-limiting example, the initial dose (s) of the apomimetic (eg, the first to fifth doses) may be given by injection (eg, intravitreal, subconjunctival, subretinal or subtenon injection). ), Followed by subsequent administration (s) of the apomimetic is, for example, oral, parenteral (eg, subcutaneous, intramuscular or intravenous), or topical (eg, intranasal). Or it may be systemic (such as lungs). In other embodiments, the apomimetic is administered topically only. In yet another embodiment, the apomimetic is administered systemically only.

  Apo mimetic [eg, Apo AI mimic (eg, L-4F or variant or salt thereof) and / or Apo E mimetic (eg, AEM-28-14 or variant or salt thereof]] The angiogenic agent (eg, anti-VEGF agent (eg, aflibercept, bevacizumab and / or ranibizumab)) can be in the same pharmaceutical composition or in separate pharmaceutical compositions (the composition being further one or more pharmaceutically acceptable). (Including an excipient or a carrier). If the apomimetic (eg, Apo AI and / or Apo E mimetic) and the anti-angiogenic agent are administered via the same composition, such composition may be prepared in advance. Or by combining the apomimetic and the anti-angiogenic agent in the same formulation shortly before or just before the formulation is administered (eg, by injection). It can be prepared. Administration of an apomimetic (eg, Apo AI mimetic and / or Apo E mimetic) and an anti-angiogenic agent in the same composition is potentially invasive compared to administration of the therapeutic agents separately. Fewer patients are given sexual treatment (eg, intravitreal injection). This may have benefits such as improved patient compliance and health due to less invasive procedures being performed.

  In certain embodiments, a composition comprising an apo mimetic [eg, an apo AI mimic (eg, L-4F) and / or an apo E mimic (eg, AEM-28-14)] The neoplastic drug (eg, with or without an anti-VEGF drug) is about 75-95% (eg, about 90%) apomimetic (eg, about 90%) by weight or molar amount relative to its total amount. One or more and about 5 to 25% (eg, about 10%) of the corresponding apolipoprotein (s) (eg, apo AI and / or apo E) or active portion or domain thereof.

  In some embodiments, a composition comprising an apo mimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)], and / or Alternatively, the composition comprising an anti-angiogenic agent (eg, an anti-VEGF agent) (whether in the same composition or in separate compositions) comprises one or more excipients and the peptide / Inhibiting aggregation of proteins / proteins, increasing solubility of peptides / proteins, decreasing solution viscosity, or increasing stability of peptides / proteins, or performing any combination or all thereof .. Examples of such excipients include, but are not limited to, those described elsewhere herein, and the use of such excipients is not otherwise limited herein. May have the benefits described in section. For example, such excipients may improve the injectability of the composition and allow the use of smaller injection standard needles. Moreover, the use of such excipients can reduce the volume required to administer a given amount of peptide or protein. Therefore, intraocular pressure when the peptide or protein is administered by injection into the eye can be reduced. Also, the use of such excipients may allow higher doses of peptide or protein to be administered in a given volume. This allows the peptide or protein to be administered less frequently relative to a given total dose administered over a period of time.

  In some embodiments, in the absence of treatment with an apomimetic [eg, apo AI mimic (eg, L-4F) and / or apo E mimetic (eg, AEM-28-14)]. Anti-angiogenic agent (eg, by intravitreal injection) at a dose higher than the conventional or recommended dose of the anti-angiogenic agent at Anti-VEGF drug). In certain embodiments, in the absence of treatment with an apomimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)]. At least about 10%, 20%, 30%, 50%, 75%, 100%, 150% or 200% (eg, at least about 30%), or about the conventional or recommended dose of the anti-angiogenic agent. 10-30%, 30-50%, 50-100%, 100-150% or 150-200% (eg, about 50-100%) High doses (eg, by intravitreal injection) of anti-angiogenic agents (eg, by intravitreal injection) , Anti-VEGF drug). In a further embodiment, in the absence of treatment with an apo mimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)]. Antivascular with at least about 1.5, 2, 3, 4, 5, or 6 (eg, at least about 2) times less frequent (eg, by intravitreal injection) than the conventional or recommended dosing frequency of anti-angiogenic agents. Administer new drugs (eg, anti-VEGF drugs).

  In certain embodiments, the anti-angiogenic agent comprises or is aflibercept (EYLEA®), and an apo mimetic [eg, Apo AI mimetic (eg, L-4F) and / Or ApoE mimetic (eg, AEM-28-14)] in the absence of treatment with a 2 mg dose once a month for the first 3 months followed by an intravitreal injection once every two months. When compared to the conventional or recommended dose and dosing frequency of 2 mg aflibercept, which is optional, once a month for the first 1, 2 or 3 months, or for the first 1.5 Or 3, 4, 5 or 6 after administration at a dose of about 2.2-2.5 mg, 2.5-3 mg, 3-3.5 mg or 3.5-4 mg once every 6 weeks for 3 months. Aflibercept is administered once monthly (eg, by intravitreal injection) at a dose of about 2.2-2.5 mg, 2.5-3 mg, 3-3.5 mg or 3.5-4 mg.

  In other embodiments, the anti-angiogenic agent comprises or is ranibizumab (LUCENTIS®) and is an apo mimetic [eg, apo AI mimic (eg, L-4F) and / or Or conventional or recommended dose and dosing of 0.5 mg ranibizumab administered by intravitreal injection once a month in the absence of treatment with an ApoE mimetic (eg, AEM-28-14). Compared to frequency, but optionally, about 0.55 once a month for the first 1, 2 or 3 months, or once every 6 weeks for the first 1.5 or 3 months. About 0.55-0.25 once every 2, 3, 4, 5 or 6 months after administration at a dose of 0.75 mg, 0.75-1 mg, 1-1.25 mg or 1.25-1.5 mg. Ranibizumab is administered at a dose of 75 mg, 0.75-1 mg, 1-1.25 mg or 1.25-1.5 mg (eg, by intravitreal injection).

  In yet another embodiment, the anti-angiogenic agent comprises or is bevacizumab (AVASTIN®), and an apo mimetic [eg, apo AI mimic (eg, L-4F) and / Or apoE mimetic (eg, AEM-28-14)] conventional or recommended about 1.25 mg of AMD therapeutic bevacizumab administered by intravitreal injection once a month in the absence of treatment. Optionally, once a month for the first 1, 2 or 3 months, or once every 6 weeks for the first 1.5 or 3 months, as compared to the dose and frequency of administration. About 1.4 to 1.75 mg, 1.75 to 2 mg, 2 to 2.5 mg, or 2.5 to 3 mg after administration, once every 2, 3, 4, 5 or 6 months. Bevacizumab is administered (eg, by intravitreal injection) at a dose of ˜1.75 mg, 1.75-2 mg, 2-2.5 mg or 2.5-3 mg.

  One or more other therapeutic agents described herein are apomimetics [eg, apoA-I mimics (eg, L-4F) and / or apoE mimetics for the treatment of AMD. (Eg, AEM-28-14)] and an anti-angiogenic drug (eg, anti-VEGF drug) can be used in combination. In some embodiments, the additional therapeutic agent (s) is an antihyperlipidemic agent (eg, statin such as atorvastatin), antioxidant (eg, vitamins, saffron carotenoids and / or zinc) or complement inhibition. Or an agent (eg, a C5 inhibitor such as ARC1905 or LFG316, or a complement factor D inhibitor such as lampalizumab), or any combination thereof, or all thereof. Use of apomimetics [eg, apo AI mimics (eg, L-4F) and / or apo E mimetics (eg, AEM-28-14)] ameliorates changes in lipid homeostasis or oxidation. It may enhance the efficacy of one or more other therapeutic agents that reduce stress and / or suppress inflammation. In certain embodiments, the additional therapeutic agent comprises or is ARC1905 or LFG316.

  In some embodiments, an apomimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] and an anti-angiogenic drug (eg. , An anti-VEGF drug), an anti-inflammatory agent (eg, NSAID such as bromfenac, and / or a corticosteroid such as triamcinolone acetonide), or an immunosuppressant (eg, daclizumab) for treating neovascular AMD. Or an IL-2 inhibitor such as rapamycin or a TNF-α inhibitor such as infliximab). Inflammation is a stimulus to NV, and therefore anti-inflammatory or immunosuppressive agents may suppress NV. Thus, the use of anti-inflammatory or immunosuppressive agents may reduce the frequency or frequency of (eg, injection) administration of anti-angiogenic agents. In a further embodiment, an apomimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] and an anti-angiogenic agent (eg, anti-angiogenic agent). VEGF drug) in combination with a neuroprotective agent (eg, an endogenous neuroprotective agent (eg, CNTF)). The use of neuroprotective agents can prevent or reduce degeneration of retinal cells (eg, photoreceptor cells).

  In some embodiments, the additional therapeutic agent (s) is administered at least during the advanced stages of AMD. In a further embodiment, the additional therapeutic agent (s) is administered at least mid-stage of AMD. In a further embodiment, the additional therapeutic agent (s) is administered at least early in AMD. In certain embodiments, the additional therapeutic agent (s) administered at least early in AMD are anti-dyslipidemic agents (eg, statins) that reduce lipid production, and optionally, antioxidants (eg, , Vitamins, saffron carotenoids and / or zinc) and / or anti-inflammatory agents (eg NSAIDs). The additional therapeutic agent (s) is then administered systemically (eg, orally) or locally (eg, by eye drop).

  An apo mimetic [eg, apo AI mimetic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] is used as an anti-angiogenic agent (eg, aflibercept, bevacizumab). Or in combination with an anti-VEGF drug such as ranibizumab and / or an anti-PDGF drug such as E10030) to treat other eye diseases and disorders in addition to AMD. Non-limiting examples of other eye diseases and disorders treatable with such combinations include diabetic macular disease (DMP) (including partial ischemic DMP), diabetic macular edema (DME) (of clinical significance). DME [CSME], including focal DME and diffuse DME), diabetic retinopathy (including in DME patients), retinal vein occlusion (RVO), central RVO (cystic macular edema [CME] with central RVO (including RVO), branched RVO (including branched RVO with CME), macular edema after RVO (including central RVO and branched RVO), Irvine-Gas syndrome (postoperative macular edema), and uveitis (CME). (Including posterior uveitis). The beneficial properties (eg, potent anti-inflammatory) of apomimetics [eg, Apo AI Mimics (eg, L-4F) and / or Apo E Mimetics (eg, AEM-28-14)] are , May increase the effectiveness of anti-angiogenic agents (eg, anti-VEGF agents) in the treatment of such eye diseases and disorders. Apomimetic [eg, Apo AI Mimic (eg, L-4F) and / or Apo E Mimetic (eg, AEM-28-14)] and an anti-angiogenic drug (eg, anti-VEGF drug) Embodiments relating to the treatment of AMD with agents also find application in the treatment of other eye diseases and disorders using such combination agents.

VII. Treatment of AMD with Apolipoprotein Mimetics and Complement Inhibitors A further embodiment of the present disclosure is a method of treating AMD, comprising treating a subject in need thereof with a therapeutically effective amount of apolipoprotein (apo) mimetics. Administering an effective amount of a complement inhibitor, wherein the apomimetic is a dose of about 0.1 or 0.3 mg to about 1.5 mg per administration (eg, per injection), Alternatively, it may be administered topically, intraocularly, into or around the eye, at a total dose of about 0.5 or 1 mg to about 10 mg over a period of about 6 months. It may or may not be about the method. All embodiments relating to the treatment of AMD with an apolipoprotein mimetic described in Chapter IV or elsewhere herein also relate to treatment of AMD with an apomimetic and a complement inhibitor. Is also applied.

Examples of apolipoprotein mimetics, including Apo AI mimics and Apo E mimetics, include, but are not limited to, those described elsewhere herein. In some embodiments, the apomimetic comprises, or is an Apo AI mimic. In some embodiments, the Apo AI mimetic comprises or is 4F or a variant or salt thereof (eg, acetate). In some embodiments, all amino acid residues in 4F are in the L form (L-4F). In other embodiments, one or more or all amino acid residues of 4F are in D form (eg, D-4F where all amino acid residues are in D form). 4F may have a protecting group (eg, an acyl group (eg, acetyl group)) at the N-terminus and / or a protecting group (eg, an amide group (eg, —C (O) NH ₂ )) at the C-terminus. Good. In some embodiments, Apo A-I mimetic structure Ac-DWFKAFYDKVAEKFKEAF-NH ₂ (SEQ ID NO: 13) containing L-4F with, or is. In a further embodiment, the apo mimetic comprises or is an apo E mimetic. In some embodiments, the ApoE mimetic comprises or is AEM-28-14 or a variant or salt thereof.

  Non-limiting examples of complement inhibitors include those described elsewhere herein. In some embodiments, the complement inhibitor comprises or is ramparizumab, LFG316 or ARC1905 (ZIMURA®), or any combination or all thereof. In certain embodiments, the complement inhibitor comprises or is rampalizumab. In some embodiments, the subject has a mutation in the gene encoding complement factor I (CFI), which may be a biomarker for being positively responsive to treatment with lampalizumab. CFI, a C3b / C4b inactivator, regulates complement activation by cleaving C3b and C4b in cell-bound or liquid phase.

  In some embodiments, apomimetics [eg, Apo AI mimics (eg, L-4F) and / or Apo E mimetics (eg, AEM-28-14)] and complement inhibitors (eg. , Lamparizumab) to treat geographic atrophy (GA). In some embodiments, apomimetics [eg, Apo AI mimics (eg, L-4F) and / or Apo E mimetics (eg, AEM-28-14)] and complement inhibitors (eg. , Ramparizumab) to prevent central GA, delay its onset, or delay its progression. In certain embodiments, an apomimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] and a complement inhibitor (eg, rampalizumab). ) And at least during the advanced (late) stage of atrophic (dry) AMD to treat central GA or delay its progression, and / or prevent neovascular AMD or its Delay onset. In a further embodiment, an apomimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] and a complement inhibitor (eg, rampalizumab). ) And at least mid-stage of AMD to treat non-central GA or delay its progression and / or prevent central GA and / or neovascular AMD or delay its onset .. In another embodiment, an apo mimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] and a complement inhibitor (eg, Lamparizumab) is administered at least during the early phase of AMD or in the early phase of mid-stage AMD to prevent or delay the onset of non-central GA. In certain embodiments, complement inhibitors (eg, Lampalizumab) and / or apo mimetics [eg, Apo AI mimics (eg, L-4F) and / or Apo E mimetics (eg, AEM-28-). 14)] is administered less frequently and / or at lower doses to prevent or develop non-central or central GA, rather than to treat or slow the progression of central GA. Delay.

  In certain embodiments, an apomimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] and a complement inhibitor (eg, rampalizumab). Treatment with at least about 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% (eg, at least about 20% or 40%), or about 20-40. %, 40-60% or 60-80%, slow the progression of central GA and / or non-central GA (eg, reduce the rate of GA progression or reduce GA lesion area or size). In a further embodiment, an apo mimetic [eg, apo AI mimic (eg L-4F) and / or an apo E mimetic (eg AEM-28-14)] and a complement inhibitor (eg ramparizumab). ) And treatment with at least about 10%, 20%, 30%, 50%, 100%, 150%, 200% of treatment with a complement inhibitor in the absence of treatment with an apomimetic. % Or 300% (eg at least about 20% or 30%), or about 10-30%, 30-50%, 50-100%, 100-200% or 200-300% (eg about 50-100). %) Often slows the progression of central and / or non-central GA (eg, reduces the rate of GA progression or reduces GA lesion area or size).

  AMD with apomimetics [eg, apo AI mimics (eg, L-4F) and / or apo E mimetics (eg, AEM-28-14)] and complement inhibitors (eg ramparizumab) Treatment (including central and non-central GA) may have a synergistic effect. For example, treatment with apomimetics (eg, ApoA-I and / or ApoE mimetics) can enhance the efficacy of complement inhibitors and vice versa. As an example, L-4F can remove the lipid barrier from Bruch's membrane, which enhances the exchange of nutrients (including vitamin A) from the choriocapillaris to RPE cells and photoreceptor cells, thereby increasing RPE. And reduce the death of photoreceptor cells. As another example, the ability of L-4F to reduce inflammation may reduce the frequency and / or dose of complement inhibitors (eg, by injection) required. The synergy between an apomimetic (eg, Apo AI and / or Apo E mimetic) and a complement inhibitor is that of a complement inhibitor in the absence of treatment with the apomimetic. Allows, but is not required to administer, eg, a complement inhibitor at a lower frequency than conventional or recommended dosing and / or at a lower dose than conventional or recommended doses .. Administration of lower doses of complement inhibitors may have benefits (eg, a better safety profile due to fewer side effects). Less frequent administration of complement inhibitors (eg, by intravitreal injection) may have significant benefits to patients and health care providers, as described elsewhere herein.

  In some embodiments, in the absence of treatment with an apomimetic [eg, Apo AI Mimic (eg, L-4F) and / or Apo E Mimetic (eg, AEM-28-14)]. The complement inhibitor (eg, rampalizumab) is administered at a frequency less than the conventional or recommended dosing frequency of the complement inhibitor and / or at a dose lower than the conventional or recommended dose. At that time, the apomimetic is administered at a dose of about 0.1 or 0.3 mg to about 1.5 mg per administration (eg, per injection) or over a period of about 6 months. It may or may not be administered topically at a total dose of 0.5 or 1 mg to about 10 mg. In some embodiments, in the absence of treatment with an apomimetic [eg, Apo AI Mimic (eg, L-4F) and / or Apo E Mimetic (eg, AEM-28-14)]. At least about 1.5, 2, 3, 4, 5, or 6 (eg, at least about 2) times less frequently (eg, by intravitreal injection) than the conventional or recommended dosing frequency of complement inhibitors in Administer a complement inhibitor (eg, Lampalizumab). In certain embodiments, a complement inhibitor (eg, rampalizumab) is administered to the eye once every 2, 3, 4, 5 or 6 months (eg, once every 2 months) (eg, by intravitreal injection). In contrast, it is administered topically intraocularly, in or around the eye. In a further embodiment, treatment with an apomimetic [eg, apo AI mimic (eg, L-4F) and / or apo E mimetic (eg, AEM-28-14)] is a complement inhibitor. Decrease the total number of doses (eg, Rampalizumab) administered (eg, total number of injections). In certain embodiments, the complement inhibitor (eg, rampalizumab) is locally administered (eg, by intravitreal injection) no more than about 20, 18, 15, 12 or 10 times. In another embodiment, in the absence of treatment with an apomimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)]. At least about 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% (eg, at least about 20%) of a conventional or recommended dose of a complement inhibitor of A complement inhibitor (eg, rampalizumab) is administered at a dose about 10-30%, 30-50%, or 50-70% less (eg, by intravitreal injection).

  In certain embodiments, the complement inhibitor comprises, or is rampalizumab, and is an apo mimetic [eg, an apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg. , AEM-28-14)] is optional, as compared to the conventional or recommended dose and dosing frequency of about 10 mg of ranibizumab administered by intravitreal injection once a month in the absence of treatment with , About 4-6 mg, 6-8 mg, or 8-10 mg once a month for the first 1, 2 or 3 months, or once every 6 weeks for the first 1.5 or 3 months. Rampalizumab is administered at a dose of about 4-6 mg, 6-8 mg or 8-10 mg (eg, by intravitreal injection) once every 2, 3, 4, 5 or 6 months after administration of the dose.

  In other embodiments, the complement inhibitor comprises or is lampalizumab and is about 3-5 mg once every month (4 weeks) or once every 1.5 months (6 weeks), 5-5 mg. Rampalizumab is administered at a dose of 7 mg or 7-9 mg (eg, by intravitreal injection).

  In some embodiments, the duration / length of treatment with a complement inhibitor (eg, ramparizumab) is within about 36, 30, 24, 18 or 12 months. In some embodiments, the length of treatment with a complement inhibitor (eg, ramparizumab) is within about 24, 18 or 12 months. In some embodiments, the length of treatment with a complement inhibitor (eg, rampalizumab) is about 6-12, 12-18 or 18-24 months.

  With respect to the apomimetic, in some embodiments, the apomimetic [eg, apo AI mimic (eg, L-4F) and / or apo E mimetic (eg, AEM-28-14)] is given once. Per administration (eg, per injection) about 0.1 or 0.3-1.5 mg, 0.1-0.5 mg, 0.5-1 mg, 1-1.5 mg, 0.1-0 .3 mg, 0.3 to 0.5 mg, 0.5 to 0.75 mg, 0.75 to 1 mg, 1 to 1.25 mg or 1.25 to 1.5 mg (eg, about 0.1 to 0.5 mg or 0.5-1 mg) is administered topically to the eye (eg, by intravitreal injection), intraocularly, into the eye, or around the eye. Apomimetics can also be administered topically at a dose of greater than 1.5 mg per dose, such as up to about 2 mg per dose (eg, per injection) or more. In a further embodiment, the apo mimetic [eg, Apo AI mimic (eg, L-4F) and / or Apo E mimetic (eg, AEM-28-14)] is administered for a period of about 6 months. About 0.5 or 1-10 mg over time (where the duration / length of treatment with the apomimetic may be, for example, about 6-12, 12-18 or 18-24 months or more) , 0.5 or 1 to 5 mg, 5 to 10 mg, 0.5 or 1 to 3 mg, 3 to 5 mg, 5 to 7.5 mg or 7.5 to 10 mg (eg, about 0.5 to 3 mg or 3 to 5 mg) Locally (eg, by intravitreal injection or via a sustained release composition). The apomimetic can also be topically administered at a total dose of greater than 10 mg over about 6 months, such as up to about 15 mg or more over about 6 months. In a further embodiment, an apomimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] is used to treat the apo mimetic. Approximately 1 or 2 to 20 mg, 5 to 15 mg, 1 to 5 mg, 5 to 10 mg, 10 to 15 mg, 15 to 20 mg, 1 to 3 mg, 3 to 5 mg, 5 to 7.5 mg and 7. Topically administered at a total dose of 5-10 mg, 10-12.5 mg, 12.5-15 mg, 15-17.5 mg or 17.5-20 mg (eg about 1-5 mg or 5-10 mg). The apomimetic can also be administered locally in a total dose greater than 20 mg for the entire treatment regimen, such as up to about 25 mg, 30 mg, 40 mg, 50 mg or more for the entire treatment regimen.

