WO2019199976A1 - Apoe mimetic peptide compositions - Google Patents

Abstract

Disclosed herein are aqueous compositions comprising a mixture of synthetic apolipoprotein E (ApoE)-mimicking peptides, a polyethylene sorbitan ester, and a cationic amino acid. Also disclosed iS the use of these aqueous compositions for reducing plasma cholesterol.

Description

APOE MIMETIC PEPTIDE COMPOSITIONS

RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 62/655,995, filed April 11, 2018, the entire contents of which are incorporated herein by reference.

BACKGROUND

[0002] Apo lipoprotein E (ApoE) plays an important role in the metabolism of triglyceride rich lipoproteins, such as very low density lipoprotein (VLDL) and chylomicrons.

Apo lipoprotein E mediates the high affinity binding of apo E-containing lipoproteins to the low density lipoprotein (LDL) receptor (apo B, E receptor) and the members of its gene family, including LDL receptor related protein (LRP), very low density lipoprotein receptor (VLDLR) and the apoE2 receptor (apoE2R) (Mahley, R. W., (1988) Science 240, 622-630). The putative and complex role of apo E in atherosclerosis has been emphasized by several observations: (i) mice that overexpress human apo E have lower levels of total plasma cholesterol levels (Shimono, H. N., et al, (1992) Eur. J. Clin. Invest. 90,2084-2991), (ii) intravenous injection of human apo E into cholesterol- fed rabbits protects these animals from atherosclerosis (Yamada, et al, (1989) Proc. Natl. Acad. Sci. U.S.A. 86,665-669), and (iii) loss of the apo E gene in mice produces spontaneous atherosclerosis (Zhang, S. H., et al, (1992) Science 258,468-471) which is ameliorated when macrophage-specific apo E expression is initiated in apo E-deficient mice (Spangenberg, J., et al, (1997) Biochem. Biophys. Acta 1349, 109-121).

[0003] Synthetic ApoE mimicking peptides that enhance LDL/VLDL binding, increase LDL/VLDL degradation, and lower LDL/VLDL cholesterol in individuals with

atherosclerosis have been previously described and include, e.g., Ac-hel8A-NH₂ (AEM-28), Ac- [R] he 18 A-NH2 (AEM-28(R)), Aha- [R]hE 18 A-NH₂ (AES-21), Myr[R]hEl8A- NH₂ (AEM-28-14), and Octa[R]hEl 8A-NH₂ (AEM-28-08). See e.g., U.S. 6,506,880, WO 2009/032702, and WO 2016/0188665. Despite the ability to significantly reduce total levels of cholesterol, ApoE peptides such as AEM-28-08 and AEM-28-14 were found to suffer from poor aqueous solubility. See PCT/US2017/041663. This problem was overcome by adding a polyoxyethylene sorbitan fatty acid ester to the formulations comprising these peptides. See PCT/US2017/041663. Now, however, it has been found that these peptides are not well tolerated in animal models. Thus, means for reducing the toxicity of these otherwise efficacious peptides exists.

SUMMARY

[0004] Aqueous formulations comprising a synthetic apolipoprotein E (ApoE) mimicking peptide, such as e.g., AEM-28-08 and AEM-28-14, and a polyoxyethylene sorbitan fatty acid ester, such as e.g., polysorbate 20 (e.g., Tween™ 20) or polysorbate 80 (e.g., Tween™ 80) have now been found to be undesirably toxic. For example, administering aqueous formulations comprising Tween™ 20 at concentrations as low as 15 mg/kg of AEM-28-14 resulted in full thickness necrosis (infarction) of rat tails. In addition, administration of Tween™ 20 and > 10 mg/kg AEM-28-14 led to acute hemorrhage, subcutaneous crystals, perivascular inflammatory cell infiltrates, and muscular atrophy in rates. However, it has now been discovered that adding the cationic amino acid arginine reduces hemolysis and provides formulations that are well tolerated in rats at levels of up to 15 mg/kg AEM-28-14. See

Example 4. Additionally, arginine appears to have little or no effect on the total cholesterol reducing effects of the formulation. See e.g., Figure 1. Thus, there is little or no compromise in efficacy.