  An apo mimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] to the eye, intraocularly, in the eye, or In embodiments that are administered locally around the eye, the dose per administration, the total dose over a period of about 6 months, and the total dose for the entire treatment regimen are, in certain embodiments, per eye administered. And in other embodiments for both eyes. The blood system may allow some (eg, therapeutically effective) amount of apomimetic locally administered (eg, injected) into or in one eye to circulate in the other eye. .. In that case, the dose of the apomimetic can be adjusted arbitrarily (eg, increased) in view of the other eye (which may have milder symptoms of the disease). This may allow treatment of both eyes with the apomimetic at the same time without further administration (eg, injection) of the apomimetic in or into the other eye. For example, intravitreally injected apomimetics can cross the blood-retinal barrier and reach two target regions (RPE-BL subluminal and Bruch's membrane). From there, the apomimetic may enter the choriocapillaris and eventually the other non-administering eye. While not intending to be bound by theory, some amount of the apomimetic is mediated by aqueous humor (exhausted through the trabecular meshwork and Schlemm's canal into the blood system). May enter the other non-administered eye. Accordingly, some embodiments are methods of treating AMD, comprising the step of administering to a subject in need thereof a therapeutically effective amount of an apomimetic and a therapeutically effective amount of a complement inhibitor. The invention relates to a method wherein the apomimetic is topically administered to one eye, intraocularly, in or around the eye, to have a therapeutic effect on both eyes.

  In another embodiment, the apo mimetic [eg, Apo AI mimetic (eg, L-4F) and / or Apo E mimetic (eg, AEM-28-14)] is administered for 1 month (4 weeks). ) Or once every 1.5 months (6 weeks) (eg, by intravitreal injection). In another embodiment, the apo mimetic [eg, Apo AI mimic (eg, L-4F) and / or Apo E mimetic (eg, AEM-28-14)] is given for 2 months (8 weeks). ), Once every 2.5 months (10 weeks) or once every 3 months (12 weeks) (eg, by intravitreal injection). In still other embodiments, the apo mimetic [eg, apo AI mimic (eg, L-4F) and / or apo E mimetic (eg, AEM-28-14)] is added to 4, 5 or 6 Topical administration once a month (eg, by intravitreal injection or via a sustained release composition). In a further embodiment, the apomimetic [e.g., apo AI mimic (e.g., L-4F) and / or the apo E mimetic (e.g., AEM-28-14)] is added for a total of about 15 or less, 12 or less. Local administration is performed by administration (eg, injection) less than 9 times, less than 9 times, less than 6 times or less than 3 times (eg, 3 to 6 times or 7 to 10 times). The apomimetic can also be administered topically in a total of more than 15 administrations (eg, injections), such as up to about 20 or more administrations (eg, injections) in total. In embodiments in which the apomimetic is locally administered to, intraocularly, in, or around the eye, the frequency of administration and the total number of administrations (eg, injections) may be, in certain embodiments, per eye administered. Yes, in other embodiments, both eyes (because the apomimetic may also be therapeutically effective in the other non-administered eye).

  In some embodiments, apomimetics [eg, Apo AI mimics (eg, L-4F) and / or Apo E mimetics (eg, AEM-28-14)] and / or complement inhibitors (Eg, Lampalizumab) is administered topically to, intraocularly, in, or around the eye. Possible routes, sites and means of topical administration are described elsewhere in this specification. In some embodiments, apomimetics [eg, Apo AI mimics (eg, L-4F) and / or Apo E mimetics (eg, AEM-28-14)] and / or complement inhibitors (Eg, Lampalizumab) is administered by injection (eg, intravitreal, subconjunctival, subretinal or subtenon injection), eye drop or transplant (eg, intravitreal, subretinal or subtenon transplant). In certain embodiments, an apomimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] and a complement inhibitor (eg, rampalizumab). ) And are administered by injection (eg, intravitreal, subconjunctival, subretinal or subtenon injection). In further embodiments, apomimetics [eg, apo AI mimics (eg, L-4F) and / or apo E mimetics (eg, AEM-28-14)] and / or complement inhibitors (eg. , Rampalizumab) is administered via a sustained release composition. Non-limiting examples of sustained release compositions include those described elsewhere herein.

  In some embodiments, an apo mimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] is applied to the eye early in treatment. In contrast, topical administration is intraocularly, in or around the eye, followed by systemic administration of the apomimetic. By way of non-limiting example, the initial dose (s) of the apomimetic (eg, the first to fifth doses) may be given by injection (eg, intravitreal, subconjunctival, subretinal or subtenon injection). ), Followed by subsequent administration (s) of the apomimetic is, for example, oral, parenteral (eg, subcutaneous, intramuscular or intravenous), or topical (eg, intranasal). Or it may be systemic (such as lungs). In other embodiments, the apomimetic is administered topically only. In yet another embodiment, the apomimetic is administered systemically only.

  Supplement with apomimetics [eg, Apo AI mimics (eg, L-4F or variants or salts thereof) and / or Apo E mimetics (eg, AEM-28-14 or variants or salts thereof]] The body inhibitor (eg, Lampalizumab) can be administered via the same pharmaceutical composition or separate pharmaceutical compositions (the composition further comprising one or more pharmaceutically acceptable excipients or carriers). . If the apomimetic (eg, Apo AI Mimic and / or Apo E Mimetic) and the complement inhibitor are administered via the same composition, such composition may be prepared in advance. Or by combining the apomimetic and the complement inhibitor in the same formulation shortly before or just before the formulation is administered (eg, by injection). It can be prepared. Administration of an apomimetic (eg, apo AI mimetic and / or apo E mimetic) and a complement inhibitor in the same composition is potentially invasive compared to administration of the therapeutic agents separately. Fewer patients are given sexual treatments (eg, intravitreal injection). This may have significant benefits to patients and health care providers as described elsewhere herein.

  In some embodiments, a composition comprising an apomimetic [e.g., an apo AI mimic (e.g., L-4F) and / or an apo E mimetic (e.g., AEM-28-14)], and / or Alternatively, the composition comprising a complement inhibitor (eg, Lampalizumab) may be an injectable solution (eg, for intravitreal, subconjunctival, subretinal or subtenon injection), regardless of the same composition or separate compositions. Formulated as a suspension. Examples of formulations for injection into the eye include, but are not limited to, those described elsewhere herein. In another embodiment, a composition comprising an apo mimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)], and / or , A composition containing a complement inhibitor (eg, rampalizumab) is formulated as an eye drop or transplant (eg, intravitreal, subretinal or sub-Tenon), regardless of the same or separate compositions .. By using or implanting eye drops once or twice, the potential problems associated with repeated injections can be avoided. In a further embodiment, a composition comprising an apo mimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)], and / or A composition comprising a complement inhibitor (eg, Lampalizumab), whether in the same composition or a separate composition, is configured to provide sustained release of the apomimetic and / or complement inhibitor. Non-limiting examples of sustained release compositions include those described elsewhere herein. The use of sustained release compositions can potentially perform invasive procedures (eg, intravitreal injection) to reduce the number of doses of the drug and deliver it to the target site over a period of time. It may also improve the profile of the amount of drug delivered.

  In certain embodiments, a composition comprising an apo mimetic [eg, an apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)], which is complement The inhibitor (eg, with or without rampalizumab) is present in about 75-95% (eg, about 90%) of the apomimetic (s) in a weight or molar amount relative to its total amount. ) And about 5 to 25% (eg, about 10%) of the corresponding apolipoprotein (s) (eg, apo AI and / or apo E) or an active portion or domain thereof.

  In some embodiments, a composition comprising an apomimetic [e.g., an apo AI mimic (e.g., L-4F) and / or an apo E mimetic (e.g., AEM-28-14)], and / or Alternatively, the composition comprising a complement inhibitor (eg, rampalizumab), whether the same composition or separate compositions, is one or more excipients and comprises peptides / proteins Including those that inhibit aggregation, increase peptide / protein solubility, decrease solution viscosity, increase peptide / protein stability, or perform any combination or all thereof. Examples of such excipients include, but are not limited to, those described elsewhere herein, and the use of such excipients is not otherwise limited herein. May have the benefits described in section. For example, such excipients may improve the injectability of the composition and allow the use of smaller injection standard needles. Moreover, the use of such excipients can reduce the volume required to administer a given amount of peptide or protein. Therefore, intraocular pressure when the peptide or protein is administered by injection into the eye can be reduced. Also, the use of such excipients may allow higher doses of peptide or protein to be administered in a given volume. This allows the peptide or protein to be administered less frequently relative to a given total dose administered over a period of time.

  In some embodiments, in the absence of treatment with an apomimetic [eg, Apo AI Mimic (eg, L-4F) and / or Apo E Mimetic (eg, AEM-28-14)]. Complement inhibitors (eg, by intravitreal injection) at doses higher than conventional or recommended doses of complement inhibitors and less frequently than conventional or recommended dosing frequencies. Rampalizumab) is administered. In certain embodiments, in the absence of treatment with an apomimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)]. At least about 10%, 20%, 30%, 50%, 75%, 100%, 150% or 200% (eg, at least about 30%), or about, a conventional or recommended dose of a complement inhibitor. 10 to 30%, 30 to 50%, 50 to 100%, 100 to 150% or 150 to 200% (eg, about 50 to 100%) at high doses (eg, by intravitreal injection) complement inhibitors (eg, intravitreal injection) , Lamparizumab) is administered. In a further embodiment, in the absence of treatment with an apomimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)]. Complement at least about 1.5, 2, 3, 4, 5, or 6 (eg, at least about 2) times less frequently (eg, by intravitreal injection) than conventional or recommended dosing frequencies of complement inhibitors Administer an inhibitor (eg, Lampalizumab).

  In certain embodiments, the complement inhibitor comprises, or is rampalizumab, and is an apo mimetic [eg, an apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg. , AEM-28-14)] is optional, as compared to the conventional or recommended dose and dosing frequency of about 10 mg ranibizumab administered by intravitreal injection once a month in the absence of treatment with Once a month for the first 1, 2 or 3 months, or once every 6 weeks for the first 1.5 or 3 months about 12-14 mg, 14-16 mg, 16-18 mg or Once every 2, 3, 4, 5 or 6 months after administration at a dose of 18-20 mg, at a dose of about 12-14 mg, 14-16 mg, 16-18 mg or 18-20 mg (eg, by intravitreal injection). Administer Rampalizumab.

  In another embodiment, an apo mimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] and a complement inhibitor, Wet AMD, which is administered at least in the advanced stage of AMD to further prevent or delay neovascular type (wet type) AMD, and / or includes type 1, 2 and 3 neovascularization To treat or delay its progression. The complement inhibitor used to treat wet AMD is the same as or different from the complement inhibitor used to treat dry AMD (including geographic atrophy), or It may be in addition to that. In certain embodiments, the complement inhibitor comprises or is ARC1905 (ZIMURA®) or LFG316. In some embodiments, an apo mimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14) for treating wet AMD. )] In combination with a complement inhibitor to use an anti-angiogenic drug. In certain embodiments, the anti-angiogenic agent is an anti-VEGF agent (eg, aflibercept [EYLEA®], bevacizumab [AVASTIN®] or ranibizumab [LUCENTIS®], or any thereof. A combination or all) and / or an anti-PDGF drug (eg, E10030 [FOVISTA®]) or.

  In some embodiments, in the absence of treatment with an apomimetic [eg, Apo AI Mimic (eg, L-4F) and / or Apo E Mimetic (eg, AEM-28-14)]. Anti-angiogenic drugs and / or complement inhibitors at a lower frequency than conventional or recommended dosing and / or at a dose lower than conventional or recommended doses (eg , An anti-VEGF drug) or a complement inhibitor (eg, ARC1905) is administered. In certain embodiments, in the absence of treatment with an apomimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)]. At least about 1.5, 2, 3, 4, 5 or 6 (eg, at least about 2) times less frequently (eg, at least about 2) times less than the conventional or recommended dosing frequency of the anti-angiogenic agent and / or complement inhibitor. Administer anti-angiogenic agents (eg, anti-VEGF agents) and / or complement inhibitors (eg, ARC1905) by intravitreal injection. In a further embodiment, in the absence of treatment with an apomimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)]. At least about 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% (eg, at least about about 10%, 20%, 30%, 40%, 60%, 70% or 80% of conventional or recommended doses of anti-angiogenic agents and / or complement inhibitors. 20%), or about 10-30%, 30-50% or 50-70% lesser dose (eg, by intravitreal injection), an anti-angiogenic agent (eg, anti-VEGF agent) and / or complement inhibitor. (Eg, ARC1905) is administered. Non-limiting examples of dosing frequencies and dosages of aflibercept, bevacizumab and ranibizumab are provided elsewhere herein.

  One or more other therapeutic agents described herein include apomimetics [eg, apoA-I mimics (eg, L-4F) and / or for the treatment of dry or wet AMD. / Or ApoE mimetics (eg, AEM-28-14)] and complement inhibitors. In some embodiments, the additional therapeutic agent (s) are antioxidants (eg, vitamins, saffron carotenoids and / or zinc), anti-dyslipidemic agents (eg, statins such as atorvastatin), anti-inflammatory agents. (Eg, NSAID such as bromfenac, and / or corticosteroid (eg, fluocinolone acetonide or triamcinolone acetonide)), or neuroprotective agent (eg, endogenous neuroprotective agent such as CNTF), or Include, or all of, any combination. The use of apomimetics [eg, apo AI mimics (eg, L-4F) and / or apo E mimetics (eg, AEM-28-14)] can be used, for example, to reduce oxidative stress or lipid homeostasis. One or more other that improve the changes of the cells, suppress inflammation, reduce degeneration of RPE cells and retinal cells (eg, photoreceptor cells), or perform any combination or all of them. May enhance the efficacy of the therapeutic drug.

  In some embodiments, the additional therapeutic agent (s) is administered at least during the advanced stages of AMD. In a further embodiment, the additional therapeutic agent (s) is administered at least mid-stage of AMD. In a further embodiment, the additional therapeutic agent (s) is administered at least early in AMD. In certain embodiments, the additional therapeutic agent (s) administered at least early in AMD are anti-dyslipidemic agents (eg, statins) that reduce lipid production, and optionally, antioxidants (eg, , Vitamins, saffron carotenoids and / or zinc) and / or anti-inflammatory agents (eg NSAIDs). The additional therapeutic agent (s) is then administered systemically (eg, orally) or locally (eg, by eye drop).

VIII. Treatment of AMD with Apolipoprotein Mimetics and Antioxidants Another embodiment of the present disclosure is a method of treating AMD, comprising treating a subject in need thereof with a therapeutically effective amount of apolipoprotein (apo) mimetic. Administering an effective amount of an antioxidant, wherein the apomimetic is a dose of about 0.1 or 0.3 mg to about 1.5 mg per administration (eg, per injection), or , May or may not be administered topically to the eye, intraocularly, in or around the eye at a total dose of about 0.5 or 1 mg to about 10 mg over a period of about 6 months. In some cases, regarding the method. Moreover, minerals such as zinc or selenium (both of which may also function as antioxidants) can be used in combination with apomimetics and antioxidants to treat AMD. All embodiments relating to the treatment of AMD with an apolipoprotein mimetic, described in Section IV and elsewhere herein, also include an apomimetic and an antioxidant (and, optionally, It is also applied to the treatment of AMD with (mineral).

Examples of apolipoprotein mimetics, including Apo AI mimics and Apo E mimetics, include, but are not limited to, those described elsewhere herein. In some embodiments, the apomimetic comprises, or is an Apo AI mimic. In some embodiments, the Apo AI mimetic comprises or is 4F or a variant or salt thereof (eg, acetate). In some embodiments, all amino acid residues in 4F are in the L form (L-4F). In other embodiments, one or more or all amino acid residues of 4F are in D form (eg, D-4F where all amino acid residues are in D form). 4F may have a protecting group (eg, an acyl group (eg, acetyl group)) at the N-terminus and / or a protecting group (eg, an amide group (eg, —C (O) NH ₂ )) at the C-terminus. Good. In some embodiments, Apo A-I mimetic structure Ac-DWFKAFYDKVAEKFKEAF-NH ₂ (SEQ ID NO: 13) containing L-4F with, or is. In a further embodiment, the apo mimetic comprises or is an apo E mimetic. In some embodiments, the ApoE mimetic comprises or is AEM-28-14 or a variant or salt thereof.

Non-limiting examples of antioxidants are described elsewhere in this specification. In certain embodiments, the antioxidant is one or more vitamins (eg, vitamin B ₆ , vitamin C and vitamin E), one or more carotenoids (eg, xanthophyll [eg, lutein, zeaxanthin, meso-zeaxanthin], And carotenoids [eg, crocin and crocetin] in saffron), zinc, or any combination thereof (eg, AREDS or AREDS2 formulations described elsewhere herein, ICAPS®). Formulation, Ocuvite® formulation or Saffron 2020 ™). In addition to their ability to reduce oxidative stress, antioxidants may have other beneficial properties. For example, saffron carotenoids have anti-inflammatory and cytoprotective effects along with antioxidant effects.

  In some embodiments, in the absence of treatment with an apomimetic [eg, apo AI mimic (eg, L-4F) and / or apo E mimetic (eg, AEM-28-14)]. Administration of antioxidants (eg, vitamins and / or carotenoids) at doses lower than conventional or recommended doses and / or less frequently than conventional or recommended dosing frequencies To do. At that time, the apomimetic is administered at a dose of about 0.1 or 0.3 mg to about 1.5 mg per administration (eg, per injection) or over a period of about 6 months. It may or may not be administered topically at a total dose of 0.5 or 1 mg to about 10 mg. Administration of lower doses of antioxidants may have benefits (eg, fewer side effects) in the subject. For example, high β-carotene intake may increase lung cancer risk for smokers. In another example, high intakes of vitamin E may increase the risk of heart failure in at-risk subjects. In some embodiments, in the absence of treatment with an apomimetic [eg, apo AI mimic (eg, L-4F) and / or apo E mimetic (eg, AEM-28-14)]. At least about 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% (eg, at least about 20%) of the conventional or recommended dose of antioxidants in , Antioxidants (eg vitamins and / or carotenoids) are administered at doses lower by about 10-30%, 30-50% or 50-70%. In some embodiments, in the absence of treatment with an apomimetic [eg, Apo AI Mimic (eg, L-4F) and / or Apo E Mimetic (eg, AEM-28-14)]. Antioxidants (eg, vitamins and / or carotenoids) at least about 2, 3, 5, 7 or 10 (eg, at least about 2) times less frequently than the conventional or recommended dosing frequency of antioxidants in Is administered. In certain embodiments, one is in the absence of treatment with an apomimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)]. Systemic (eg, oral) or locally non-invasive modalities (eg, eye drops) once every two or three days compared to conventional or recommended dosing frequency of antioxidants administered orally at least once daily. Antioxidants (eg, vitamins and / or carotenoids).

  Apomimetics [eg, Apo AI mimics (eg, L-4F) and / or Apo E mimetics (eg, AEM-28-14)] and antioxidants (eg, vitamins and / or carotenoids) Treatment of AMD with may have a synergistic effect. For example, treatment with apomimetics (eg, Apo AI and / or Apo E mimetics) may enhance the efficacy of antioxidants and vice versa. As an example, L-4F significantly reduces lipid deposition from Bruch's membrane and the RPE-BL subspace, thereby reducing the amount of lipids that are sensitive to oxidation. As another example, L-4F's ability to reduce lipid oxidation and remove pro-inflammatory oxidized lipids can reduce the required dose and / or frequency of administration of antioxidants. The synergy between apomimetics (eg, Apo AI and / or Apo E mimetics) and antioxidants can be compared to conventional antioxidants in the absence of treatment with apomimetics. Or, it is possible, but not essential, to administer, for example, an antioxidant at a lower dose than recommended and / or at a lower frequency than conventional or recommended dosing.

  With respect to the apomimetic, in some embodiments, the apomimetic [eg, apo AI mimic (eg, L-4F) and / or apo E mimetic (eg, AEM-28-14)] is given once. Per administration (eg, per injection) about 0.1 or 0.3-1.5 mg, 0.1-0.5 mg, 0.5-1 mg, 1-1.5 mg, 0.1-0 .3 mg, 0.3 to 0.5 mg, 0.5 to 0.75 mg, 0.75 to 1 mg, 1 to 1.25 mg or 1.25 to 1.5 mg (eg, about 0.1 to 0.5 mg or 0.5-1 mg) is administered topically to the eye (eg, by intravitreal injection), intraocularly, into the eye, or around the eye. The apomimetic can also be topically administered at a dose of greater than 1.5 mg per dose, such as up to about 2 mg per dose (eg, per injection) or more. In a further embodiment, the apo mimetic [eg, Apo AI mimic (eg, L-4F) and / or Apo E mimetic (eg, AEM-28-14)] is administered for a period of about 6 months. About 0.5 or 1-10 mg over time (where the duration / length of treatment with the apomimetic may be, for example, about 6-12, 12-18 or 18-24 months or more) , 0.5 or 1 to 5 mg, 5 to 10 mg, 0.5 or 1 to 3 mg, 3 to 5 mg, 5 to 7.5 mg or 7.5 to 10 mg (eg, about 0.5 to 3 mg or 3 to 5 mg) Locally (eg, by intravitreal injection or via a sustained release composition). The apomimetic can also be topically administered at a total dose of greater than 10 mg over about 6 months, such as up to about 15 mg or more over about 6 months. In a further embodiment, an apomimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] is used to treat the apo mimetic. Approximately 1 or 2 to 20 mg, 5 to 15 mg, 1 to 5 mg, 5 to 10 mg, 10 to 15 mg, 15 to 20 mg, 1 to 3 mg, 3 to 5 mg, 5 to 7.5 mg and 7. Topically administered at a total dose of 5-10 mg, 10-12.5 mg, 12.5-15 mg, 15-17.5 mg or 17.5-20 mg (eg about 1-5 mg or 5-10 mg). The apomimetic can also be administered locally in a total dose greater than 20 mg for the entire treatment regimen, such as up to about 25 mg, 30 mg, 40 mg, 50 mg or more for the entire treatment regimen.