[0005] Provided herein, therefore, are aqueous pharmaceutical composition comprising i) a synthetic apolipoprotein E (ApoE)-mimicking peptide; ii) a polyoxyethylene sorbitan fatty acid ester; and iii) a cationic amino acid.

[0006] Further provided are methods of reducing plasma cholesterol, methods of effecting plasma LDL and/or plasma VLDL, and methods of treating lipid disorders, atherosclerosis, or acute coronary syndrome (ACS) using one or more of the disclosed pharmaceutical formulations described herein.

BRIEF DESCRIPTION OF THE FIGURES

[0007] FIG. 1 illustrates the change in cholesterol (mg/dL) vs time for AEM-28-14 and AEM-28-14 with L- Arginine at concentrations of 0.4 mg/kg, where a) represents total cholesterol and b) represents percent (%) change in total cholesterol.

DETAILED DESCRIPTION

A. General Description of the Compositions

[0008] In a first exemplary embodiment, provided herein are aqueous pharmaceutical compositions comprising i) a synthetic apolipoprotein E (ApoE) mimicking peptide of the formula CH₃(CH₂)_XC(0)-LRY¹LRY²RLLR-DWLKAFYDKVAEKLKEAF-NH₂, or a pharmaceutically acceptable salt thereof, wherein x is an integer from 1 to 20 and Y¹ and Y² are each independently lysine or arginine; ii) a polyethylene sorbitan ester; and iii) a cationic amino acid.

B. Definitions

[0009] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0010] Peptides are written from left to right from N- to C-terminus according to convention. Thus, when -NH₂ is written on the C-terminus, it is to be understood that the C- terminus is an amide, i.e., -C(=0)NH₂. Similarly, when H₃C(CO)- is written on the N- terminus, it is to be understood that the amine on the N-terminus is protected with an acetyl group, i.e., H₃C(CO)-.

[0011] Ac-hEl8A-NH₂, used interchangeably with AEM-28, refers to the synthetic apolipoprotein E (ApoE)-mimicking peptide having the structure H₃C(CO)-LRKLRKRLLR- DWLKAFYDKVAEKLKEAF-NH₂.

[0012] Myr[R]hEl 8A-NH₂, used interchangeably with AEM-28-14, refers to the synthetic apolipoprotein E (ApoE)-mimicking peptide having the structure

Myr LRRLRRRLLR-D WLKAF YDKV AEKLKE F -NH₂ or written alternatively as

CH₃ (CH₂) _l2C(0)LRRLRRRLLR-D WLKAF YDKVAEKLKE AF -NH₂, each being used interchangeably.

[0013] Octa[R]hEl 8A-NH₂, used interchangeably with AEM-28-08 or AEM-28-8, refers to the synthetic apolipoprotein E (ApoE)-mimicking peptide having the structure

OctaLRRLRRRLLR-D WLKAF YDKV AEKLKE AF-NH₂ or written alternatively as

CH₃(CH₂)₆C(0)LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH₂, each being used interchangeably.

[0014] “Myr” refers to myristoyl, i.e., CH₃(CH₂)_l2C(0)-.

[0015] “Octa” refers to octanoyl, i.e., CH₃(CH₂)₆C(0)-.

[0016] The Apo E mimicking peptides disclosed herein comprise amino acids that contain basic groups (e.g., -NH₂) and acid groups (e.g., -COOH). The basic groups can be protonated when the Apo E mimicking peptides are dissolved in an acidic aqueous solution; and the acid group can be deprotonated when the Apo E mimicking peptides are dissolved in basic solution.“Pharmaceutically acceptable salt thereof’ refers to Apo E mimicking peptides that have been obtained from such solutions which contain acids or bases that are suitable for pharmaceutical use, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, sulfuric, acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p- toluenesulfonic, and tartaric acids. Suitable pharmaceutically acceptable basic salts include e.g., ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts). Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, p 1445, the disclosure of which is hereby incorporated by reference.