  An apo mimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] to the eye, intraocularly, in the eye, or In embodiments that are administered locally around the eye, the dose per administration, the total dose over a period of about 6 months, and the total dose for the entire treatment regimen are, in certain embodiments, per eye administered. And in other embodiments for both eyes. The blood system may allow some (eg, therapeutically effective) amount of apomimetic locally administered (eg, injected) into or in one eye to circulate in the other eye. .. In that case, the dose of the apomimetic can be adjusted arbitrarily (eg, increased) in view of the other eye (which may have milder symptoms of the disease). This may allow treatment of both eyes with the apomimetic at the same time without further administration (eg, injection) of the apomimetic in or into the other eye. For example, intravitreally injected apomimetics can cross the blood-retinal barrier and reach two target regions (RPE-BL subluminal and Bruch's membrane). From there, the apomimetic may enter the choriocapillaris and eventually the other non-administering eye. Without intending to be bound by theory, some amount of the apomimetic is via aqueous humor (excreted via the trabecular meshwork and Schlemm's canal to the blood system). May enter the other non-administered eye. Accordingly, some embodiments include a method of treating AMD, comprising the step of administering to a subject in need thereof a therapeutically effective amount of an apomimetic and a therapeutically effective amount of an antioxidant. A method wherein the mimetic is topically administered to one eye, intraocularly, in or around the eye to have a therapeutic effect on both eyes.

  In another embodiment, the apo mimetic [eg, Apo AI mimetic (eg, L-4F) and / or Apo E mimetic (eg, AEM-28-14)] is administered for 1 month (4 weeks). ) Or once every 1.5 months (6 weeks) (eg, by intravitreal injection). In another embodiment, the apo mimetic [eg, Apo AI mimic (eg, L-4F) and / or Apo E mimetic (eg, AEM-28-14)] is given for 2 months (8 weeks). ), Once every 2.5 months (10 weeks) or once every 3 months (12 weeks) (eg, by intravitreal injection). In still other embodiments, the apo mimetic [eg, apo AI mimic (eg, L-4F) and / or apo E mimetic (eg, AEM-28-14)] is added to 4, 5 or 6 Topical administration once a month (eg, by intravitreal injection or via a sustained release composition). In a further embodiment, the apomimetic [e.g., apo AI mimic (e.g., L-4F) and / or the apo E mimetic (e.g., AEM-28-14)] is added for a total of about 15 or less, 12 or less. Local administration is carried out by administration (eg, injection) of not more than 9 times, not more than 9 times, not more than 6 times, or not more than 3 times (eg, 3 to 6 times or 7 to 10 times). The apomimetic can also be administered topically in a total of more than 15 administrations (eg, injections), such as up to about 20 or more administrations (eg, injections) in total. In embodiments in which the apomimetic is locally administered to, intraocularly, in, or around the eye, the frequency of administration and the total number of administrations (eg, injections) may be, in certain embodiments, per eye administered. Yes, in other embodiments, both eyes (because the apomimetic may also be therapeutically effective in the other non-administered eye).

  In some embodiments, an apomimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] and an antioxidant (eg, Vitamins and / or carotenoids) at least during advanced stages of AMD to treat or progress central geographic atrophy (GA) and / or neovascular AMD (including NVs 1, 2 and 3) And / or prevent neovascular AMD or delay its onset. The use of antioxidants may inhibit the formation of oxidized lipids, which have potent pro-inflammatory properties and thus pro-angiogenic properties. In a further embodiment, an apo mimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] and an antioxidant (eg, vitamin and And / or carotenoids) at least in the middle of AMD to treat non-central GA or slow its progression and / or prevent central GA and / or neovascular AMD or its onset. Delay. In a further embodiment, an apo mimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] and an antioxidant (eg, vitamin and And / or carotenoids) are administered at least in the early or early phases of AMD to prevent non-central GA or delay its onset. In another embodiment, antioxidants (eg, vitamins and / or carotenoids) and optionally, apomimetics [eg, apo AI mimics (eg, L-4F) and / or apo E mimics. (Eg, AEM-28-14)] is administered at least early in AMD.

  In certain embodiments, apomimetics [eg, apo AI mimics (eg, L-4F) and / or apo E mimetics (eg, AEM-28-14)] and antioxidants (eg, vitamins and Treatment with at least about 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% (eg, at least about 20%), or about 20-40. %, 40-60% or 60-80%, slowing the progression of central GA and / or non-central GA (eg, reducing the rate of GA progression or reducing GA lesion area or size). In a further embodiment, an apo mimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] and an antioxidant (eg, vitamin and / Or carotenoid) and at least about 10%, 20%, 30%, 50%, 100%, 150% of treatment with an antioxidant in the absence of treatment with an apomimetic. , 200% or 300% (eg at least about 20% or 30%), or about 10-30%, 30-50%, 50-100%, 100-200% or 200-300% (eg about 50%). -100%) slows the progression of central GA and / or non-central GA (eg, reduces the rate of GA progression or reduces GA lesion area or size).

  Apomimetics [eg, Apo AI mimics (eg, L-4F) and / or Apo E mimetics (eg, AEM-28-14)] and antioxidants (eg vitamins and / or carotenoids) , Can be administered by any suitable method. In some embodiments, an apomimetic (eg, apo AI mimic and / or apo E mimetic) and / or an antioxidant is administered, eg, by injection (eg, intravitreal, subconjunctival, subretinal or Sub-Tenon injection), eye drop or transplant (eg, intravitreal, subretinal or sub-Tenon implant), topically administered to, intraocularly, in, or around the eye. In certain embodiments, the apomimetic (eg, apo AI mimetic and / or apo E mimetic) is administered locally (eg, by intravitreal, subconjunctival, subretinal or subtenon injection). In other embodiments, the apo mimetic (eg, Apo AI mimetic and / or Apo E mimetic) and / or antioxidants are administered systemically (eg, intravenously or orally). In certain embodiments, the antioxidant is administered systemically (eg, orally). In some embodiments, the apomimetic (eg, apo AI mimetic and / or apo E mimetic) and / or antioxidant is administered via a sustained release composition.

  In some embodiments, an apo mimetic [eg, apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)] is applied to the eye early in treatment. In contrast, topical administration is intraocularly, in or around the eye, followed by systemic administration of the apomimetic. By way of non-limiting example, the initial dose (s) of the apomimetic (eg, the first to fifth doses) may be given by injection (eg, intravitreal, subconjunctival, subretinal or subtenon injection). ), Followed by subsequent administration (s) of the apomimetic is, for example, oral, parenteral (eg, subcutaneous, intramuscular or intravenous), or topical (eg, intranasal). Or it may be systemic (such as lungs). In other embodiments, the apomimetic is administered topically only. In yet another embodiment, the apomimetic is administered systemically only.

  Apo mimetic [eg, Apo AI mimic (eg, L-4F or variant or salt thereof) and / or Apo E mimetic (eg, AEM-28-14 or variant or salt thereof]] The oxidizing agent (eg, vitamins and / or carotenoids) can be administered via the same pharmaceutical composition or separate pharmaceutical compositions. If the apomimetic (e.g., apo AI mimetic and / or apo E mimetic) and the antioxidant are administered in the same composition, such composition can be prepared in advance, Alternatively, the apomimetic and the antioxidant can be prepared by combining the apomimetic and the antioxidant in the same formulation shortly before or just before the formulation is administered (eg, by injection). You can In some embodiments, an apomimetic (eg, apo AI mimic and / or apo E mimetic) and an antioxidant are administered, for example, by injection (eg, intravitreal, subconjunctival, subretinal, or Tenon's capsule). Topical injection), instillation, or by instillation (eg, intravitreal, subretinal or sub-Tenon implantation), to the eye, intraocularly, intraocularly, or around the eye, topically in the same composition.

  In certain embodiments, a composition comprising an apo mimetic [eg, an apo AI mimic (eg, L-4F) and / or an apo E mimetic (eg, AEM-28-14)], which is an antioxidant. The agent (eg, with or without vitamins and / or carotenoids) comprises about 75-95% (eg, about 90%) of the apomimetic relative to its total weight or molar amount. Containing about 5 to 25% (eg, about 10%) of the corresponding apolipoprotein (s) (eg, Apo AI and / or Apo E) or active portion or domain thereof.

  One or more other therapeutic agents described herein are apomimetics [eg, ApoA-I Mimics for the treatment of atrophic (dry) or neovascular (wet) AMD. (Eg L-4F) and / or ApoE mimetics (eg AEM-28-14)] and antioxidants (eg vitamins and / or carotenoids). In some embodiments, the additional therapeutic agent (s) are anti-angiogenic agents (eg, anti-VEGF agents (eg, aflibercept, bevacizumab or ranibizumab) and / or anti-PDGF agents such as E10030), Body inhibitor (eg, C5 inhibitor (eg, ARC1905 or LFG316), and / or complement factor D inhibitor (eg, lampalizumab)), anti-inflammatory agent (eg, NSAID (eg, bromfenac) and / or corti A costeroid (eg, fluocinolone acetonide or triamcinolone acetonide), a neuroprotective agent (eg, glatiramer acetate and / or CNTF), or an antidyslipidemic agent (eg, statin such as atorvastatin), or any thereof It includes a combination or all of them, or. The use of apomimetics [eg, apo AI mimics (eg, L-4F) and / or apo E mimetics (eg, AEM-28-14)] reduces, for example, the growth and leakage of new blood vessels. , Reduce inflammation, reduce oxidative stress, reduce degeneration of RPE cells and retinal cells (eg, photoreceptor cells), improve changes in lipid homeostasis, or any combination or It may enhance the efficacy of one or more other therapeutic agents that do all of that.

  In some embodiments, the additional therapeutic agent is administered at least during the advanced stages of AMD. In certain embodiments, the additional therapeutic agent comprises an anti-angiogenic agent (eg, anti-VEGF agent) and optionally a neuroprotective agent (eg, an endogenous neuroprotective agent (eg, CNTF)), or , And is administered at least during the advanced stages of AMD to treat or delay wet AMD, including types 1, 2, and 3 neovascularization. In other embodiments, the additional therapeutic agent comprises or is a complement inhibitor (eg, ramparizumab) and / or a neuroprotective agent (eg, an endogenous neuroprotective agent (eg, CNTF)), and , AMD at least in the advanced stage to treat central geographic atrophy (GA) or slow its progression.

  In a further embodiment, the additional therapeutic agent is administered at least in the middle of AMD. In certain embodiments, the additional therapeutic agent comprises or is a complement inhibitor (eg, ramparizumab) and / or a neuroprotective agent (eg, glatiramer acetate and / or CNTF). Then, it is administered at least in the middle stage of AMD to treat non-central GA or delay its progression and / or prevent central GA or delay its onset. Alternatively, it is administered at least in the early phase of AMD or in the early phase of mid-stage AMD to prevent or delay the onset of non-central GA. In a further embodiment, the additional therapeutic agent is administered at least early in AMD. In certain embodiments, the additional therapeutic agent administered at least early in AMD comprises an anti-dyslipidemic agent (eg, statin) that reduces lipid production and, optionally, an anti-inflammatory agent (eg, NSAID). Includes or is. Then, the additional therapeutic agent is administered systemically (eg, oral) or locally (eg, by eye drop).

IX. Treatment of Other Eye Diseases The therapeutic agents described herein may be used to treat other eye diseases and disorders in addition to age-related macular degeneration (AMD). Non-limiting examples of other eye diseases and disorders treatable with one or more therapeutic agents described herein include juvenile macular degeneration (eg, Stargardt disease), maculopathy (eg, age-related Macular disease [ARM] and diabetic macular disease [DMP] [including partial ischemic DMP]), macular edema (eg, diabetic macular edema [DME] [clinically significant DME, localized DME, and diffuse] DME], Irvine-Gas Syndrome [postoperative macular edema], and macular edema after RVO [including central RVO and branched RVO], retinopathy (eg, diabetic retinopathy [in DME patients. Include], Pulture retinopathy and radiation retinopathy), retinal artery occlusion (RAO) (eg, central and bifurcated RAO), retinal vein occlusion (RVO) (eg, central RVO [central RVO with cystic macular edema {CME}) ] And branch RVO [including branch RVO with CME]), glaucoma (including hypotonic, normotensive and ocular glaucoma), ocular hypertension, retinitis (eg, Court's disease [exudative] Retinitis] and retinitis pigmentosa), chorioretinitis, choroiditis (eg, claudication choroiditis), uveitis (anterior uveitis, medial uveitis, posterior grape with or without CME). Membranitis, and panuveitis), retinal pigment epithelium (RPE) detachment, and diseases associated with increased intracellular or extracellular lipid storage or accumulation in addition to AMD.

  In some embodiments, an apolipoprotein mimetic (eg, apo AI mimic [eg, L-4F] and / or an apo E mimetic [eg, AEM-28-14]), alone or in one or more. Used in combination with multiple other additional therapeutic agents to treat eye diseases or disorders other than AMD. In certain embodiments, an apo mimetic having anti-inflammatory properties (eg, apo AI mimics [eg, L-4F] and / or apo E mimetics [eg, AEM-28-14]), alone or. Administered either in combination with another therapeutic agent to treat an inflammatory eye disease or disorder (eg, uveitis). In such cases, the apomimetic (eg, L-4F) acts as an anti-inflammatory drug and can be used in place of steroids or non-steroidal anti-inflammatory drugs. Apomimetics (eg, ApoA-I Mimics [eg, L-4F] and / or ApoE Mimics [eg, AEM-28-14]) for treating eye diseases and disorders in addition to AMD Uses in combination with anti-angiogenic agents (eg, anti-VEGF agents) are described elsewhere herein. In a further embodiment, an apomimetic (eg, apo AI mimic [eg, L-4F] and / or an apo E mimetic [eg, AEM-28-14]), an anti-VEGF agent, a neuroprotective agent. , A kinase inhibitor, or a c-peptide (connecting peptide), or any combination or all thereof, is administered to treat diabetic retinopathy. Apomimetics [eg, Apo AI mimics (eg, L-4F) and / or Apo E mimetics (eg, AEM-28-14)] alone or with another therapeutic agent (eg, anti-angiogenic agent [ Examples, such as anti-VEGF drugs], complement inhibitors, or antioxidants) for use in combination with the treatment of AMD described elsewhere herein include apomimetics alone or of a given type. It also finds application in the treatment of other eye diseases and disorders used in combination with therapeutic agents.

X. Administration of Therapeutic Agents The therapeutic agents listed herein can be administered to a subject by any suitable method, including any suitable means for local or systemic administration. In certain embodiments, the therapeutic agent is an intravitreal injection or transplant, a subconjunctival injection or transplant, a subretinal injection or transplant, a sub-Tenon injection or transplant, a periocular injection, an eye drop, an oral intake, or an intravenous injection or an infusion. Administered by.

  In some embodiments, one or more or all of the therapeutic agent (s) are administered locally. Topical administration of a therapeutic agent can deliver the agent more effectively to the target site (s), avoid first pass metabolism, and require a lower dose of the drug, thereby Can reduce any side effects due to. If the pathogenesis of AMD occurs in the eye, the therapeutic agent (s) used to treat AMD is administered locally to the eye for a more effective treatment. For example, lipid-containing substances (eg, lipids, lipoproteins, apolipoproteins) that accumulate in Bruch's membrane (BrM), the RPE-BL sub- and subretinal spaces are of intraocular origin (eg, retinal pigment). It is secreted by endothelial [RPE] cells). Therefore, a more effective reduction of the accumulation of such substances requires local administration of one or more antidyslipidemic agents to the target site in the eye.

  Possible routes / modes of topical administration include, but are not limited to, aqueous humor (aqueous humor), periocular, posterior eye, suprachoroidal, subconjunctival, intraocular, periocular, subretinal, intrascleral, posterior. Includes near sclera, transsclera, sub-Tenon, intravitreal and transvitreous. By subretinal administration, the therapeutic agent is administered subretinally (eg, subretinal space, RPE, RPE-BL subspace or choroid, or any combination or all thereof). Possible sites for local administration include, but are not limited to, the anterior chamber (aqueous humor) and posterior chamber of the eye, vitreous humor (vitreous body), retina (including the macula and / or photoreceptor layer), subretinal space, Includes RPE, RPE-BL subspace, choroid (including BrM and choriocapillary endothelium), sclera, and sub-Tenon's capsule / cavity.

  In some embodiments, the therapeutic agent is delivered to the vitreous humor across the sclera and choroid. From there, the therapeutic agent diffuses to the target tissue (s) (eg, retina (eg, photoreceptor cells), subretinal space, RPE, RPE-BL subspace or BrM, or any combination thereof or all thereof). It is possible. In other embodiments, the therapeutic agent traverses the sclera and choroid to the target tissue (s) (eg, retina (eg, photoreceptor cells), subretinal space, RPE and / or RPE-BL subspace). Delivered. If BrM is the target tissue, from there the therapeutic agent can diffuse into BrM. In a further embodiment, the therapeutic agent is administered intraocularly, eg, into the anterior or posterior chamber of the eye, the vitreous humor, the retina or the subretinal space.

  Possible means of topical administration include, but are not limited to, injection, implantation, topical topical means of administration to the eye (eg eye drops and contact lenses). In some embodiments, one or more or all of the therapeutic agent (s) are administered by intravitreal (eg, intravitreal), subconjunctival, subretinal or subtenon injection or transplant. As an example, in some embodiments, one or more apo mimetics [eg, apo AI mimics (eg, L-4F) and / or apo E mimetics (eg, AEM-28-14)] 4 weeks (1 month) in the vitreous humor of the eye, in the subconjunctival, subretinal or sub-Tenon's sheath during a period (eg, about June, December, 18 months, or 24 months or more), Inject at least once every 6 weeks, 8 weeks (2 months), 10 weeks, 12 weeks (3 months), 4 months, 5 months or 6 months, which may be, for example, dry AMD (non- Central and / or Central Geographic Atrophy) and / or Neovascular AMD.

  A method that allows therapeutic agents to be administered less frequently than intravitreal injection is the posterior scleral depot. For example, Retaane® is a dull, pigmented, posterior juxtascleral depot cannula that is placed directly behind the macula with a specific amount (eg, about 15 mg) of anecortave acetate, leaving the eye intact. It is delivered on the sclera. Anecortab acetate may be administered once every 6 months using this delivery method, as compared to intravitreal injections of ranibizumab or aflibercept each once or every two months. Moreover, the posterior juxtascleral depot method greatly reduces the risk of intraocular infection, endophthalmitis and retinal detachment.

  Topical administration of therapeutic agents to the eye for the treatment of AMD or another eye disease may have advantages (eg, greater efficacy and reduced side effects), but systemic administration of therapeutic agents is desirable in certain situations There are cases. For example, oral administration of therapeutic agents can increase patient compliance. The reason is that, for example, if a topical formulation for topical delivery (eg, eye drops or contact lenses) cannot be developed for the therapeutic agent, it will be easy to use and non-invasive. As another example, the pathogenesis of AMD may have a non-local component. For example, the amount of lipid-containing substances secreted by RPE cells into BrM, RPE-BL subluminal space and subretinal space is partly due to the uptake of plasma lipids (eg cholesterol and fatty acids) and lipoproteins (eg LDL) by RPE cells. Can be negatively affected. In such cases, it may be desirable to systemically administer one or more antidyslipidemic agents that reduce hepatic production of such lipids and lipoproteins.

  In some embodiments, one or more therapeutic agent (s) are administered systemically. Routes which can be administered systemically include, but are not limited to, oral, parenteral (eg, intracutaneous, subcutaneous, intramuscular, intravascular, intravenous, intraarterial, intramedullary and intrathecal), intracavity, intraperitoneal Internal and topical (eg, transdermal, transmucosal, intranasal [eg, by nasal spray or nasal drop], lung [eg, by inhalation], oral mucosa, sublingual, rectal and vaginal).

  In certain embodiments, one or more antidyslipidemic agents are administered systemically. For example, in certain embodiments, the fibrate and / or statin are administered orally and / or the GLP-1 receptor agonist is administered subcutaneously. In a further embodiment, one or more antioxidants are administered systemically. By way of example, in one embodiment the vitamins, saffron carotenoids and / or zinc are administered orally. In a further embodiment, the one or more anti-inflammatory agents are administered systemically. For example, in some embodiments, the NSAID (eg, coxib) is administered orally and / or the complement inhibitor (eg, anti-C5 antibody (eg, LFG316)) is administered intravenously.

  In some embodiments, one or more polypeptide therapeutic agents (eg, an endogenous angiogenesis inhibitor (eg, soluble VEGFR [eg, VEGFR1] or angiostatin and / or endostatin)) is used as the polypeptide therapeutic agent (eg. Administered by an expressed virus (eg, adenovirus or lentivirus) vector, eg, AVA-101 comprises an adeno-associated virus 2 (AAV2) vector containing a gene encoding soluble VEGFR1 (FLT-1). Topical administration of AVA-101 into the eye (eg, RPE or choriocapillaris endothelium) results in expression of soluble VEGFR1 by host retinal cells, which binds to VEGF in the extracellular space, Thereby blocking VEGF from binding to membrane-bound VEGFR and thereby inhibiting angiogenesis AVA-101 is, for example, neovascularized (including type 1, 2 and / or type 3 neovascularization). It can be administered, eg, as a single subretinal injection for the treatment of vascular AMD, thereby eliminating the need for multiple or multiple injections.

  In another embodiment, one or more polypeptide therapeutic agents (eg, neuroprotective agents [eg, ciliary neurotrophic factor] or anti-angiogenic agents [eg, anti-VEGF agents (eg, potential VEGFR)]) Are administered by genetically modified cells (eg, NTC-201 cells) that produce the polypeptide therapeutic agent (s) and are encapsulated in polymeric particles or polymeric implants. As an example, an expression vector containing a gene encoding ciliary neurotrophic factor (CNTF) is transfected into RPE cells to produce genetically modified NTC-201 cells. NTC-201 cells are encapsulated, for example, in semipermeable hollow fiber-membrane capsules enclosed in a scaffold made of 6-stranded polyethylene terephthalate yarn. Capsules and scaffolds maintain cells (eg, growth support and nutrient delivery). After implantation of an encapsulated cell transplantation-based drug delivery system (eg, accessed through the sclera), NTC-201 cells produce CNTF and secrete through semipermeable capsules. Such encapsulated cell technology (eg, NT-501) provides controlled, continuous, and sustained CNTF delivery, with a CNTF half-life of from about 1-3 minutes to about 20-50 months. extend. Intraocular CNTF delivery using such encapsulated cell technology can be used, for example, to reduce photoreceptor cell loss associated with degeneration of retinal cells and thus, for example, to treat geographic atrophy.

  One or more polypeptide therapeutic agents can also be delivered via administration of natural cells which produce and release such agents. For example, cells from umbilical cord tissue can rescue photoreceptor cells and visual function, reportedly through the production and release of neuroprotective agents (eg, neurotrophic factors).

  The therapeutically effective amount of the specific therapeutic agent for AMD or another eye disease, the administration frequency, and the treatment period depend on various factors (eye disease, severity of disease, administration mode, age, weight of the subject, general health, sex and diet). , As well as the subject's response to treatment), and may be determined by the treating physician. In some embodiments, the regimen of one or more or all therapeutic agent (s) comprises one or more loading doses followed by one or more maintenance doses. The loading dose or doses are designed to establish a relatively high or therapeutically effective level of therapeutic agent at the target site (s) relatively quickly. And one or more maintenance doses are designed to establish a therapeutically effective level of therapeutic agent for the duration of the treatment. Providing a loading dose can be carried out, for example, by administering a dose that is greater than the maintenance dose (eg, 2, 3, 4 or 5 times greater), or a dose that is substantially similar to the maintenance dose can be initiated. Occasionally, it will be administered by frequent administration (eg, 2, 3, 4, or 5 times more frequently). By way of example, for the treatment of neovascular AMD (including neovascularization of type 1, 2 and / or 3), in one embodiment, three loading doses of the anti-angiogenic agent aflibercept (3 months Intravitreal injection (about 2 mg once per month) for a period of time, followed by a maintenance dose (about 2 mg) every 2 months for a period determined by the treating physician.

XI. Pharmaceutical Compositions, Delivery Systems and Kits The therapeutic agents can be administered as pharmaceutical compositions that include one or more pharmaceutically acceptable carriers or excipients. When two or more therapeutic agents are used to treat AMD or another eye disease, the therapeutic agents can be administered in the same pharmaceutical composition or separate pharmaceutical compositions.

  Pharmaceutically acceptable carriers and excipients include pharmaceutically acceptable materials, vehicles and substances. Non-limiting examples of excipients include liquid and solid fillers, diluents, binders, lubricants, glidants, surfactants, dispersants, disintegrants, emulsifiers, wetting agents, suspending agents, thickeners. Agents, solvents, isotonic / isotonic agents, buffers, pH adjusters, absorption delay agents, sweeteners, flavors, colorants, stabilizers, preservatives, antioxidants, antibacterial agents, antibacterial agents, antifungals Agents, adjuvants, encapsulating materials and coating materials are included. The use of such excipients in pharmaceutical formulations is known in the art. The disclosure includes the use of conventional carriers and excipients in formulations containing therapeutic agents described herein, unless any conventional carriers or excipients are compatible with the therapeutic agents. . For example, Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (Philadelphia, Pennsylvania [2005]); Handbook of Pharmaceutical Excipients, 5th Ed., Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association (2005); Handbook of Pharmaceutical Additives, 3rd Ed., Ash and Ash, Eds., Gower Publishing Co. (2007); and Pharmaceutical Preformulation and Formulation, Gibson, Ed., CRC Press LLC (Boca Raton, Florida [2004]).

  The compositions and formulations (eg, injectable formulations) for use in the present disclosure can be prepared in sterile form. Sterile pharmaceutical formulations are defined by pharmaceutical grade sterilization standards known to those of skill in the art (e.g., United States Pharmacopeia Chapters 797, 1072 and 1211; California Business & Professions Code 4127.7; 16 California Code of Regulations 1751; and 21 Code of Federal Regulations 211. Disclosed or required).

  As an illustrative example, one or more therapeutic agents can be formulated for delivery into the eye (eg, by intravitreal, subconjunctival, subretinal or subtenon injection, or by instillation). Excipients and carriers that can be used to produce such formulations include, but are not limited to, solvents (eg, aqueous solvents (eg, water, saline and phosphate buffered saline)), etc. Tonic / isotonic agents (eg, NaCl and sugars [eg, sucrose]), pH adjusters (eg, sodium dihydrogen phosphate and disodium hydrogen phosphate), and emulsifiers (eg, nonionic surfactants). (Eg, polysorbate [eg, polysorbate 20])). Where the one or more therapeutic agents comprises peptides or proteins, such formulations (and any other type of formulation) are one or more substances that inhibit peptide / protein aggregation and It may include those that increase the solubility of the protein, decrease the solution viscosity or increase the stability of the peptide / protein, or perform any combination or all thereof. For example, non-hydrophobic amino acids (eg, arginine and histidine), polyols (eg, myo-inositol and sorbitol), sugars (eg, glucose, lactose, sucrose and trehalose), osmolytes (eg, trehalose, amino acids [eg, glycine, Proline and sarcosine], and betaine [eg, trimethylglycine]), nonionic surfactants (eg, alkyl polyglycosides), and ProTek® alkyl saccharides (eg, long chain fatty acids or corresponding long chain alcohols). Bound disaccharides [eg maltose or sucrose)]). Since such substances increase the solubility of peptides / proteins, such substances are used to increase the concentration of peptides / proteins and to reduce the volume required to administer a given amount of peptide or protein, which It may have beneficial effects such as lowering intraocular pressure (eg, in intravitreal injection). Also, such materials may be employed to stabilize peptides and proteins during preparation, storage and reconstitution of lyophilized peptides and proteins.

  In some embodiments, one or more or all therapeutic agents are independently delivered from the sustained release composition. The term "sustained release composition" as used herein includes sustained release, extended release, extended release, delayed release and controlled release compositions, systems and devices. The use of sustained release compositions can be beneficial, for example, improving the profile of the amount of drug delivered to a target site over a period of time, and invasive procedures in which administration of the drug is carried out ( There is improved patient compliance and health due to less intraocular injection). In some embodiments, the sustained release composition is a drug encapsulation system (eg, nanoparticles, microparticles, cylinders or capsules made of biodegradable polymers and / or hydrogels). In some embodiments, the sustained release composition comprises a hydrogel. Non-limiting examples of polymers that can comprise the hydrogel include polyvinyl alcohol, acrylate polymers (eg, sodium polyacrylate), and other homopolymers having multiple hydrophilic groups (eg, hydroxyl and / or carboxylate groups). And copolymers. In another embodiment, a sustained release drug encapsulation system includes a reservoir surrounded by a membrane, the reservoir containing the drug and the membrane being permeable to the drug.

  In some embodiments, the sustained release composition is composed of a hydrogel formed by combining a cellulosic polymer (eg, hydroxypropylmethylcellulose or a derivative thereof) and polystyrene nanoparticles. Such hydrogels can be topically administered intraocularly, for example, by instillation, injection or implantation. The polymer chains of cellulosic polymers and polystyrene nanoparticles can form a loose bond under pressure (which allows the hydrogel to flow easily when extruded through a needle), but only a few seconds after the pressure is released. A hard bond can be formed within it, which allows the hydrogel to transform into a drug-bearing capsule in the eye. In certain embodiments, the hydrogel is loaded with peptides or proteins (eg, apolipoprotein mimetics or anti-VEGF / VEGFR drugs). Peptides or proteins can be released from the hydrogel as the tip of the hydrogel is gradually eroded by exposure to water in the eye, thereby allowing the hydrogel to survive for months, and sometimes years. The peptide or protein can be released from the gel.

  In some embodiments, the sustained release composition is a polymeric implant (eg, in a cylinder, capsule or any other suitable form) or polymeric nanoparticles or microparticles. There, the polymeric particles can be delivered from, for example, eye drops, injections or implants. In some embodiments, the polymeric implant or polymeric nanoparticles or microparticles are composed of biodegradable polymers (one or more biodegradable homopolymers, one or more biodegradable copolymers, or mixtures thereof). To be done. In some embodiments, the biodegradable polymer is lactic acid and / or glycolic acid [eg, L-lactic acid based copolymers (eg, poly (L-lactic acid-co-glycolide) or poly (L-lactic acid-co-D, L-2-hydroxyoctanoic acid))]]. The polymeric implant or the biodegradable polymer of polymeric nanoparticles or microparticles can be selected. Thus, the polymer degrades substantially completely around the end of the treatment period. Thus, the by-products of polymer degradation, like polymers, are biocompatible.

  Non-limiting examples of biodegradable polymers include polyesters, poly (α-hydroxy acids), polylactides, polyglycolides, poly (ε-caprolactone), polydioxanones, poly (hydroxyalkanoates), poly (hydroxypropionates), Poly (3-hydroxypropionate), poly (hydroxybutyrate), poly (3-hydroxybutyrate), poly (4-hydroxybutyrate), poly (hydroxypentanoate), poly (3-hydroxypentanoate) Ate), poly (hydroxyvalerate), poly (3-hydroxyvalerate), poly (4-hydroxyvalerate), poly (hydroxyoctanoate), poly (2-hydroxyctanoate), poly (3-hydroxyvalerate). Hydroxyctanoate), polysalicylate / polysalicylic acid, polycarbonate, poly (trimethylene carbonate), poly (ethylene carbonate), poly (propylene carbonate), tyrosine-derived polycarbonate, L-tyrosine-derived polycarbonate, polyiminocarbonate, poly ( DTH iminocarbonate), poly (bisphenol A iminocarbonate), poly (amino acid), poly (ethyl glutamate), poly (propylene fumarate), polyanhydride, polyorthoester, poly (DETOSU-1,6HD), poly ( DETOSU-t-CDM), polyurethane, polyphosphazene, polyimide, polyamide, nylon, nylon 12, polyoxyethylated castor oil, poly (ethylene glycol), polyvinylpyrrolidone, poly (L-lactide-co-D-lactide), Poly (L-lactide-co-D, L-lactide), poly (D-lactide-co-D, L-lactide), poly (lactide-co-glycolide), poly (lactide-co-ε-caprolactone), Poly (glycolide-co-ε-caprolactone), poly (lactide-co-dioxanone), poly (glycolide-co-dioxanone), poly (lactide-co-trimethylene carbonate), poly (glycolide-co-trimethylene carbonate) , Poly (lactide-co-ethylene carbonate), poly (glycolide-co-ethylene carbonate), poly (lactide-co-propylene carbonate), poly (glycolide-co-propylene carbonate), poly (lactide-co-2-methyl) -2-carboxyl-propylene carbonate), poly (glycolyl) De-co-2-methyl-2-carboxyl-propylene carbonate), poly (lactide-co-hydroxybutyrate), poly (lactide-co-3-hydroxybutyrate), poly (lactide-co-4-hydroxybutyrate) Rate), poly (glycolide-co-hydroxybutyrate), poly (glycolide-co-3-hydroxybutyrate), poly (glycolide-co-4-hydroxybutyrate), poly (lactide-co-hydroxyvalerate) , Poly (lactide-co-3-hydroxyvalerate), poly (lactide-co-4-hydroxyvalerate), poly (glycolide-co-hydroxyvalerate), poly (glycolide-co-3-hydroxyvalerate) , Poly (glycolide-co-4-hydroxyvalerate), poly (3-hydroxybutyrate-co-4-hydroxybutyrate), poly (hydroxybutyrate-co-hydroxyvalerate), poly (3-hydroxybutyrate) Rate-co-3-hydroxyvalerate), poly (3-hydroxybutyrate-co-4-hydroxyvalerate), poly (4-hydroxybutyrate-co-3-hydroxyvalerate), poly (4-hydroxy) Butyrate-co-4-hydroxyvalerate), poly (ε-caprolactone-co-fumarate), poly (ε-caprolactone-co-propylene fumarate), poly (ester-co-ether), poly (lactide-co). -Ethylene glycol), poly (glycolide-co-ethylene glycol), poly (ε-caprolactone-co-ethylene glycol), poly (ester-co-amide), poly (DETOSU-1,6HD-co-DETOSU-t- CDM), poly (lactide-co-cellulose ester), poly (lactide-co-cellulose acetate), poly (lactide-co-cellulose butyrate), poly (lactide-co-cellulose acetate butyrate), poly (lactide- co-cellulose propionate), poly (glycolide-co-cellulose ester), poly (glycolide-co-cellulose acetate), poly (glycolide-co-cellulose butyrate), poly (glycolide-co-cellulose acetate butyrate) , Poly (glycolide-co-cellulose propionate), poly (lactide-co-glycolide-co-ε-caprolactone), poly (lactide- co-glycolide-co-trimethylene carbonate), poly (lactide-co-ε-caprolactone-co-trimethylene carbonate), poly (glycolide-co-ε-caprolactone-co-trimethylene carbonate), poly (3-hydroxy) Butyrate-co-3-hydroxyvalerate-co-4-hydroxybutyrate), poly (3-hydroxybutyrate-co-4-hydroxyvalerate-co-4-hydroxybutyrate), collagen, casein, poly Includes sugars, cellulose, cellulose esters, cellulose acetate, cellulose butyrate, cellulose acetate butyrate, cellulose propionate, chitin, chitosan, dextran, starch, modified starch, and copolymers and mixtures thereof (lactide is L-lactide, (Including D-lactide and D, L-lactide).

  As an illustrative example, one or more peptides or proteins for injection (eg intravitreal, subconjunctival, subretinal or subtenon injection) (eg apolipoprotein mimics [eg apo AI or apo E. Mimetics] and / or antibodies or fragments thereof (eg, anti-VEGF antibodies or fragments thereof)) may comprise one or more biodegradable polymers (eg, hexyl-substituted poly (lactic acid) (hexPLA)). ). HexPLA is a hydrophobic polyester in a semi-solid aggregate state that facilitates formulation. Peptides / proteins can be micronised and incorporated into a liquid hexPLA polymer matrix by lyophilization to form a homogeneous injectable suspension. Peptides / proteins are well compatible with hexPLA polymers, have good storage stability (eg, long term [eg, about 3 months or more] at about 4 ° C.), and are shielded from the surrounding aqueous medium. In this case, the stability inside the polymer is improved. A peptide / protein formulation comprising hexPLA can have a drug loading of, for example, about 1-5% or 5-10%, and hexPLA can be, for example, about 1000-2000 g / mol, 2000-3000 g / mol. It can have a molecular weight (MW) of mol or 3000-4000 g / mol. The formulation is capable of forming a spherical depot in an aqueous medium (eg, buffer) and is capable of releasing the peptide / protein for a long period of time (eg, about 1, 2, 3, 4, 5 or 6 months). is there. The peptide / protein release rate may be influenced by the polymer viscosity based on the polymer MW and, to a lesser extent, the drug loading, which allows fine tuning of the drug release profile. The peptide / protein can maintain its structure upon incorporation into the polymer matrix and maintain its biological activity (eg, high affinity for biological targets) after release from the polymer matrix.

  Instead of being released from the polymeric microparticles, the solid therapeutic agent can be administered in the form of microparticles which predominantly comprise or consist essentially of the therapeutic agent. As compared to drugs that are substantially completely dissolved in the aqueous medium upon administration, such microparticulate form of the drug may be substantially completely dissolved over time after administration, thereby providing a longer period of time. And may require fewer administrations (eg, injections). Furthermore, such microparticles can form depots for long-term delivery of therapeutic agents. Such microparticles may optionally include relatively small amounts of one or more excipients. Microparticles that mainly comprise or consist essentially of a therapeutic agent can be, for example, injection (eg, intravitreal, subconjunctival, subretinal or subtenon injection), eye drop or transplant (eg, intravitreal, retina). Or by sub-Tenon transplantation).

  In some embodiments, the sustained release composition provides a low or relatively low but therapeutically effective dose of one or more therapeutic agents for about 1 week, 2 weeks, 4 weeks (1 month), 6 months. It is released over a week, 8 weeks (2 months), 10 weeks, 3 months, 6 months, 1 year, 1.5 years, 2 years, 2.5 years or 3 years or more.

  An example of a sustained release polymeric implant is ILUVIEN®. ILUVIEN® is a mini-tubular intravitreal implant made of polyimide, sealed at one end with a silicone adhesive and at the other end with polyvinyl alcohol, for up to 3 years in very small amounts. Releases the corticosteroid fluocinolone acetonide. Another example of a sustained release polymeric implant is OZURDEX®. OZURDEX® is a biodegradable intravitreal implant that delivers the corticosteroid dexamethasone with extended release using the NOVADUR® solid polymer delivery system. Other therapeutic agents that can be delivered via sustained release, biodegradable intravitreal implants include, but are not limited to, the neuroprotective agent brimonidine.

  Further examples of sustained release ophthalmic drug delivery systems are those described in Guo et al., US Pat. No. 6,375,972. The Guo system includes an inner drug core containing a drug and an inner tube impermeable to the passage of the drug, the inner tube having first and second ends and covering at least a portion of the inner drug core, Because the inner tube is formed of a material and sized, the inner tube is dimensionally stable and can receive the inner drug core without changing shape. A non-permeable member is located at the first end of the inner tube and blocks the passage of the drug out of the inner drug core through the first end of the inner tube. A member of permeable membrane is located at the second end of the inner tube and allows the drug to diffuse out of the inner drug core through the second end of the inner tube. Guo's sustained release system is applicable, for example, to vitreous humor, subretinal or episcleral injections or implants.

  Another example of a controlled release ophthalmic drug delivery system is that described in US Pat. No. 6,413,540 to Yaacobi. The Yaacobi system includes a body having an in situ scleral surface proximate to the sclera, and a well having an opening to the scleral surface and a drug-containing inner core. This system delivers the drug at a controlled rate to the retina either through the sclera or through the choroid.

  Another exemplary ocular drug delivery device is an osmotic pump such as that described by Ambati et al. The Ambati osmotic pump was able to deliver IgG and anti-ICAM-1 monoclonal antibody separately across the sclera to the choroid and retina with negligible systemic absorption (J. Ambati et al., Invest). .Opthalmol. Vis. Sci., 41: 1186-91 (2000)).

  Drug eluting contact lenses can also be used as a sustained release drug delivery system. Such contact lenses can be considered as implantable devices or compositions for topical administration. The duration of release of a drug-eluting contact lens can be, for example, molecular imprinting, a barrier or dispersion of nanoparticles / microparticles, increased drug binding to the polymer, or polymer in the lens [eg poly (lactide-co-glycolide). ] It can be increased by sandwiching the layers, or performing any combination or all thereof. Contact lenses can, for example, provide long-term drug release for hours to days, if desired, and enhance patient compliance due to their ease of use and minimal invasiveness. You can

  In some embodiments, one or more therapeutic agents (eg, a polynucleotide [eg, an antisense polynucleotide] and / or a polypeptide [eg, an apolipoprotein mimetic]) is attached to a nanoparticle having a lipid bilayer membrane. , Microparticles or liposomes. In certain embodiments, the lipid bilayer is composed of one or more phospholipids. Non-limiting examples of phospholipids include phosphatidic acid (eg DMPA, DPPA and DSPA), phosphatidylcholine (eg DDPC, DEPC, DLPC, DMPC, DOPC, DPPC, DSPC and POPC), phosphatidylethanolamine (eg DMPE, DOPE, DPPE and DSPE), phosphatidyl glycerol (eg DMPG, DPPG, DSPG and POPG), and phosphatidyl serine (eg DOPS). Nanoparticles, microparticles or liposomes having a lipid bilayer membrane composed of fusogenic lipids (eg DPPG) can fuse with the plasma membrane of cells, thereby delivering therapeutic agents to target cells. be able to. The nanoparticles, microparticles or liposomes with lipid bilayers can be administered locally or systemically.

  In some embodiments, anti-angiogenic agents (eg, anti-VEGF / VEGFR agents) and anti-inflammatory agents (eg, apolipoprotein mimetics [eg, apo AI mimics], CRP inhibitors, complement inhibitors) , Inflammasome inhibitors, corticosteroids or NSAIDs, or any combination thereof or all) in the same or different liposomes, nanoparticles or microparticles composed of biodegradable polymers or lipid bilayers. Encapsulate. Then, for example, it is administered for the treatment of neovascular AMD (including type 1, 2 and / or type 3 neovascularization). In certain embodiments, the liposomes, nanoparticles or microparticles are administered locally, for example, by instillation or injection (eg, intravitreal, subconjunctival, subretinal or subtenon injection).