[0017] Cationic amino acids refer to natural and unnatural amino acids which comprise positivity charged sidechains. Such amino acids include e.g., arginine, lysine, histidine, and ornithine.

[0018] As used herein, polyethylene sorbitan fatty acid esters are amphipathic, nonionic surfactants composed of fatty acid esters of polyoxyethylene sorbitan. Typically“fatty acid ester of polyoxyethylene sorbitan” refers to a mixture of fatty acid esters of polyoxyethylene sorbitan, such as a mixture of fatty acid esters of polyoxyethylene comprising primarily sorbitan polyoxyethylene (20) sorbitan monolaurate or sorbitan polyoxyethylene (20) sorbitan oleic acid (e.g., at least 50% w/w, 60% w/w, 70% w/w, 80% w/w or 90% w/w). Examples include, but are not limited to, polysorbate 20 (comprising polyoxyethylene (20) sorbitan monolaurate) such as e.g., Tween™ 20 comprised of e.g., a polyethylene sorbitan ester with a calculated molecular weight of 1,225 daltons, assuming 20 ethylene oxide units,

1 sorbitol, and 1 lauric acid as the primary fatty acid; polysorbate 40 (comprising

polyoxyethylene (20) sorbitan monopalmitate) such as e.g., Tween™ 40; polysorbate 60 (comprising polyoxyethylene (20) sorbitan monostearate) such as e.g., Tween™ 60; and polysorbate 80 (comprising polyoxyethylene (20) sorbitan monooleate) such as e.g.,

Tween™ 80 comprised of e.g., polyethylene sorbitan ester with a calculated molecular weight of 1,310 daltons, assuming 20 ethylene oxide units, 1 sorbitol, and 1 oleic acid as the primary fatty acid. Examples include Tween™ 80.

[0019] As used herein,“effective amount” is meant to mean a sufficient amount of the composition or Apo E mimetic to provide the desired effect. For example, an effective amount of an Apo E mimetic can be an amount that provides a therapeutic affect and provides sustained therapeutic effects after withdrawal of the treatment. An effective amount of an Apo E mimetic is an amount that is able to cause a benefit illustrated by a decrease in atherosclerosis, a decrease in artery wall stiffness, a decrease in isolated systolic

hypertension, a decrease in arterial inflammation, an increase in anti-oxidant capability of the high-density lipoprotein (HDL) fraction and/or an improvement in myocardial function, as well as an amount that allows for a sustained therapeutic effect after withdrawal of the Apo E mimetic. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of disease (or underlying genetic defect) that is being treated, the particular compound used, its mode of

administration, and the like. Thus, it is not possible to specify an exact“effective amount.” However, an appropriate“effective amount” may be determined by one of ordinary skill in the art using only routine experimentation.“Therapeutically effective amount” and“effective amount” are used interchangeably. In one aspect, the effective amount of ApoE mimicking peptide described herein ranges from 0.1 mg/kg to 20 mg/kg, e.g., 5 mg/kg for a human subject.

[0020] As used herein,“subject” refers to the target of administration, e.g. an animal. Thus, the subject of the disclosed methods can be a vertebrate, such as a mammal. For example, the subject can be a human. The term does not denote a particular age or sex. Subject can be used interchangeably with“individual” or“patient”.

[0021] As used herein, the terms“treatment,”“treat,” and“treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed, i.e., therapeutic treatment. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors), i.e., to reduce the likelihood of developing. A susceptible individual is one who is at risk of developing one or more of the conditions recited herein.

[0022] The phrase“lipid disorder” is meant to mean when a subject has an excess of lipids or increased inflammatory lipids in their blood. Lipids include, but are not limited to lipids such as ox-LDL (i.e., oxidized PAPC (l-palmitoyl 2-arachidonyl phophyatidyl choline). Oxidation of PAPC or PLPC, the lipid components of low-density lipoprotein (LDL), produce oxidized lipids. Having a lipid disorder can make you more likely to develop inflammatory disease such as atherosclerosis and heart disease. Lipid disorders can be caused by genetic predispositions or diet. Lipid disorders include e.g., coronary artery disease, rheumatoid arthritis, diabetes, Alzheimer’s disease, peripheral arterial disease (PAD), cerebral vascular disease, diabetes-derived cardiovascular diseases, macular degeneration, congestive heart failure, hypertriglyceridemic pancreatitis, sepsis, and systemic lupus. [0023] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of skill in the art to which the disclosed method and compositions belong.