  A composition containing one or more therapeutic agents can be presented in unit dosage form as a single dose in which all active and inactive ingredients are combined in a suitable manner such that the ingredients form the composition to be administered. No need to mix to do. The unit dosage form may comprise an effective dose or an appropriate fraction thereof for each of the one or more therapeutic agents. Examples of unit dosage forms are tablets, capsules or pills for oral administration. Another example of a unit dosage form is a single-use vial containing a composition of one or more therapeutic agents and excipients, dissolved or suspended in a suitable carrier (eg, an aqueous solvent), Ampule or prefilled syringe. The vial or ampoule may be included in a kit including a tool for administering the composition (eg, a syringe for injecting the composition, a filter or filter needle, and a needle). The kit may also include instructions for storing and administering the composition.

  Alternatively, the composition comprising one or more therapeutic agents is provided in a kit and the one or more therapeutic agents, excipients and carriers (eg, solvents) are two or more separate containers (ampoules, vials). , Tubes, bottles or syringes) and may need to be combined for the preparation of the composition to be administered. In some embodiments, two or more therapeutic agents (eg, an apo AI and / or an apo E mimetic plus an anti-angiogenic agent, neuroprotective agent, anti-inflammatory agent, complement inhibitor, anti- The oxidizing agent or agent that reduces lipid production) is combined in the same formulation shortly before or just before the formulation is administered (eg, by injection). The therapeutic agent (s) can be provided in any suitable form (eg, in stable medium or in lyophilized form). The kit includes tools for administering the composition (eg, syringes for injecting solutions or suspensions, filters or filter needles, and needles). The kit may also include instructions for preserving the contents of the kit and for preparing and administering the composition.

XII. Salt form compounds / molecules (eg, apolipoprotein mimetics (eg, L-4F and AEM-28-14)) are (eg, free base or free acid, or have a basic or acidic atom or functional group). It may be present in non-salt form (without) and as a salt if they can form a salt. The compound capable of forming a salt can be used in a non-salt form or a pharmaceutically acceptable salt form. When the compound has, for example, a basic nitrogen atom, the compound is an acid (eg, mineral acid [eg, HCl, HBr, HI, nitric acid, phosphoric acid or sulfuric acid] or an organic acid [eg, carboxylic acid or sulfonic acid]). ) And an addition salt thereof can be formed. Acids suitable for use in preparing pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzene. Sulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S) -camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, Cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid , D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (±) -DL-lactic acid, (+ ) -L-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (±) -DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1. , 5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, propionic acid, L-pyroglutamic acid, Pyruvate, sugar acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (±) -DL-tartaric acid, (+)-L-tartaric acid, thiocyanic acid, p-toluene sulfone Acids, undecylenic acid, and valeric acid are included.

  When a compound has an acidic group (eg, carboxyl group), the compound can form an addition salt with a base. Pharmaceutically acceptable base addition salts can be formed with, for example, metals (eg, alkali metals or alkaline earth metals) or amines (eg, organic amines). Non-limiting examples of metals useful as cations include alkali metals (eg, lithium, sodium, potassium and cesium), alkaline earth metals (eg, magnesium and calcium), aluminum and zinc. Metal cations can be provided, for example, by inorganic bases (eg, hydroxides, carbonates and bicarbonates). Non-limiting examples of organic amines useful in forming base addition salts include chloroprocaine, choline, cyclohexylamine, dibenzylamine, N, N'-dibenzylethylenediamine, dicyclohexylamine, diethanolamine, ethylenediamine, N-ethylpiperidine, Includes histidine, isopropylamine, N-methylglucamine, procaine, pyrazine, triethylamine and trimethylamine. Pharmaceutically acceptable salts are discussed in detail in the Handbook of Pharmaceutical Salts, Properties, Selection and Use, P. Stahl and C. Wermuth, Eds., Wiley-VCH (2011).

XIII. Exemplary embodiment
  The following embodiments of the present disclosure are provided as examples only.
  1. A method of treating age-related macular degeneration, comprising the step of administering to a subject in need thereof a therapeutically effective amount of an apolipoprotein (apo) mimetic, wherein the apo mimetic is about 0 per dose. 1 or 0.3 mg to about 1.5 mg, or a total dose of about 0.5 or 1 mg to about 10 mg over a period of about 6 months to the eye, intraocularly, into the eye, or A method, which is administered locally around the eye.
  2. The method of embodiment 1, wherein the apomimetic comprises, or is an Apo AI mimic.
  3. The method of embodiment 2, wherein the Apo AI mimic comprises or is 4F or a variant or salt thereof (eg, acetate).
  4. The apo AI mimics, or is, L-4F or D-4F, each optionally having a protecting group at the N- and / or C-termini [eg Ac-DWFKAFYDKVAEKFKEAF- NH_TwoThe method according to embodiment 3, which is (SEQ ID NO: 13).
  5. The method of any one of embodiments 1-4, wherein the apo mimetic comprises or is an Apo E mimetic.
  6. The method of embodiment 5, wherein the ApoE mimetic comprises or is AEM-28-14 or a variant or salt thereof.
  7. The apomimetic (eg, L-4F) is about 0.1 to 0.5 mg, 0.5 to 1 mg, 1 to 1.5 mg, 0.1 to 0.5 mg per administration (eg, per injection). 1 to 0.3 mg, 0.3 to 0.5 mg, 0.5 to 0.75 mg, 0.75 to 1 mg, 1 to 1.25 mg or 1.25 to 1.5 mg (eg, about 0.1 to 0) The method of any of embodiments 1-6, wherein the method is administered topically at a dose of 0.5 mg or 0.5-1 mg).
  8. The apomimetic (eg, L-4F) is about 0.5 or 1-5 mg, 5-10 mg, 0.5 or 1-3 mg, 3-5 mg, 5-5 over a period of about 6 months. 8. The method of any one of embodiments 1-7, which is topically administered at a total dose of 7.5 mg or 7.5-10 mg (eg, about 0.5-3 mg or 3-5 mg).
  9. Embodiments 1-8, wherein the apomimetic (eg, L-4F) is locally administered at a total dose of about 1 or 2-20 mg or 5-15 mg for the entire treatment regimen. The method described.
  10. The apomimetic (eg, L-4F) is about 1-5 mg, 5-10 mg, 10-15 mg, 15-20 mg, 1-3 mg, 3-5 mg, 5-7.5 mg for the entire treatment regimen. , 7.5-10 mg, 10-12.5 mg, 12.5-15 mg, 15-17.5 mg or 17.5-20 mg (eg, about 1-5 mg or 5-10 mg), topically administered at a total dose The method of embodiment 9.
  11. Any of embodiments 1-10, wherein said dose per administration, said total dose over a period of about 6 months, and said total dose for the entire treatment regimen are per eye treated. The method described in the section.
  12. The apomimetic (eg, L-4F) is injected (eg, intravitreal, subconjunctival, subretinal or subtenon injection), instilled or transplanted (eg, intravitreal, intraaqueous, subretinal or subtenon). The method according to any one of embodiments 1-11, wherein the method is locally administered by sub-implantation).
  13. 13. The method of embodiment 12, wherein the apomimetic (eg, L-4F) is locally administered by injection (eg, intravitreal, subconjunctival, subretinal or subtenon injection).
  14. The apomimetic (eg L-4F) is locally administered by injection (eg intravitreal injection) at a dose concentration of about 1, 2, 3, 4 or 5 mg / mL to about 12 or 15 mg / mL. The method of embodiment 13.
  15. The apomimetic (eg, L-4F) is injected (eg, intravitreal injection) to give about 1 to 4 mg / mL, 4 to 8 mg / mL, 8 to 12 mg / mL, 1 to 5 mg / mL, 5 to 5 mg / mL. 10 mg / mL, 10-15 mg / mL, 1-3 mg / mL, 3-5 mg / mL, 5-7.5 mg / mL, 6-8 mg / mL, 7.5-10 mg / mL, 10-12.5 mg / 15. The method of embodiment 14, which is topically administered at a dose concentration of mL or 12.5-15 mg / mL (eg, about 1-5 mg / mL, 5-10 mg / mL or 6-8 mg / mL).
  16. 16. Any one of embodiments 13-15, wherein the apomimetic (eg, L-4F) is locally administered by injection (eg, intravitreal injection) in a dose volume of about 50-150 μL or 50-100 μL. The method described in.
  17. The apomimetic (eg, L-4F) is injected by injection (eg, intravitreal injection) to give about 50-75 μL, 75-100 μL, 100-125 μL or 125-150 μL, or about 50 μL, 75 μL, 100 μL, 125 μL or 17. The method of embodiment 16, which is topically administered in a dose volume of 150 μL (eg, about 100 μL).
  18. The embodiment wherein the apomimetic (eg, L-4F) is locally administered by injection (eg, intravitreal injection) once every month (4 weeks) or 1.5 months (6 weeks). The method according to any one of 13 to 17.
  19. The apomimetic (eg, L-4F) is injected (eg, intravitreal injection) every 2 months (8 weeks), 2.5 months (10 weeks) or 3 months (12 weeks). 18. The method of any one of embodiments 13-17, which is administered once once.
  20. 18. The embodiment of any of embodiments 13-17, wherein the apomimetic (eg, L-4F) is locally administered once every 4, 5 or 6 months by injection (eg, intravitreal injection). the method of.
  21. The apomimetic (eg, L-4F) is locally administered in a total of about 15 or less, 12 or less, 9 or less, 6 or less, or 3 or less injections (eg, intravitreal injection), 21. The method according to any one of embodiments 13-20.
  22. The apomimetic (eg L-4F) has a total of about 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4 or 3 (eg, about 3-6 or 7-). 10) The method according to embodiment 21, which is locally administered in 10 injections (eg, intravitreal injection).
  23. Any one of embodiments 1-22, wherein said apomimetic (eg, L-4F) is administered locally early, at higher doses and / or more frequently (eg, by intravitreal injection) of treatment. The method described in the section.
  24. The treatment regimen using the apomimetic (eg, L-4F) is about 36 months or less, 30 months or less, 24 months or less, 18 months or less, 12 months or less, or 6 months or less. 24. The method of any one of embodiments 1-23, which continues for a period of time.
  25. The treatment regimen using the apomimetic (eg, L-4F) is about 6-12, 12-18, 18-24, 24-30 or 30-36 (eg, about 6-12 or 12-24). The method of embodiment 24, which lasts for a month.
  26. The apomimetic (eg, L-4F) (eg, to treat central geographic atrophy [GA] and / or to prevent or prevent neovascular AMD and / or neovascular type) 26. The method of any one of embodiments 1-25, which is administered at least in the advanced (late) phase of AMD (to treat AMD).
  27. The apomimetic (eg, L-4F) is injected by injection (eg, intravitreal, subconjunctival, subretinal or subtenon injection) for about 4-8 weeks or once every 4-6 weeks for a total of about 8-8 minutes. Twelve or more injections, at a dose of up to about 1-1.5 mg per injection, or at a total dose of up to about 15-20 mg for the entire treatment regimen, or any combination or all thereof. 27. The method of embodiment 26, wherein the method is administered locally in advanced AMD by performing.
  28. The apomimetic (eg, L-4F) is at least in the middle of AMD (eg, to treat non-central GA and / or to block or prevent central GA and / or neovascular AMD) 28. The method of any one of embodiments 1-27, which is administered or is administered in the early phase of mid-stage AMD (eg, to prevent or prevent non-central GA).
  29. The apomimetic (eg, L-4F) is injected by injection (eg, intravitreal, subconjunctival, subretinal or subtenon injection) about 4 to 12 weeks or once every 4 to 8 weeks, for a total of about 4 to 4 weeks. Eight or more injections, a dose of up to about 0.5-1 mg or 1-1.5 mg per injection, or a total dose of about 10-15 mg or more for the entire treatment regimen, or any thereof. 29. The method of embodiment 28, wherein the method is locally administered in mid-term AMD by performing a combination of or all of
  30. 30. The method of any one of embodiments 1-29, wherein the apomimetic (eg, L-4F) is administered at least early in AMD (eg, to prevent or prevent non-central GA). ..
  31. The apomimetic (eg, L-4F) is less frequently (eg, about every 3, 4, or 6 months) by injection (eg, intravitreal, subconjunctival, subretinal or subtenon injection). Injection), at a lower total number of injections (eg, about 1, 2 or 3 injections), or at a higher dose per injection (eg, about 0.5-1 mg per injection or 1-1.5 mg), or any combination thereof, or all thereof, for local administration in early AMD.
  32. The apomimetic (eg, L-4F) is more frequently (more total dosing times) and / or later stages of AMD or more severe AMD symptoms and / or Or locally administered at a higher dose (a higher dose per administration and / or a higher total dose for the entire treatment regimen) (eg, by intravitreal injection). The method described in the section.
  33. The apomimetic (eg, L-4F) is administered locally (eg, by intravitreal injection) in a fixed routine schedule, an on-demand schedule or a treat-and-extend schedule. 33. The method according to any one of Forms 1-32.
  34. The apomimetic (eg, L-4F) is about 75-95% (eg, about 90%) apomimetic and about 5-25% (eg, L-4F) in a weight or molar amount relative to the total amount. , About 10%) of the corresponding apolipoprotein (eg, apoA-I) or an active portion or domain thereof is locally administered via the composition of any of embodiments 1-33. ..
  35. The apomimetic (eg, L-4F) is one or more excipients that inhibit peptide / protein aggregation, increase peptide / protein solubility, decrease solution viscosity, or 35. The method of any one of embodiments 1-34, wherein the method is administered topically as a composition comprising one that increases peptide / protein stability, or performs any combination or all thereof.
  36. 36. The method of any one of embodiments 1-35, wherein the apomimetic (eg, L-4F) is administered topically via a sustained release composition.
  37. 37. The method of any one of embodiments 1-36, further comprising administering one or more additional therapeutic agents.
  38. The one or more additional therapeutic agents are antihyperlipidemic agents, PPAR-α agonists, PPAR-δ agonists, PPAR-γ agonists, anti-amyloid agents, inhibitors of lipofuscin or its components, and antioxidants. , Neuroprotective agents (neuroprotective agents), apoptosis inhibitors, necrosis inhibitors, C-reactive protein (CRP) inhibitors, inhibitors of the complement system or its components (proteins, etc.), inflammasome inhibitors, anti-inflammatory 38. The method of embodiment 37, selected from the group consisting of an agent, an immunosuppressive agent, a matrix metalloproteinase (MMP) modulator, an anti-angiogenic agent, and RPE cell replacement therapy.
  39. A method of preventing age-related macular degeneration (AMD), delaying the onset of AMD, delaying the progression of AMD, or reducing the extent of AMD-related visual impairment or loss, in a therapeutically effective amount for a subject in need thereof. 39. A method comprising administering an apolipoprotein (apo) mimetic according to any of embodiments 1-38.
  40. 40. The method of embodiment 39, wherein the AMD is dry AMD (including non-central and / or central geographic atrophy) or neovascular AMD (including type 1, 2 and / or type 3 neovascularization). ..
  41. A method of treating age-related macular degeneration (AMD), wherein a therapeutically effective amount of the apolipoprotein (apo) mimetic of any one of embodiments 1-38 is therapeutically effective for a subject in need thereof. A method comprising administering an amount of an anti-angiogenic drug.
  42. Embodiment 41, wherein the apomimetic comprises or is an Apo AI Mimic (eg, L-4F or D-4F) and / or an Apo E Mimetic (eg, AEM-28-14). The method described in.
  43. The anti-angiogenic drug comprises or is a drug that inhibits the action of vascular endothelial growth factor (anti-VEGF drug) and / or a drug that inhibits the action of platelet-derived growth factor (anti-PDGF drug), or A method according to form 41 or 42.
  44. The anti-VEGF drug is squalamine, PAN-90806, an anti-VEGF antibody and a fragment thereof (eg, bevacizumab [AVASTIN (registered trademark)], ranibizumab [LUCENTIS (registered trademark)], ESBA1008 and ESBA903), anti-VEGF aptamer (eg, Pegaptanib [MACUGEN®]), anti-VEGF engineered ankyrin repeat protein (DARPin) (eg Avisipearl pegol), soluble VEGF receptor (eg VEGFR1), one or more cells of one or more VEGFRs 44. The method of embodiment 43, which is selected from the group consisting of a soluble fusion protein containing an ectodomain (eg, Aflibercept [EYLEA®] and Converte), and combinations thereof.
  45. 45. The method of embodiment 44, wherein the anti-VEGF agent comprises or is aflibercept, bevacizumab or ranibizumab, or any combination thereof, or.
  46. Less frequent and / or conventional or recommended dosing frequency of the anti-angiogenic agent in the absence of treatment with the apomimetic (eg, L-4F). 46. The method of any one of embodiments 41-45, wherein the anti-angiogenic drug (eg, anti-VEGF drug) is administered at a lower dose than the dose.
  47. At least about 1.5, 2, 3, 4, 5, or 6 more than the conventional or recommended dosing frequency of the anti-angiogenic agent in the absence of treatment with the apomimetic (eg, L-4F). The method of embodiment 46, wherein the anti-angiogenic agent (eg, anti-VEGF agent) is administered (eg, by at least about 2) times less frequently (eg, by intravitreal injection).
  48. At least about 10%, 20%, 30%, 40%, 50% over conventional or recommended doses of the anti-angiogenic agent in the absence of treatment with the apomimetic (eg, L-4F). , 60%, 70% or 80% (eg, at least about 20%), or about 10-30%, 30-50% or 50-70% lower doses (eg, by intravitreal injection). 48. The method of embodiment 46 or 47, wherein a crude drug (eg, anti-VEGF drug) is administered.
  49. Of embodiments 46-48, wherein treatment with the apomimetic (eg, L-4F) reduces the total number of administrations (eg, total injections) of the anti-angiogenic drug (eg, anti-VEGF drug). The method according to any one of items.
  50. 50. The method of embodiment 49, wherein the anti-angiogenic agent (eg, anti-VEGF agent) is administered no more than about 20, 18, 15, 12, or 10 times (eg, by intravitreal injection).
  51. 51. The method of any one of embodiments 46-50, wherein treatment with the apomimetic (eg, L-4F) and the anti-angiogenic drug (eg, anti-VEGF drug) has a synergistic effect.
  52. The anti-angiogenic drug comprises or is aflibercept (EYLEA®); and
  2 mg afri administered by intravitreal injection once every 2 months after 2 mg once a month for the first 3 months in the absence of treatment with said apomimetic (eg L-4F). Optionally, once per month for the first 1, 2 or 3 months, or for the first 1.5 or 3 months, as compared to conventional or recommended doses and dosing frequency of Belcept For about 1 to 1.5 mg or 1.5 to 2 mg once every 6 weeks for about 1 to 1.5 mg or 1.5 to 2 mg once every 3, 4, 5 or 6 months after administration 52. The method of any one of embodiments 46-51, wherein the aflibercept is administered in a dose (eg, by intravitreal injection).
  53. The anti-angiogenic agent comprises or is aflibercept; and
  About 1 to 1.25 mg, substantially similar to or at the same or conventional frequency of dosing of aflibercept in the absence of treatment with the apomimetic (eg, L-4F). The method of any one of embodiments 46-51, wherein said aflibercept is administered at a dose of 1.25-1.5 mg or 1.5-1.75 mg (eg, by intravitreal injection). ..
  54. The anti-angiogenic agent comprises or is ranibizumab (LUCENTIS®); and
  When compared to the conventional or recommended dose and dosing frequency of 0.5 mg ranibizumab administered by intravitreal injection once a month in the absence of treatment with said apomimetic (eg L-4F). , Optionally, about 0.2-0.3 mg once a month for the first 1, 2 or 3 months, or once every 6 weeks for the first 1.5 or 3 months, About 0.2-0.3 mg, 0.3-0., Once every 2, 3, 4, 5 or 6 months after administration at a dose of 0.3-0.4 mg or 0.4-0.5 mg. 52. The method of any one of embodiments 46-51, wherein said ranibizumab is administered at a dose of 4 mg or 0.4-0.5 mg (eg, by intravitreal injection).
  55. The anti-angiogenic agent comprises or is ranibizumab; and
  52. Any one of embodiments 46-51, wherein said ranibizumab is administered at a dose of about 0.2-0.3 mg or 0.3-0.4 mg once a month (eg, by intravitreal injection). The method described in.
  56. The anti-angiogenic agent comprises or is bevacizumab (AVASTIN®); and
  A conventional or recommended dose and dosage of about 1.25 mg of AMD therapeutic bevacizumab administered by intravitreal injection once a month in the absence of treatment with the apomimetic (eg, L-4F). Compared to the frequency, but optionally, about 0.5 to once a month for the first 1, 2 or 3 months, or once every 6 weeks for the first 1.5 or 3 months. About 0.5-0.75 mg, 0.75-1 mg or once every 2, 3, 4, 5 or 6 months after administration at a dose of 0.75 mg, 0.75-1 mg or 1-1.25 mg. 52. The method of any one of embodiments 46-51, wherein the bevacizumab is administered at a dose of 1-1.25 mg (eg, by intravitreal injection).
  57. The anti-angiogenic agent comprises or is bevacizumab; and
  52. Any one of embodiments 46-51, wherein said bevacizumab is administered at a dose of about 0.5-0.75 mg or 0.75-1 mg once a month (eg, by intravitreal injection). the method of.
  58. 52. Any one of embodiments 46-51, wherein said anti-angiogenic drug (eg, anti-VEGF drug) is administered once (eg, by intravitreal injection) every 2, 3, 4, 5 or 6 months. The method described in.
  59. The anti-angiogenic drug (eg, anti-VEGF drug) is, for example, injection (eg, intravitreal, subconjunctival, subretinal or subtenon injection), eye drop or transplant (eg, intravitreal, aqueous humor, subretinal). Or sub-Tenon implantation), for topical administration to, intraocularly, in, or around the eye, according to any one of embodiments 41-58.
  60. An embodiment in which the anti-angiogenic drug (eg, anti-VEGF drug) is administered to treat neovascular (wet) AMD, including neovascularization of types 1, 2, and 3, or to delay its progression. 41. The method according to any one of 41 to 59.
  61. Embodiments 41 to 60, wherein the anti-angiogenic drug (eg, anti-VEGF drug) is administered at least during the advanced (late) stage of AMD to prevent, delay the onset of, or delay the onset of neovascular AMD. The method according to any one of 1.
  62. 62. The method of any one of embodiments 41-61, wherein the apomimetic (eg, L-4F) is administered at least during the advanced stages of AMD.
  63. Administering the apomimetic (eg, L-4F) to treat central geographic atrophy and / or prevent neovascular AMD (including neovascularization of types 1, 2 and 3), 63. The method of embodiment 62, wherein the onset is delayed or its progression is delayed.
  64. 64. Any one of embodiments 41-63, wherein the anti-angiogenic agent (eg, anti-VEGF agent) is administered in a fixed routine schedule, an on-demand schedule or a treat-and-extend schedule. The method described in.
  65. 65. The method of any one of embodiments 41-64, wherein the apomimetic (eg, L-4F) and the anti-angiogenic drug (eg, anti-VEGF drug) are administered in separate compositions.
  66. 65. The method of any one of embodiments 41-64, wherein the apomimetic (eg, L-4F) and the anti-angiogenic drug (eg, anti-VEGF drug) are administered in the same composition.
  67. A method of treating age-related macular degeneration (AMD), wherein a therapeutically effective amount of the apolipoprotein (apo) mimetic of any one of embodiments 1-38 is therapeutically effective for a subject in need thereof. A method comprising administering an amount of a complement inhibitor.
  68. Embodiment 67, wherein the apomimetic comprises, or is, an Apo AI mimic (eg, L-4F or D-4F) and / or an Apo E mimic (eg, AEM-28-14). The method described in.
  69. 69. The method of embodiment 67 or 68, wherein the apomimetic (eg, L-4F) and the complement inhibitor are administered to treat Geographic Atrophy (GA).
  70. The embodiment according to embodiment 69, wherein the apomimetic (eg, L-4F) and the complement inhibitor are administered to prevent, delay the onset of, or delay the progression of central GA and / or non-central GA. Method.
  71. Administering the apomimetic (eg, L-4F) and the complement inhibitor at least in the advanced (late) stage of atrophic (dry) AMD to treat central GA or delay the progression thereof; And / or the method of embodiment 69 or 70, wherein neovascular AMD is prevented or its onset is delayed.
  72. The apomimetic (eg, L-4F) and the complement inhibitor are administered at least in the middle of AMD to treat or slow the progression of non-central GA and / or central GA and / or 72. The method of any one of embodiments 69-71, which prevents neovascular AMD or delays its onset.
  73. Administering the apomimetic (eg, L-4F) and the complement inhibitor during at least the early phase of AMD or the early phase of mid-stage AMD to prevent or delay the development of non-central GA. 73. The method according to any one of embodiments 69-72.
  74. The complement inhibitor includes an anti-complement factor B (CFB) antibody and a fragment thereof (eg, TA106), an anti-CFD antibody and a fragment thereof (eg, lampalizumab), a C3 inhibitor (eg, compstatin). ) And derivatives thereof [eg, POT-4], soluble forms of mycophenolic acid-glucosamine conjugates and proteins or fragments thereof [eg, CR1, decay-promoting factor and membrane cofactor protein]), anti-C3b / iC3b antibody. And fragments thereof (eg, 3E7), anti-C5 antibodies and fragments thereof (eg, eculizumab and LFG316), anti-C5 aptamers (eg, ARC1905 [Zimura (registered trademark)]), other C5 inhibitors (eg, Coversin, C5a receptor antagonist (eg, JPE-1375, JSM-7717, PMX-025, PMX-53, and anti-C5aR antibody and fragments thereof (eg, neutrazimab)), supplement Inhibitors of alternative body pathway (eg, sCR1, TT30 and zinc), inhibitors of classical complement pathway (eg, sCR1), inhibitors of lectin complement pathway (eg, inhibition of mannose-related serine protease [MASP]) Agents (eg, anti-MASP antibody and fragments thereof [eg, OMS721]), inhibitors of membrane attack complex (MAC) formation (eg, zinc, CD59 and modified CD59 having glycolipid anchor), and analogs thereof 74. The method of any one of embodiments 67-73, selected from the group consisting of :, derivatives, fragments, salts, and combinations.
  75. 75. The method of embodiment 74, wherein the complement inhibitor comprises or is ramparizumab, LFG316 or ARC1905, or any combination or all thereof.
  76. The method of embodiment 75, wherein the complement inhibitor comprises or is lampalizumab.
  77. The method of embodiment 76, wherein the subject has a mutation in the gene encoding complement factor I (CFI).
  78. Treatment with the apomimetic (eg, L-4F) and the complement inhibitor (eg, lampalizumab) is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%. Or 80% (eg, at least about 20% or 40%), or about 20-40%, 40-60% or 60-80%, slowing the progression of central GA and / or non-central GA (eg, GA progression). The method of any one of embodiments 67-77, wherein the rate is reduced or the GA lesion area or size is reduced).
  79. Treatment with the apomimetic (eg, L-4F) and the complement inhibitor (eg, lampalizumab) is more effective than treatment with the complement inhibitor in the absence of treatment with the apomimetic. At least about 10%, 20%, 30%, 50%, 100%, 150%, 200% or 300% (eg, at least about 20% or 30%), or about 10-30%, 30-50. %, 50-100%, 100-200% or 200-300% (eg, about 50-100%) as much as possible to slow the progression of central GA and / or non-central GA (eg reduce the rate of GA progression, Alternatively, the GA lesion area or size is reduced), the method of any one of embodiments 67-78.
  80. Frequency of the complement inhibitor (eg, Lampalizumab) lower than conventional or recommended dosing frequency of the complement inhibitor in the absence of treatment with the apomimetic (eg, L-4F). The method of any one of embodiments 67-79, which is administered at and / or at a dose lower than a conventional or recommended dose.
  81. The complement inhibitor (eg, Lampalizumab) is at least about 1 times the conventional or recommended dosing frequency of the complement inhibitor in the absence of treatment with the apomimetic (eg, L-4F). 81. The method of embodiment 80, wherein the method is administered 5, 2, 3, 4, 5, or 6 (eg, at least about 2) times less frequently (eg, by intravitreal injection).
  82. The complement inhibitor (eg, ramparizumab) is at least about 10% above the conventional or recommended dose of said complement inhibitor in the absence of treatment with said apomimetic (eg, L-4F), 20%, 30%, 40%, 50%, 60%, 70% or 80% (eg, at least about 20%), or about 10-30%, 30-50% or 50-70% lesser dose ( 82. The method of embodiment 80 or 81, which is administered (eg, by intravitreal injection).
  83. Any of Embodiments 80-82, wherein treatment with the apomimetic (eg, L-4F) reduces the total number of administrations (eg, total injections) of the complement inhibitor (eg, ramparizumab). The method according to paragraph 1.
  84. 84. The method of embodiment 83, wherein said complement inhibitor (eg, Lampalizumab) is administered no more than about 20, 18, 15, 12, or 10 times (eg, by intravitreal injection).
  85. 85. The method of any one of embodiments 80-84, wherein treatment with the apomimetic (eg, L-4F) and the complement inhibitor (eg, lampalizumab) has a synergistic effect.
  86. The complement inhibitor comprises or is ramparizumab; and
  Compared to the conventional or recommended dose and dosing frequency of about 10 mg ramparizumab administered by intravitreal injection once a month in the absence of treatment with the apomimetic (eg, L-4F), Optionally, about 4-6 mg, 6-8 mg or 8 once a month for the first 1, 2 or 3 months, or once every 6 weeks for the first 1.5 or 3 months. The palpalizumab is administered once every 2, 3, 4, 5 or 6 months after administration at a dose of -10 mg (eg, by intravitreal injection) at a dose of about 4-6 mg, 6-8 mg or 8-10 mg. The method of any one of embodiments 80-85, wherein:
  87. The complement inhibitor comprises or is ramparizumab; and
  The lumpalizumab is administered once every month (4 weeks) or every 1.5 months (6 weeks) at a dose of about 3-5 mg, 5-7 mg or 7-9 mg (eg, by intravitreal injection). , The method of any one of embodiments 80-85.
  88. An embodiment in which the complement inhibitor (eg, Lampalizumab) is administered once every 2, 3, 4, 5 or 6 months (eg once every 2 months) (eg by intravitreal injection). 87. The method according to any one of 80-86.
  89. The complement inhibitor (eg, Lamparizumab) is, for example, injection (eg, intravitreal, subconjunctival, subretinal or subcapsular Tenon injection), eye drop or transplant (eg, intravitreal, intraaqueous, subretinal or tenon). 89. The method of any one of embodiments 67-88, which is administered topically to, into, into, or around the eye by subcapsular implantation).
  90. 90. The method of any one of embodiments 67-89, wherein the apomimetic (eg, L-4F) and the complement inhibitor (eg, lampalizumab) are administered in separate compositions.
  91. 90. The method of any one of embodiments 67-89, wherein the apomimetic (eg, L-4F) and the complement inhibitor (eg, lampalizumab) are administered in the same composition.
  92. The apomimetic (eg, L-4F) and the complement inhibitor are administered at least in the advanced stage of AMD to prevent neovascular AMD including neovascularization of types 1, 2, and 3, and prevent its development. 92. The method according to any one of embodiments 67-91, wherein the delay is delayed or its progression is delayed.
  93. 93. The method of embodiment 92, further comprising administering a therapeutically effective amount of an anti-angiogenic drug.
  94. The anti-angiogenic drug is an anti-VEGF drug (eg, aflibercept [EYLEA (registered trademark)], bevacizumab [AVASTIN (registered trademark)] or ranibizumab [LUCENTIS (registered trademark)], or any combination thereof or all thereof. ) And / or an anti-PDGF agent (eg, E10030 [FOVISTA®]), or is a method of embodiment 93.
  95. 95. The method of any one of embodiments 92-94, wherein the complement inhibitor comprises or is ARC1905 (ZIMURA®) or LFG316.
  96. The complement inhibitor (eg, ramparizumab, ARC1905 or LFG316, or any combination thereof) is administered on a fixed routine schedule, an on-demand schedule or a treatment-and-extend schedule. The method according to any one of embodiments 67-95.
  97. A method of treating age-related macular degeneration (AMD), wherein a therapeutically effective amount of the apolipoprotein (apo) mimetic of any one of embodiments 1-38 is therapeutically effective for a subject in need thereof. A method comprising administering an amount of an antioxidant.
  98. Embodiment 97, wherein the apomimetic comprises, or is, an Apo AI Mimic (eg, L-4F or D-4F) and / or an Apo E Mimetic (eg, AEM-28-14). The method described in.
  99. The antioxidant is anthocyanin, benzenediol abietane diterpene (eg, carnosic acid), carnosine, carotenoid (eg, carotene [eg, β-carotene], xanthophyll [eg, lutein, zeaxanthin and meso-zeaxanthin], and saffron. Carotenoids [eg, crocin and crocetin]), curcuminoids (eg, curcumin), cyclopentenone prostaglandins (eg, 15d-PGJ)_Two), Flavonoids (eg, flavonoids of Ginkgo biloba (Ginkgo biloba) [eg, myricetin and quercetin]), prenyl flavonoids (eg, isoxanthohumol), retinoids, stilbenoids (eg, resveratrol), uric acid, vitamin A, Vitamin B₁(Thiamine), vitamin B_Two(Riboflavin), vitamin B_Three(Niacin), vitamin B₆(Eg, pyridoxal, pyridoxamine, 4-pyridoxic acid and pyridoxine), vitamin B₉(Folic acid), vitamin B₁₂(Cobalamin), vitamin C, vitamin E (eg, tocopherol and tocotrienol), selenium, zinc (eg, zinc monocysteine), an inhibitor and scavenger of lipid peroxidation and its by-products (eg, vitamin E [eg, α- Tocopherol], tililazad, NXY-059 and XJB-5-131), activator of nuclear factor (erythrocyte-derived 2) -like 2 (NFE2L2 or NRF2) (eg, OT-551), superoxide dismutase (SOD) mimic The method of embodiment 97 or 98, which is selected from the group consisting of (eg, OT-551) and analogs, derivatives, salts and combinations thereof.
  100. The antioxidant is one or more vitamins (eg vitamin B₆, Vitamin C and Vitamin E), one or more carotenoids (eg, xanthophyll [eg, lutein, zeaxanthin and meso-zeaxanthin] and carotenoids in saffron [eg, crocin and crocetin]), or zinc, or any combination thereof. The method of embodiment 99, comprising all or all of them, eg, an AREDS or AREDS2 formulation, an ICAPS® formulation, an Ocuvite® formulation or Saffron2020 ™.
  101. The antioxidant (eg vitamin and / or carotenoid) is lower than the conventional or recommended dose of the antioxidant in the absence of treatment with the apomimetic (eg L-4F). 101. The method of any one of embodiments 97-100, which is administered in a dose and / or less frequently than conventional or recommended dosing frequency.
  102. Said antioxidant (eg vitamin and / or carotenoid) is at least more than the conventional or recommended dose of said antioxidant in the absence of treatment with said apomimetic (eg L-4F). About 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% (eg, at least about 20%), or about 10-30%, 30-50% or 50-70%. The method of embodiment 101, wherein the method is administered at a low dose.
  103. The antioxidant (eg, vitamins and / or carotenoids) is less than the conventional or recommended dosing frequency of the antioxidant in the absence of treatment with the apomimetic (eg, L-4F). 103. The method of embodiment 101 or 102, wherein the method is administered at least about 2, 3, 5, 7 or 10 (eg, at least about 2) times less frequently.
  104. The antioxidant (eg, vitamin and / or carotenoid) is administered at least once a day in the absence of treatment with the apomimetic (eg, L-4F) of the antioxidant or conventional The method of embodiment 103, which is administered once every two or three days as compared to the recommended dosing frequency.
  105. The apomimetic (eg, L-4F) and the antioxidant (eg, vitamin and / or carotenoid) are central geographic atrophy (GA) and / or (including NVs 1, 2 and 3) neovascularization Embodiments 97-, wherein at least the advanced (late) stage of AMD is administered to treat or delay type AMD and / or to prevent neovascular AMD or delay its onset. 104. The method according to any one of 104.
  106. The apomimetic (eg L-4F) and the antioxidant (eg vitamins and / or carotenoids) are used to treat or slow the progression of non-central GA and / or central GA and / or 106. The method of any one of embodiments 97-105, which is administered at least mid-stage of AMD to prevent neovascular AMD or delay its onset.
  107. The apomimetic (eg, L-4F) and the antioxidant (eg, vitamins and / or carotenoids) prevent at least early- or mid-stage AMD from preventing non-central GA or delaying its onset. 107. The method according to any of embodiments 97-106, wherein the method is administered in the early phase.
  108. Any of Embodiments 97-107 wherein the antioxidant (eg, vitamin and / or carotenoid) and optionally the apomimetic (eg, L-4F) is administered at least early in AMD. The method described in paragraph 1.
  109. Treatment with the apomimetic (eg, L-4F) and the antioxidant (eg, vitamin and / or carotenoid) is at least about 10%, 20%, 30%, 40%, 50%, 60%. , 70% or 80% (eg, at least about 20%), or about 20-40%, 40-60% or 60-80%, slowing the progression of central GA and / or non-central GA (eg, GA progression). The method of any one of embodiments 105-108, wherein the rate is reduced or the GA lesion area or size is reduced).
  110. Treatment with the apomimetic (eg, L-4F) and the antioxidant (eg, vitamin and / or carotenoid) uses the antioxidant in the absence of treatment with the apomimetic Than treatment, at least about 10%, 20%, 30%, 50%, 100%, 150%, 200% or 300% (eg, at least about 20% or 30%), or about 10-30%, 30. -50%, 50-100%, 100-200% or 200-300% (eg, about 50-100%) more, slowing the progression of central GA and / or non-central GA (eg, reducing the rate of GA progression) Or reduce the GA lesion area or size), the method of any one of embodiments 105-109.
  111. 111. The method of any one of embodiments 101-110, wherein treatment with the apomimetic (eg, L-4F) and the antioxidant (eg, vitamin and / or carotenoid) has a synergistic effect.
  112. The antioxidant (eg, vitamin and / or carotenoid) is systemically administered (eg, oral), or (eg, injection [eg, intravitreal, subconjunctival, subretinal or subtenon injection], instillation or transplantation]. Intraocular, intravitreal, subretinal or sub-Tenon implants), intraocularly, intraocularly, or around the eye, topically administered to any one of embodiments 97-111. Method.
  113. 113. The method of any one of embodiments 97-112, wherein the apomimetic (eg, L-4F) and the antioxidant (eg, vitamin and / or carotenoid) are administered in separate compositions.
  114. 113. The method of any one of embodiments 97-112, wherein the apomimetic (eg, L-4F) and the antioxidant (eg, vitamin or carotenoid) are administered in the same composition.

XIV. Examples The following examples are intended only to illustrate the present disclosure. Other assays, treatments, methods, procedures, conditions and reagents can be used alternatively, where appropriate, and other tests can be performed.

Example 1: Reduction of lipid deposits from Bruch's membrane in aged monkeys by L-4F The macaque test was performed according to approved guidelines. Sterile to 9 female aged macaques (macaca fascicularis, all older than 20 years old) with spontaneous age-related macular disease (demonstrating age-related drusen-like macular change / macular disease similar to early AMD in humans) Apo AI Mimic L-4F (Ac-DWFKAFYDKVAEKFKEAF-NH ₂ Acetate (SEQ ID NO: 13)) (n = 7) or placebo (scrambled L- in sterile BSS) in balanced salt solution (BSS). 4F (sL-4F) (amino acids are identical but in non-functional order) (n = 2) were injected intravitreally, one eye per animal, 6 times a month, in a volume of 50 μL. The dose of L-4F or scrambled L-4F was similarly escalated (625 μg total) for injection and was not observed in the other eye per animal, only observed. It showed worse drusen-like changes per baseline animal than the non-injected eye.Table 1 shows the dosing regimen used in the macaque study.

  Laboratory tests (including serology, hemograms and liver enzymes) were performed, and ophthalmologic tests (including fundus photography, optical coherence tomography (OCT), intraocular pressure examination and blood sampling) were also performed. After 7 months, all animals were sacrificed and both eyes were immediately prepared for histology. Histochemistry was performed with oil red O for neutral lipids and filipin for esterified cholesterol. Immunohistochemistry was performed on complement factor D (CFD) and the membrane attack complex (MAC, C5b-9), both of which are activation markers for the alternative complement pathway.

  For Oil Red O (ORO) staining, the specimens were treated with 0.3% Oil Red O (Sigma-Aldrich Biochemie GmbH, Hamburg, Germany) solution (in 99% isopropanol) for 30 minutes at room temperature (RT), then. Immersion treatment in a 60% isopropanol solution for 12 minutes. After washing the specimens with deionized water for 3 minutes, counterstaining was performed with hematoxylin (Carl Roth GmbH, Karlsruhe, Germany). The specimens are then mounted with mounting solution (Aquatex from Merck Millipore, Darmstadt, Germany), covered with glass coverslips (Menzel-Graeser GmbH), and a fully automated inverted optical microscope for life sciences (DMI6000 from Leica Microsystems). , Wetzlar, Germany). Image analysis was performed by scoring the intensity of ORO staining (red) of Bruch's membrane (BrM), with scores ranging from 0-4, four of two separate sections from each eye. Quantitative evaluation was performed, with evaluation in different areas (total of 8 different areas from each eye). Quantitative ORO staining scores on BrM and choroid are: 0 = no stain; 1 = +; 2 = ++; 3 = ++++; 4 = ++++.

  For Filipino staining, the specimens were washed once with deionized water for 5 minutes and then treated with 70% ethanol for 45 minutes. After washing with deionized water for 5 minutes, the sample was treated with cholesterol esterase (8.12 units / mL) diluted with 0.1 M potassium phosphate buffer (PPB, pH 7.4) for 3.5 hours at 37 ° C. did. Specimens were then washed twice with PPB and phosphate buffered saline (PBS) for 3 minutes over time followed by cold (4 ° C.) PBS overnight. Filipin staining was then performed with 250 μg / mL Philippines (Sigma-Aldrich Biochemie GmbH, Hamburg, Germany) diluted with N, N-dimethylformamide (Merck Millipore, Darmstadt, Germany) and protected from light at RT for 60 minutes. Carried out. Specimens were then washed with PBS and deionized water over time, mounted with mounting solution (Mowiol®; Carl Roth GmbH, Karlsruhe, Germany), covered with glass coverslips, and inverted fluorescent microscope ( Tested with Leica Microsystems DMI6000, Wetzlar, Germany). Filipino fluorescence was observed using a UV filter set (λex / λem = 350 nm / 455 nm). As a negative control, cholesterol esterase was replaced with PBS, which blocked the release of cholesterol from the cholesteryl ester and its subsequent binding by filipin. A semi-quantitative analysis of Filipin fluorescence intensity on three different areas of BrM on three different slides from the same eye (total nine different areas from each eye) was performed.