C. Compositions

[0024] As described above, in a first embodiment, provided herein are aqueous pharmaceutical compositions comprising i) a synthetic apo lipoprotein E (ApoE) mimicking peptide of the formula CH₃(CH₂)_XC(0)-LRY¹LRY²RLLR-DWLKAFYDKVAEKLKEAF- NH₂, or a pharmaceutically acceptable salt thereof, wherein x is an integer from 1 to 20 and Y¹ and Y² are each independently lysine or arginine; ii) a polyoxyethylene sorbitan fatty acid ester; and iii) a cationic amino acid.

[0025] In a second embodiment, the cationic amino acid in the compositions described herein is selected from arginine, lysine, histidine, and ornithine. Alternatively, the cationic amino acid in the compositions described herein is selected from arginine and lysine. In yet another alternative, the cationic amino acid in the compositions described herein is arginine.

[0026] In a third embodiment, x in the peptides described herein is an integer from 3 to 18, wherein the remaining features are as described in the first or second embodiment.

Alternatively, x is 4 to 16, wherein the remaining features are as described in the first or second embodiment. In another alternative, x is 5 to 14, wherein the remaining features are as described in the first or second embodiment. In another alternative, x is 5 to 13, wherein the remaining features are as described in the first or second embodiment. In another alternative, x is 6 to 12, wherein the remaining features are as described in the first or second

embodiment.

[0027] In a fourth embodiment, the ApoE mimicking peptide in the aqueous

compositions described herein is of the formula CH₃(CH₂)_l2C(0)-LRRLRRRLLR- DWLKAFYDKVAEKLKEAF-NH₂, or a pharmaceutically acceptable salt thereof, wherein the remaining features are as described in the first or second embodiment.

[0028] In a fifth embodiment, the ApoE mimicking peptide in the aqueous compositions described herein is of the formula CH₃(CH₂)_l2C(0)-LRKLRKRLLR- DWLKAFYDKVAEKLKEAF-NH₂ or a pharmaceutically acceptable salt thereof, wherein the remaining features are as described in the first or second embodiment.

[0029] In a sixth embodiment, the ApoE mimicking peptide in the aqueous compositions described herein is of the formula CH₃(CH₂)₆C(0)-LRRLRRRLLR- DWLKAFYDKVAEKLKEAF-NH₂, or a pharmaceutically acceptable salt thereof, wherein the remaining features are as described in the first or second embodiment. [0030] In a seventh embodiment, the ApoE mimicking peptide in the aqueous compositions described herein is of the formula CH₃(CH₂)₆C(0)-LRKLRKRLLR- DWLKAFYDKVAEKLKEAF-NH₂, or a pharmaceutically acceptable salt thereof, wherein the remaining features are as described in the first or second embodiment.

[0031] In an eighth embodiment, the aqueous pharmaceutical composition comprises sterile water for injection (WFI), saline, or phosphate-buffered saline (PBS), or a combination thereof, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, or seventh embodiment.

[0032] In a ninth embodiment, the polyoxyethylene sorbitan fatty acid ester in the aqueous compositions described herein is selected from polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80, wherein the remaining features are as described in the first, second, third, fourth, fifth, or sixth embodiment. Alternatively, the polyoxyethylene sorbitan fatty acid ester in the aqueous compositions described herein is selected from polysorbate 20 and polysorbate 80, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh or eighth embodiment. In another alternative, the polyoxyethylene sorbitan fatty acid ester in the aqueous compositions described herein is polysorbate 80, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh or eighth embodiment.