  Immunohistochemical assays of membrane attack complex (MAC, C5b-9) and complement factor D (CFD) were performed similarly except that a monoclonal antibody specific for each complement component was adopted. Specimens were treated with 10 μg / mL Protease K (Sigma-Aldrich Biochemie GmbH, Hamburg, Germany) in PBS for antigen retrieval for 30 minutes at RT. Subsequently, the samples were blocked with a goat serum solution (5% goat serum in PBS, 0.3% Triton X-100) for 60 minutes at RT. Specimens were then primary antibody to C5b-9 (diluted 1:30 in PBS; mouse monoclonal antibody; Dako Deutschland GmbH, Hamburg, Germany) or primary antibody to complement factor D (diluted 1: 200 in PBS; Mouse monoclonal antibody; Santa Cruz Biotechnology, Dallas, Texas, USA) overnight at 4 ° C. After washing with PBS, the specimen was reacted with a secondary antibody (diluted 1: 200 in PBS; Alexa Fluor 488 anti-mouse antibody, Life Technologies Deutschland GmbH, Darmstadt, Germany) for 1 hour at 37 ° C. After washing the sample three times with PBS, nuclear staining was performed with DAPI (1 μg / mL; Life Technologies GmbH, Darmstadt, Germany) for 10 minutes. Specimens were then washed 3 times with PBS, mounted with anti-bleaching solution (Mowiol®, Carl Roth GmbH, Karlsruhe, Germany) and covered with glass coverslips for microscopy. Fluorescent microscopy was performed using an inverted fluorescent microscope (DMI6000 from Leica Microsystems, Wetzlar, Germany) and a filter set (for λex / λem = 470 nm / 525 nm). For semi-quantitative analysis of C5b-9 fluorescence intensity, 3-5 different areas per slide were analyzed for 3 different slides from each eye (total 9-15 different areas from each eye). Analyzed. For semi-quantitative analysis of complement factor D fluorescence intensity, three different areas were evaluated for each eye.

  In both control animals injected with placebo (scrambled L-4F) staining of Bruch's membrane (BrM) and choriocapillaris with Oil Red O for neutral lipids and Filipin for esterified cholesterol was strong in both eyes and It was specifically shown. For example, staining with Oil Red O showed that large amounts of lipid were present in and on BrM in both control animals. In contrast, staining of L-4F-injected Oil Red O eyes resulted in an approximately 56% reduction in lipid deposits from BrM after 6 months compared to placebo-injected eyes. FIG. 2 shows the Bruch's membrane and Bruch's membrane in the eye of the macaque injected with L-4F or placebo (scrambled L-4F) 6 times a month into the vitreous once a month and in the other non-injected eye. The neutral lipids above are stained with Oil Red O (ORO) and scored. A semi-quantitative evaluation of Filipino fluorescence revealed a reduction in ester cholesterol in BrM of about 68% in Br-4 injected eyes compared to placebo injected eyes. Figure 3 shows the ester form in Bruch's membrane in the eye of the macaque injected with L-4F or placebo (scrambled L-4F) 6 times in the vitreous once a month and in the other non-injected eye. Cholesterol shows staining intensity in the Philippines.

  Through semi-quantitative analysis of fluorescence intensity of each specific antibody, L-4F-injected eyes showed higher levels of BrM and MAC (C5b-9) in choriocapillaris than in scrambled peptide-injected eyes. Levels were reduced by about 58% and complement factor D levels were reduced by about 41%. Figure 4 shows Bruch's membrane and choriocapillaris in the eye of the macaque injected with L-4F or placebo (scrambled L-4F) 6 times intravitreally once a month and in the other non-injected eye. The staining intensity of the membrane attack complex (MAC, C5b-9) inside is shown. FIG. 5: Staining of complement factor D in the eyes of the macaques injected with L-4F or placebo (scrambled L-4F) 6 times intravitreally once a month and in the other non-injected eye. Indicates strength.

  Lipid deposits in Bruch's membrane contribute to BrM thickening. Bruch's membrane thickness was measured post mortem by electron microscopy in the temporal outer macula of the blunted eye. L-4F-injected eyes had a decrease in BrM thickness (1.31 μm ± SE0.11) of about 24% compared to placebo-injected eyes (1.73 μm ± SE0.02). FIG. 6 shows the lateral temporal macula measured in the eye of the macaque injected with L-4F or placebo (scrambled L-4F) 6 times intravitreally once a month and in the other non-injected eye. The thickness of the Bruch's film formed is shown.

  L-4F had a similar effect on the injection side eye as well as on the other non-injection side after 6 intravitreal injections monthly (see Figures 2-6). ). Without intending to be bound by theory, intravitreally injected L-4F in one eye reaches BrM, from where it reaches the choriocapillaris, and thus systemic circulation, and finally May have entered the other non-injection eye. Also, without intending to be bound by theory, the magnitude of the therapeutic effect of L-4F on the other non-injected eye is that macaques weigh more than the size of the eye. It may be partly due to its relatively small size and the macaque's predominantly vegetarian diet (the macaque did not exhibit atherosclerosis, a potential target for L-4F in the systemic circulation) ..

  All macaques were well tolerated by L-4F and none of the macaques intravitreally injected L-4F experienced any significant adverse events or side effects. For example, six monthly intravitreal L-4F injections can reduce blood levels of hsCRP when compared to high sensitivity C-reactive protein (hsCRP) blood levels on the day before the first injection of L-4F. Did not increase. Circulating hsCRP, produced primarily in the liver, is a non-specific marker of systemic inflammation.

  In summary, the Apo AI mimic L-4F acted as an effective lipid scavenger and cleared lipid deposits from BrM in a monkey model of age-related macular disease. Removal of lipid deposits from BrM restored BrM integrity, which was confirmed by electron microscopy. Also, the downstream effects of lipid deposits (eg, local inflammation) were reduced, which was demonstrated by a marked reduction in complement activation in the L-4F-injected eye.

Example 2: Phase I / II Safety / Efficacy Study of L-4F Alone A randomized, open-label, dose escalation Phase I / II study for patients with AMD (eg, mid-term AMD) (eg, , L-4F or its variant (eg, D-4F) or salt (eg, acetate) administered by intravitreal injection, to assess the safety, tolerability, pharmacokinetics and effective dose .. Soft drusen is a high risk factor for AMD progression and is clinically well known as a lipid rich sub-RPE-BL deposit characteristic of AMD. The cumulative dose and maximum tolerated dose of L-4F until drusen reduction was determined by other studies (L-4F (or its variants or salts) in treating neovascular (wet) AMD or atrophied (dry) AMD). For optimal L-4F dose (s) with one or more other therapeutic agents (including studies administered in combination with one or more other therapeutic agents (eg, anti-angiogenic agents or complement inhibitors)) Provide information.

  In phase I / II studies, L-4F or a variant thereof (eg, D-4F) or salt (eg, acetate) is administered at a certain frequency (eg, once a month or once every two months). ) Administered by intravitreal injection to one eye at a dose (eg, escalating dose from about 0.1 mg to about 1.5 mg) for a period of time (eg, about 6, 9 or 12 months). The other eyes are not injected, but serve as an intra-individual control eye. Post-treatment evaluation is performed, for example, for up to about 12 months. Primary criteria include, for example, reduction of soft drusen quantified by Spectral Domain Optical Coherence Tomography (SDOCT) (eg, about 30% reduction in total drusen volume) and quantitative fundus autofluorescence (qAF). Stability or increase in intensity (eg, in a time frame of about 15 months) is included. Secondary measures include, for example, stability or improvement in visual acuity (eg, deviance from baseline at about 9 and 15 months, dark adaptation, and best corrected visual acuity (BCVA)).

Example 3: Phase II Efficacy Study of L-4F in Combination with Anti-Angiogenic Drugs Anti-angiogenic drugs (eg anti-VEGF drugs (eg aflibercept [EYLEA ( Trademark)], bevacizumab [AVASTIN®] or ranibizumab [LUCENTIS®])) in combination with L-4F or a variant thereof (eg D-4F) or a salt (eg acetate) reserve Phase II trials will be performed to assess positive and corroborative efficacy. At a certain frequency (eg, by intravitreal injection) of these drugs (eg, once a month or once every 2 months), from neovascularization (eg, 1, 2 or 3 neovascularization) Administer until exudation stops. Perform post-treatment evaluation. The drugs are injected into the worse eye and the other eye is left uninjected to serve as an intra-individual control eye. Goals include reducing the dose and number of injections of anti-VEGF drug needed to reduce neovascularization.

Example 4: Phase II Efficacy Study of L-4F in Combination with Complement Inhibitors in Patients With Mid- or Advanced-stage Atrophy (Dry) AMD and Non-central or Central Geographic Atrophy (GA) Preliminary and validation of L-4F or a variant thereof (eg D-4F) or salt (eg acetate) in combination with a complement inhibitor (eg Lampalizumab, ARC1905 [Zimura®] or LFG316). Phase II trials will be performed to assess specific efficacy. Administration of these drugs (eg, by intravitreal injection) at a certain frequency (eg, once a month or once every two months) (eg, by intravitreal injection) to Efficacy to slow progression (eg reduce GA progression rate or reduce GA lesion area or size) is evaluated. Perform post-treatment evaluation. The drugs are injected into the worse eye and the other eye is left uninjected to serve as an intra-individual control eye. Goals include reducing the dose and number of injections of complement inhibitors needed to slow the progression of non-central or central GA.

  It will be understood that, although particular embodiments have been described and described, various modifications are possible and are contemplated herein. It is also understood that this disclosure is not limited by the examples provided herein. The descriptions and descriptions of the disclosed embodiments and examples herein are not intended to be construed in a limiting sense. It is further understood that all aspects of this disclosure are not limited to the specific illustrations, configurations or relative proportions described herein, which may depend on various conditions and variables. Various modifications and variations in the form and details of the embodiments and examples of the present disclosure will be apparent to those skilled in the art. Accordingly, this disclosure is also deemed to cover any and all such modifications, variations and equivalents.

Claims (114)

  A method of treating age-related macular degeneration, comprising the step of administering to a subject in need thereof a therapeutically effective amount of an apolipoprotein (apo) mimetic, wherein the apo mimetic is about 0 per dose. 1 or 0.3 mg to about 1.5 mg, or a total dose of about 0.5 or 1 mg to about 10 mg over a period of about 6 months to the eye, intraocularly, into the eye, or A method, which is administered locally around the eye.   The method of claim 1, wherein the apomimetic comprises, or is an Apo AI mimic.   3. The method of claim 2, wherein the apo AI mimetic comprises or is 4F or a variant or salt thereof (eg, acetate). The apo A-I mimetic comprises or is L-4F or D-4F, each optionally having a protecting group at the N- and / or C-termini [eg Ac-DWFKAFYDKVAEKFKEAF- The method according to claim 3, which is NH ₂ (SEQ ID NO: 13).   5. The method of any one of claims 1-4, wherein the apo mimetic comprises or is an Apo E mimetic.   6. The method of claim 5, wherein the ApoE mimetic comprises or is AEM-28-14 or a variant or salt thereof.   The apomimetic (eg, L-4F) is about 0.1 to 0.5 mg, 0.5 to 1 mg, 1 to 1.5 mg, 0.1 to 0.5 mg per administration (eg, per injection). 1 to 0.3 mg, 0.3 to 0.5 mg, 0.5 to 0.75 mg, 0.75 to 1 mg, 1 to 1.25 mg or 1.25 to 1.5 mg (eg, about 0.1 to 0) The method according to any one of claims 1 to 6, which is locally administered at a dose of 0.5 mg or 0.5 to 1 mg).   The apomimetic (eg, L-4F) is about 0.5 or 1-5 mg, 5-10 mg, 0.5 or 1-3 mg, 3-5 mg, 5-5 over a period of about 6 months. The method according to any one of claims 1 to 7, which is locally administered at a total dose of 7.5 mg or 7.5 to 10 mg (eg, about 0.5 to 3 mg or 3 to 5 mg).   9. The apomimetic (eg, L-4F) is administered locally in a total dose of about 1 or 2-20 mg or 5-15 mg for the entire treatment regimen. The method described.   The apomimetic (eg, L-4F) is about 1-5 mg, 5-10 mg, 10-15 mg, 15-20 mg, 1-3 mg, 3-5 mg, 5-7.5 mg for the entire treatment regimen. , 7.5-10 mg, 10-12.5 mg, 12.5-15 mg, 15-17.5 mg or 17.5-20 mg (eg, about 1-5 mg or 5-10 mg), topically administered at a total dose The method according to claim 9.   11. The any one of claims 1-10, wherein the dose per administration, the total dose over a period of about 6 months, and the total dose for the entire treatment regimen are per eye treated. The method described in the section.   The apomimetic (eg, L-4F) is injected (eg, intravitreal, subconjunctival, subretinal or subtenon injection), instilled or transplanted (eg, intravitreal, intraaqueous, subretinal or tenon capsule). The method according to any one of claims 1 to 11, wherein the method is locally administered by sub-implantation).   13. The method of claim 12, wherein the apomimetic (eg, L-4F) is locally administered by injection (eg, intravitreal, subconjunctival, subretinal or subtenon injection).   The apomimetic (eg, L-4F) is locally administered by injection (eg, intravitreal injection) at a dose concentration of about 1, 2, 3, 4 or 5 mg / mL to about 12 or 15 mg / mL. 14. The method according to claim 13.   The apomimetic (eg, L-4F) is injected at about 1 to 4 mg / mL, 4 to 8 mg / mL, 8 to 12 mg / mL, 1 to 5 mg / mL, 5 to 5 by injection (eg, intravitreal injection). 10 mg / mL, 10-15 mg / mL, 1-3 mg / mL, 3-5 mg / mL, 5-7.5 mg / mL, 6-8 mg / mL, 7.5-10 mg / mL, 10-12.5 mg / 15. The method of claim 14, which is locally administered at a dose concentration of mL or 12.5-15 mg / mL (eg, about 1-5 mg / mL, 5-10 mg / mL or 6-8 mg / mL).   16. The any one of claims 13-15, wherein the apomimetic (e.g. L-4F) is locally administered by injection (e.g. intravitreal injection) in a dose volume of about 50-150 [mu] L or 50-100 [mu] L. The method described in.   The apomimetic (eg, L-4F) is injected by injection (eg, intravitreal injection) to give about 50-75 μL, 75-100 μL, 100-125 μL or 125-150 μL, or about 50 μL, 75 μL, 100 μL, 125 μL or 17. The method of claim 16, which is topically administered in a dose volume of 150 μL (eg, about 100 μL).   The apomimetic (eg, L-4F) is topically administered once every month (4 weeks) or 1.5 months (6 weeks) by injection (eg, intravitreal injection). The method according to any one of 13 to 17.   The apomimetic (eg L-4F) is injected every 2 months (8 weeks), 2.5 months (10 weeks) or 3 months (12 weeks) by injection (eg intravitreal injection). 18. The method according to any one of claims 13 to 17, which is administered once locally.   18. The any one of claims 13-17, wherein the apomimetic (eg, L-4F) is locally administered by injection (eg, intravitreal injection) once every 4, 5 or 6 months. the method of.   The apomimetic (eg, L-4F) is locally administered by a total of about 15 or less, 12 or less, 9 or less, 6 or less, or 3 or less injections (eg, intravitreal injection), The method according to any one of claims 13 to 20.   The apomimetic (eg, L-4F) has a total of about 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4 or 3 (eg, about 3-6 or 7-). The method according to claim 21, which is locally administered by 10) injections (eg, intravitreal injection).   23. Any one of claims 1-22, wherein the apomimetic (e.g. L-4F) is topically administered early in treatment, at higher doses and / or more frequently (e.g. by intravitreal injection). The method described in the section.   The treatment regimen using the apomimetic (eg, L-4F) is about 36 months or less, 30 months or less, 24 months or less, 18 months or less, 12 months or less, or 6 months or less. 24. A method according to any one of claims 1 to 23, which lasts for a period of time.   The treatment regimen using the apomimetic (eg, L-4F) is about 6-12, 12-18, 18-24, 24-30 or 30-36 (eg, about 6-12 or 12-24). 25. The method of claim 24, which lasts for a month.   The apomimetic (eg, L-4F) (eg, to treat central geographic atrophy [GA] and / or to prevent or prevent neovascular AMD and / or neovascular type) 26. The method of any one of claims 1-25, which is administered at least in the advanced (late) phase of AMD) (to treat AMD).   The apomimetic (eg, L-4F) is injected by injection (eg, intravitreal, subconjunctival, subretinal or subtenon injection) for about 4 to 8 weeks or once every 4 to 6 weeks, for a total of about 8 to 8 weeks. Twelve or more injections, at a dose of up to about 1-1.5 mg per injection, or at a total dose of up to about 15-20 mg for the entire treatment regimen, or any combination or all thereof. 27. The method of claim 26, wherein the method is locally administered in advanced AMD by performing.   The apomimetic (eg, L-4F) is at least in the middle stage of AMD (eg, to treat non-central GA and / or to prevent or prevent central GA and / or neovascular AMD) 28. The method of any one of claims 1-27, which is administered or administered in the early phase of mid-stage AMD (e.g., to prevent or prevent non-central GA).   The apomimetic (eg, L-4F) is injected by injection (eg, intravitreal, subconjunctival, subretinal or subtenon injection) for about 4 to 12 weeks or once every 4 to 8 weeks for a total of about 4 to 4 weeks. 8 or more injections, at a dose of up to about 0.5-1 mg or 1-1.5 mg per injection, or at a total dose of up to about 10-15 mg or more for the entire treatment regimen, 29. The method of claim 28, wherein the method is administered locally in metaphase AMD by performing or any combination thereof or all thereof.   30. The method of any one of claims 1-29, wherein the apomimetic (e.g., L-4F) is administered at least early in AMD (e.g., to prevent or prevent non-central GA). ..   The apomimetic (eg, L-4F) is less frequently (eg, about every 3, 4, or 6 months) by injection (eg, intravitreal, subconjunctival, subretinal or subtenon injection). Injection), at a lower total number of injections (eg, about 1, 2 or 3 injections), or at a higher dose per injection (eg, about 0.5-1 mg per injection or 31. The method of claim 30, wherein the method is administered topically in early AMD by performing 1 to 1.5 mg), or any combination or all thereof.   The apomimetic (eg, L-4F) is more frequently (more total dosing times) and / or later stages of AMD or more severe AMD symptoms and / or 32. Or any of the claims 1-31, which is locally administered (eg, by intravitreal injection) at a higher dose (higher dose per administration and / or higher total dose for the entire treatment regimen). The method described in the section.   The apomimetic (eg, L-4F) is administered locally (eg, by intravitreal injection) in a fixed routine schedule, an on-demand schedule or a treat-and-extend schedule. Item 33. The method according to any one of Items 1 to 32.   The apomimetic (eg, L-4F) is about 75-95% (eg, about 90%) apomimetic and about 5-25% (eg, L-4F) in a weight or molar amount relative to the total amount. , About 10%) of the corresponding apolipoprotein (eg, apoA-I) or an active portion or domain thereof is administered locally via a composition. ..   The apomimetic (eg, L-4F) is one or more excipients that inhibit peptide / protein aggregation, increase peptide / protein solubility, decrease solution viscosity, or 35. The method of any one of claims 1-34, wherein the method is administered topically as a composition including one that increases peptide / protein stability or performs any combination or all thereof.   36. The method of any one of claims 1-35, wherein the apomimetic (eg, L-4F) is administered topically via a sustained release composition.   37. The method of any one of claims 1-36, further comprising administering one or more additional therapeutic agents.   The one or more additional therapeutic agents are antihyperlipidemic agents, PPAR-α agonists, PPAR-δ agonists, PPAR-γ agonists, anti-amyloid agents, inhibitors of lipofuscin or its components, and antioxidants. , Neuroprotective agents (neuroprotective agents), apoptosis inhibitors, necrosis inhibitors, C-reactive protein (CRP) inhibitors, inhibitors of the complement system or its components (proteins, etc.), inflammasome inhibitors, anti-inflammatory 38. The method of claim 37, wherein the method is selected from the group consisting of agents, immunosuppressive agents, matrix metalloproteinase (MMP) modulators, anti-angiogenic agents, and RPE cell replacement therapy.   A method of preventing age-related macular degeneration (AMD), delaying the onset of AMD, delaying the progression of AMD, or reducing the extent of AMD-related visual impairment or loss, in a therapeutically effective amount for a subject in need thereof. 39. A method comprising the step of administering an apolipoprotein (apo) mimetic according to any one of claims 1-38.   40. The method of claim 39, wherein the AMD is dry AMD (including non-central and / or central geographic atrophy) or neovascular AMD (including type 1, 2 and / or type 3 neovascularization). ..   A method of treating age-related macular degeneration (AMD), wherein a therapeutically effective amount of the apolipoprotein (apo) mimetic according to any one of claims 1-38 is therapeutically effective for a subject in need thereof. A method comprising administering an amount of an anti-angiogenic drug.   42. The apo mimetic comprises or is an apo AI mimetic (eg, L-4F or D-4F) and / or an apo E mimetic (eg, AEM-28-14). The method described in.   The anti-angiogenic drug contains a drug that inhibits the action of vascular endothelial growth factor (anti-VEGF drug) and / or a drug that inhibits the action of platelet-derived growth factor (anti-PDGF drug), or Item 41. The method according to Item 41 or 42.   The anti-VEGF drug is squalamine, PAN-90806, an anti-VEGF antibody and fragments thereof (eg, bevacizumab [AVASTIN (registered trademark)], ranibizumab [LUCENTIS (registered trademark)], ESBA1008 and ESBA903), anti-VEGF aptamer (eg, Pegaptanib [MACUGEN®]), anti-VEGF engineered ankyrin repeat protein (DARPin) (eg Avisipearl pegol), soluble VEGF receptor (eg VEGFR1), one or more cells of one or more VEGFRs 44. The method of claim 43, wherein the method is selected from the group consisting of soluble fusion proteins containing an ectodomain (eg, Aflibercept [EYLEA®] and Convertate), and combinations thereof.   45. The method of claim 44, wherein the anti-VEGF agent comprises, or is aflibercept, bevacizumab or ranibizumab, or any combination thereof, or all.   Less frequent and / or conventional or recommended dosing frequency of the anti-angiogenic agent in the absence of treatment with the apomimetic (eg, L-4F). 46. The method of any one of claims 41-45, wherein the anti-angiogenic drug (eg, anti-VEGF drug) is administered at a lower dose.   At least about 1.5, 2, 3, 4, 5, or 6 more than the conventional or recommended dosing frequency of the anti-angiogenic agent in the absence of treatment with the apomimetic (eg, L-4F). 47. The method of claim 46, wherein the anti-angiogenic agent (eg, anti-VEGF agent) is administered (eg, by at least about 2) times less frequently (eg, by intravitreal injection).   At least about 10%, 20%, 30%, 40%, 50% over conventional or recommended doses of the anti-angiogenic agent in the absence of treatment with the apomimetic (eg, L-4F). , 60%, 70% or 80% (eg, at least about 20%), or about 10-30%, 30-50% or 50-70% lower doses (eg, by intravitreal injection). 48. The method of claim 46 or 47, wherein a crude drug (eg, an anti-VEGF drug) is administered.   49. The method of claim 46-48, wherein treatment with the apomimetic (e.g., L-4F) reduces the total number of administrations (e.g., total injections) of the anti-angiogenic drug (e.g., anti-VEGF drug). The method according to any one of items.   50. The method of claim 49, wherein the anti-angiogenic agent (eg, anti-VEGF agent) is administered no more than about 20, 18, 15, 12, or 10 times (eg, by intravitreal injection).   51. The method of any one of claims 46-50, wherein treatment with the apomimetic (eg, L-4F) and the anti-angiogenic drug (eg, anti-VEGF drug) has a synergistic effect. The anti-angiogenic drug comprises or is aflibercept (EYLEA®); and
2 mg afri administered by intravitreal injection once every 2 months after 2 mg once a month for the first 3 months in the absence of treatment with the apomimetic (eg, L-4F). Optionally, once per month for the first 1, 2 or 3 months, or for the first 1.5 or 3 months, as compared to conventional or recommended doses and dosing frequency of Belcept For about 1 to 1.5 mg or 1.5 to 2 mg once every 6 weeks for 3 to 4, 5 or 6 months after administration. 52. The method of any one of claims 46-51, wherein the aflibercept is administered in a dose (eg, by intravitreal injection). The anti-angiogenic agent comprises or is aflibercept; and
About 1 to 1.25 mg, which is substantially similar to or at the same or conventional frequency of dosing of aflibercept in the absence of treatment with the apomimetic (eg, L-4F). 52. The method of any one of claims 46-51, wherein the aflibercept is administered at a dose of 1.25-1.5 mg or 1.5-1.75 mg (eg, by intravitreal injection). .. The anti-angiogenic agent comprises or is ranibizumab (LUCENTIS®); and
Compared to the conventional or recommended dose and dosing frequency of 0.5 mg ranibizumab administered by intravitreal injection once a month in the absence of treatment with said apomimetic (eg L-4F). , Optionally, about 0.2-0.3 mg once a month for the first 1, 2 or 3 months, or once every 6 weeks for the first 1.5 or 3 months, About 0.2-0.3 mg, 0.3-0., Once every 2, 3, 4, 5 or 6 months after administration at a dose of 0.3-0.4 mg or 0.4-0.5 mg. 52. The method of any one of claims 46-51, wherein the ranibizumab is administered at a dose of 4 mg or 0.4-0.5 mg (eg, by intravitreal injection). The anti-angiogenic agent comprises or is ranibizumab; and
52. Any one of claims 46-51, wherein said ranibizumab is administered at a dose of about 0.2-0.3 mg or 0.3-0.4 mg once a month (eg, by intravitreal injection). The method described in. The anti-angiogenic agent comprises or is bevacizumab (AVASTIN®); and
A conventional or recommended dose and dosage of about 1.25 mg of AMD therapeutic bevacizumab administered by intravitreal injection once a month in the absence of treatment with the apomimetic (eg, L-4F). Compared to frequency, but optionally, about 0.5 to once a month for the first 1, 2 or 3 months, or once every 6 weeks for the first 1.5 or 3 months. About 0.5 to 0.75 mg, 0.75 to 1 mg every 2, 3, 4, 5 or 6 months after administration at a dose of 0.75 mg, 0.75 to 1 mg or 1 to 1.25 mg. 52. The method of any one of claims 46-51, wherein the bevacizumab is administered at a dose of 1-1.25 mg (eg, by intravitreal injection). The anti-angiogenic agent comprises or is bevacizumab; and
52. Any one of claims 46-51, wherein said bevacizumab is administered at a dose of about 0.5-0.75 mg or 0.75-1 mg once a month (eg, by intravitreal injection). the method of.   52. The any one of claims 46-51, wherein the anti-angiogenic agent (eg, anti-VEGF agent) is administered once (eg, by intravitreal injection) every 2, 3, 4, 5 or 6 months. The method described in.   The anti-angiogenic drug (eg, anti-VEGF drug) is, for example, injection (eg, intravitreal, subconjunctival, subretinal or subtenon injection), eye drop or transplant (eg, intravitreal, aqueous humor, subretinal). 59. The method of any one of claims 41-58, wherein the method is locally administered to the eye, intraocularly, into or around the eye by sub-Tenon implantation).   The method of claim 1, wherein the anti-angiogenic drug (eg, anti-VEGF drug) is administered to treat or slow the progression of neovascular AMD (wet type), including types 1, 2, and 3 neovascularization. 41. The method according to any one of 41 to 59.   61. The anti-angiogenic drug (eg, anti-VEGF drug) is administered at least in the advanced (late) stage of AMD to prevent neovascular AMD, delay its onset, or delay its progression. The method according to any one of 1.   62. The method of any one of claims 41-61, wherein the apomimetic (eg, L-4F) is administered during at least the advanced phase of AMD.   Administering the apomimetic (eg, L-4F) to treat central geographic atrophy and / or prevent neovascular AMD (including neovascularization of types 1, 2 and 3), 63. The method of claim 62, wherein the onset is delayed or its progression is delayed.   64. The any one of claims 41-63, wherein the anti-angiogenic agent (e.g., anti-VEGF agent) is administered in a fixed routine schedule, an on-demand schedule or a treat-and-extend schedule. The method described in.   65. The method of any one of claims 41-64, wherein the apomimetic (eg, L-4F) and the anti-angiogenic drug (eg, anti-VEGF drug) are administered in separate compositions.   65. The method of any one of claims 41-64, wherein the apomimetic (eg, L-4F) and the anti-angiogenic drug (eg, anti-VEGF drug) are administered in the same composition.   A method of treating age-related macular degeneration (AMD), wherein a therapeutically effective amount of the apolipoprotein (apo) mimetic according to any one of claims 1-38 is therapeutically effective for a subject in need thereof. A method comprising administering an amount of a complement inhibitor.   68. The apo mimetic comprises or is an apo AI mimetic (eg, L-4F or D-4F) and / or an apo E mimetic (eg, AEM-28-14). The method described in.   69. The method of claim 67 or 68, wherein the apomimetic (eg, L-4F) and the complement inhibitor are administered to treat geographic atrophy (GA).   70. The apomimetic (e.g., L-4F) and the complement inhibitor are administered to prevent, delay the onset of, or delay the onset of central and / or non-central GA. Method.   Administering the apomimetic (eg, L-4F) and the complement inhibitor at least in the advanced (late) stage of atrophic (dry) AMD to treat central GA or delay the progression thereof; 71. And / or the method of claim 69 or 70, wherein neovascular AMD is prevented or its onset is delayed.   The apomimetic (eg, L-4F) and the complement inhibitor are administered at least in the middle of AMD to treat or slow the progression of non-central GA and / or central GA and / or 72. The method of any one of claims 69-71, which prevents neovascular AMD or delays its onset.   Administering the apomimetic (eg, L-4F) and the complement inhibitor during at least the early phase of AMD or the early phase of mid-stage AMD to prevent or delay the development of non-central GA. 73. A method according to any one of claims 69-72.   The complement inhibitor is an anti-complement factor B (CFB) antibody and a fragment thereof (eg TA106), an anti-CFD antibody and a fragment thereof (eg ramparizumab), a C3 inhibitor (eg compstatin and a derivative thereof [eg. , POT-4], soluble forms of mycophenolic acid-glucosamine conjugates and proteins or fragments thereof [eg, CR1, decay-promoting factor and membrane cofactor protein]), anti-C3b / iC3b antibodies and fragments thereof (eg, 3E7), anti-C5 antibody and fragments thereof (eg, eculizumab and LFG316), anti-C5 aptamer (eg, ARC1905 [Zimura (registered trademark)]), other C5 inhibitors (eg, coversin), C5a receptor antagonist (eg, Examples, JPE-1375, JSM-7717, PMX-025, PMX-53, and anti-C5aR antibodies and fragments thereof [eg, Neutrazumab]), inhibitors of the alternative complement pathway (eg, sCR1, TT30 and zinc). ), Inhibitors of the classical complement pathway (eg, sCR1), inhibitors of the lectin complement pathway (eg, inhibitors of mannose-related serine protease [MASP] (eg, anti-MASP antibodies and fragments thereof [eg, OMS721]) )), Inhibitors of membrane attack complex (MAC) formation (eg, zinc, modified CD59 with CD59 and glycolipid anchors), and analogs, derivatives, fragments, salts and combinations thereof. 74. A method according to any one of claims 67 to 73.   75. The method of claim 74, wherein the complement inhibitor comprises or is ramparizumab, LFG316 or ARC1905, or any combination or all thereof.   76. The method of claim 75, wherein the complement inhibitor comprises or is rampalizumab.   77. The method of claim 76, wherein the subject has a mutation in the gene encoding complement factor I (CFI).   Treatment with the apomimetic (eg, L-4F) and the complement inhibitor (eg, lampalizumab) is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%. Or 80% (eg, at least about 20% or 40%), or about 20-40%, 40-60% or 60-80%, slowing the progression of central GA and / or non-central GA (eg, GA progression). 78. A method according to any one of claims 67 to 77, wherein the rate is reduced or the GA lesion area or size is reduced).   Treatment with the apomimetic (eg, L-4F) and the complement inhibitor (eg, lampalizumab) is more effective than treatment with the complement inhibitor in the absence of treatment with the apomimetic. At least about 10%, 20%, 30%, 50%, 100%, 150%, 200% or 300% (eg, at least about 20% or 30%), or about 10-30%, 30-50. %, 50-100%, 100-200% or 200-300% (eg, about 50-100%) as much as possible to slow the progression of central GA and / or non-central GA (eg reduce the rate of GA progression, Or reduce the GA lesion area or size), the method of any one of claims 67-78.   Frequency of the complement inhibitor (eg, Lampalizumab) lower than conventional or recommended dosing frequency of the complement inhibitor in the absence of treatment with the apomimetic (eg, L-4F). 80. The method of any one of claims 67-79, which is administered at and / or at a dose lower than conventional or recommended doses.   Said complement inhibitor (eg, ramparizumab) is at least about 1 above the conventional or recommended dosing frequency of said complement inhibitor in the absence of treatment with said apomimetic (eg, L-4F). 81. The method of claim 80, wherein the method is administered 5, 2, 3, 4, 5, or 6 (eg, at least about 2) times less frequently (eg, by intravitreal injection).   The complement inhibitor (eg, ramparizumab) is at least about 10% above the conventional or recommended dose of said complement inhibitor in the absence of treatment with said apomimetic (eg, L-4F), 20%, 30%, 40%, 50%, 60%, 70% or 80% (eg, at least about 20%), or about 10-30%, 30-50% or 50-70% lesser dose ( 82. The method of claim 80 or 81, eg, administered by intravitreal injection.   83. Any of claims 80-82, wherein treatment with the apomimetic (e.g. L-4F) reduces the total number of administrations (e.g. total injections) of the complement inhibitor (e.g. ramparizumab). The method according to paragraph 1.   84. The method of claim 83, wherein the complement inhibitor (e.g., Lampalizumab) is administered no more than about 20, 18, 15, 12, or 10 times (e.g., by intravitreal injection).   85. The method of any one of claims 80-84, wherein treatment with the apomimetic (e.g. L-4F) and the complement inhibitor (e.g. ramparizumab) has a synergistic effect. The complement inhibitor comprises or is ramparizumab; and
Compared to the conventional or recommended dose and dosing frequency of about 10 mg ramparizumab administered by intravitreal injection once a month in the absence of treatment with the apomimetic (eg, L-4F), Optionally, about 4-6 mg, 6-8 mg or 8 once a month for the first 1, 2 or 3 months, or once every 6 weeks for the first 1.5 or 3 months. The palpalizumab is administered at a dose of about 4-6 mg, 6-8 mg or 8-10 mg (eg, by intravitreal injection) once every 2, 3, 4, 5 or 6 months after administration at a dose of -10 mg. 86. The method according to any one of claims 80-85. The complement inhibitor comprises or is ramparizumab; and
The lumpalizumab is administered once every month (4 weeks) or every 1.5 months (6 weeks) at a dose of about 3-5 mg, 5-7 mg or 7-9 mg (eg, by intravitreal injection). 86. The method of any one of claims 80-85.   The complement inhibitor (eg, rampalizumab) is administered once every 2, 3, 4, 5 or 6 months (eg, once every 2 months) (eg, by intravitreal injection). 87. The method according to any one of 80-86.   The complement inhibitor (eg, Rampalizumab) is, for example, injection (eg, intravitreal, subconjunctival, subretinal or subcapsular Tenon injection), eye drop or transplant (eg, intravitreal, intraaqueous, subretinal or tenon). 89. The method of any one of claims 67-88, which is administered topically to, intraocularly, into, or around the eye by subcapsular implantation).   90. The method of any one of claims 67-89, wherein the apomimetic (e.g. L-4F) and the complement inhibitor (e.g. Lampalizumab) are administered in separate compositions.   90. The method of any one of claims 67-89, wherein the apomimetic (e.g. L-4F) and the complement inhibitor (e.g. ramparizumab) are administered in the same composition.   The apomimetic (eg, L-4F) and the complement inhibitor are administered at least in the advanced stage of AMD to prevent neovascular AMD including neovascularization of types 1, 2, and 3, and prevent its development. 92. The method of any one of claims 67-91, wherein the method delays or delays its progression.   93. The method of claim 92, further comprising administering a therapeutically effective amount of an anti-angiogenic drug.   The anti-angiogenic drug is an anti-VEGF drug (eg, aflibercept [EYLEA (registered trademark)], bevacizumab [AVASTIN (registered trademark)] or ranibizumab [LUCENTIS (registered trademark)], or any combination thereof or all thereof. 94.) and / or an anti-PDGF drug (eg, E10030 [FOVISTA®]), or.   95. The method of any one of claims 92-94, wherein the complement inhibitor comprises or is ARC1905 (ZIMURA (R)) or LFG316.   The complement inhibitor (eg, ramparizumab, ARC1905 or LFG316, or any combination thereof) is administered on a fixed routine schedule, an on-demand schedule or a treatment-and-extend schedule. 96. A method according to any one of claims 67-95.   A method of treating age-related macular degeneration (AMD), wherein a therapeutically effective amount of the apolipoprotein (apo) mimetic according to any one of claims 1-38 is therapeutically effective for a subject in need thereof. A method comprising administering an amount of an antioxidant.   98. The apo mimetic comprises or is an apo AI mimic (eg, L-4F or D-4F) and / or an apo E mimetic (eg, AEM-28-14). The method described in. The antioxidant is anthocyanin, benzenediol abietane diterpene (eg, carnosic acid), carnosine, carotenoid (eg, carotene [eg, β-carotene], xanthophyll [eg, lutein, zeaxanthin and meso-zeaxanthin], and saffron. Carotenoids [eg, crocin and crocetin]), curcuminoids (eg, curcumin), cyclopentenone prostaglandins (eg, 15d-PGJ ₂ ), flavonoids (eg, Ginkgo biloba (ginkgo) flavonoids [eg, myricetin and Quercetin]), prenylflavonoids (eg, isoxanthohumol), retinoids, stilbenoids (eg, resveratrol), uric acid, vitamin A, vitamin B ₁ (thiamine), vitamin B ₂ (riboflavin), vitamin B ₃ (niacin). ), Vitamin B ₆ (eg, pyridoxal, pyridoxamine, 4-pyridoxic acid and pyridoxine), vitamin B ₉ (folic acid), vitamin B ₁₂ (cobalamin), vitamin C, vitamin E (eg, tocopherol and tocotrienol), selenium, zinc. (Eg, zinc monocysteine), inhibitors and scavengers of lipid peroxidation and its by-products (eg, vitamin E [eg, α-tocopherol], tirilazad, NXY-059 and XJB-5-131), nuclear factors (erythrocytes) Derivation 2) From activator (eg, OT-551), superoxide dismutase (SOD) mimetic (eg, OT-551) of Like 2 (NFE2L2 or NRF2), and analogs, derivatives, salts and combinations thereof. 99. The method of claim 97 or 98 selected from the group consisting of: The antioxidant is one or more vitamins (eg, vitamin B ₆ , vitamin C and vitamin E), one or more carotenoids (eg, xanthophyll [eg, lutein, zeaxanthin and meso-zeaxanthin]) and carotenoids in saffron. [Eg, crocin and crocetin]), or zinc, or any combination thereof or all thereof, eg, AREDS or AREDS2 formulation, ICAPS® formulation, Ocuvite® formulation or Saffron2020 ™. Item 99. The method according to Item 99.   The antioxidant (eg vitamin and / or carotenoid) is lower than the conventional or recommended dose of the antioxidant in the absence of treatment with the apomimetic (eg L-4F). 101. The method of any one of claims 97-100, which is administered in a dose and / or less frequently than conventional or recommended dosing frequency.   Said antioxidant (eg vitamin and / or carotenoid) is at least more than the conventional or recommended dose of said antioxidant in the absence of treatment with said apomimetic (eg L-4F). About 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% (eg, at least about 20%), or about 10-30%, 30-50% or 50-70%. 102. The method of claim 101, wherein the method is administered at a low dose.   The antioxidant (eg, vitamins and / or carotenoids) is less than the conventional or recommended dosing frequency of the antioxidant in the absence of treatment with the apomimetic (eg, L-4F). 103. The method of claim 101 or 102, wherein the method is administered at least about 2, 3, 5, 7 or 10 (eg, at least about 2) times less frequently.   The antioxidant (eg, vitamin and / or carotenoid) is administered at least once a day in the absence of treatment with the apomimetic (eg, L-4F) of the antioxidant or conventional 104. The method of claim 103, which is administered once every two or three days, as compared to the recommended dosing frequency.   The apomimetic (eg, L-4F) and the antioxidant (eg, vitamin and / or carotenoid) are central geographic atrophy (GA) and / or (including NVs 1, 2 and 3) neovascularization 98. Administered at least in the advanced (late) phase of AMD for treating or delaying progression of type AMD and / or for preventing neovascular AMD or delaying its onset. 104. The method according to any one of 104.   The apomimetic (eg L-4F) and the antioxidant (eg vitamins and / or carotenoids) are used to treat or slow the progression of non-central GA and / or central GA and / or 106. The method of any one of claims 97-105, which is administered at least mid-stage of AMD to prevent neovascular AMD or delay its onset.   The apomimetic (eg, L-4F) and the antioxidant (eg, vitamins and / or carotenoids) prevent at least early- or mid-stage AMD from preventing non-central GA or delaying its onset. 107. The method of any one of claims 97-106, wherein the method is administered in the early phase.   108. Any of claims 97-107, wherein the antioxidant (eg, vitamin and / or carotenoid) and, optionally, the apomimetic (eg, L-4F) are administered at least early in AMD. The method described in paragraph 1.   Treatment with the apomimetic (eg, L-4F) and the antioxidant (eg, vitamin and / or carotenoid) is at least about 10%, 20%, 30%, 40%, 50%, 60%. , 70% or 80% (eg, at least about 20%), or about 20-40%, 40-60% or 60-80%, slowing the progression of central GA and / or non-central GA (eg, GA progression). 110. A method according to any one of claims 105-108, wherein the rate is reduced or the GA lesion area or size is reduced).   Treatment with the apomimetic (eg, L-4F) and the antioxidant (eg, vitamin and / or carotenoid) uses the antioxidant in the absence of treatment with the apomimetic Than treatment, at least about 10%, 20%, 30%, 50%, 100%, 150%, 200% or 300% (eg, at least about 20% or 30%), or about 10-30%, 30. -50%, 50-100%, 100-200% or 200-300% (eg, about 50-100%) more, slowing the progression of central GA and / or non-central GA (eg, reducing the rate of GA progression) Or reduce the GA lesion area or size), the method of any one of claims 105-109.   112. The method of any one of claims 101-110, wherein treatment with the apomimetic (e.g. L-4F) and the antioxidant (e.g. vitamins and / or carotenoids) has a synergistic effect.   The antioxidant (eg, vitamin and / or carotenoid) is systemically administered (eg, oral), or (for example, injection [eg, intravitreal, subconjunctival, subretinal or subtenon injection], eye drop or transplantation [ 111) to the eye, by intravitreal, subretinal or sub-Tenon implantation), intraocularly, intraocularly, or around the eye. Method.   113. The method of any one of claims 97-112, wherein the apomimetic (e.g. L-4F) and the antioxidant (e.g. vitamins and / or carotenoids) are administered in separate compositions.   113. The method of any one of claims 97-112, wherein the apomimetic (eg, L-4F) and the antioxidant (eg, vitamin or carotenoid) are administered in the same composition.