[0033] In a tenth embodiment, the molar ratio of ApoE mimicking peptide to cationic amino acid present in the aqueous compositions described herein ranges from 1 : 1 to 1 :90, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment. Alternatively, the molar ratio of ApoE mimicking peptide to cationic amino acid present in the aqueous compositions described herein ranges from 1 :3 to 1 :60, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment. In another alternative, the molar ratio of ApoE mimicking peptide to cationic amino acid present in the aqueous compositions described herein ranges from 1 :30 to 1 :60, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment. In another alternative, the molar ratio of ApoE mimicking peptide to cationic amino acid present in the aqueous compositions described herein ranges from 1 :40 to 1 :60, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh or eighth embodiment. In another alternative, the molar ratio of ApoE mimicking peptide to cationic amino acid present in the aqueous compositions described herein ranges from 1 :45 to 1 :55, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh or eighth embodiment. In another alternative, the molar ratio of ApoE mimicking peptide to cationic amino acid present in the aqueous compositions described herein is 1 :48, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment.

[0034] In an eleventh embodiment, the molar ratio of ApoE mimicking peptide to polyoxyethylene sorbitan fatty acid ester present in the aqueous compositions described herein is less than 0.20, e.g., is less than or equal to 0.18, is less than or equal to 0.17, is less than or equal to 0.16, is less than or equal to 0.15, is less than or equal to 0.14, or is less than or equal to 0.12, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment. Alternatively, the molar ratio of ApoE mimicking peptide to polyoxyethylene sorbitan fatty acid ester present in the aqueous compositions described herein ranges from 0.01 to 0.17, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment. In another alternative, the molar ratio of ApoE mimicking peptide to polyoxyethylene sorbitan fatty acid ester present in the aqueous compositions described herein ranges from 0.01 to 0.05, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment. In another alternative, the molar ratio of ApoE mimicking peptide to polyoxyethylene sorbitan fatty acid ester present in the aqueous compositions described herein ranges from 0.01 to 0.02, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment. In another alternative, the molar ratio of ApoE mimicking peptide to polyoxyethylene sorbitan fatty acid ester present in the aqueous compositions described herein ranges from 0.02 to 0.17, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment. In another alternative, the molar ratio of ApoE mimicking peptide to polyoxyethylene sorbitan fatty acid ester present in the aqueous compositions described herein ranges from 0.03 to 0.17, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment. In another alternative, the molar ratio of ApoE mimicking peptide to polyoxyethylene sorbitan fatty acid ester present in the aqueous compositions described herein ranges from 0.05 to 0.17, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment. In another alternative, the molar ratio of ApoE mimicking peptide to polyoxyethylene sorbitan fatty acid ester present in the aqueous compositions described herein ranges from 0.05 to 0.19. In another alternative, the molar ratio of ApoE mimicking peptide to polyoxyethylene sorbitan fatty acid ester present in the aqueous compositions described herein ranges from 0.10 to 0.19, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment. In another alternative, the molar ratio of ApoE mimicking peptide to polyoxyethylene sorbitan fatty acid ester present in the aqueous compositions described herein ranges from 0.3 to 0.18, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment. In another alternative, the molar ratio of ApoE mimicking peptide to polyoxyethylene sorbitan fatty acid ester present in the aqueous compositions described herein ranges from 0.5 to 0.17, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment. In another alternative, the molar ratio of ApoE mimicking peptide to polyoxyethylene sorbitan fatty acid ester present in the aqueous compositions described herein is 0.16, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment.

[0035] In a twelfth embodiment, the concentration of ApoE mimicking peptide, or pharmaceutically acceptable salt thereof, present in the aqueous compositions described herein ranges from 0.1 mg/mL to 10 mg/mL, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment. Alternatively, the concentration of ApoE mimicking peptide, or

pharmaceutically acceptable salt thereof, present in the aqueous compositions described herein ranges from 0.8 mg/mL to 8.0 mg/mL, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment. In another alternative, the concentration of ApoE mimicking peptide, or pharmaceutically acceptable salt thereof, present in the aqueous compositions described herein ranges from 1.0 mg/mL to 5.5 mg/mL, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment. In another alternative, the concentration of ApoE mimicking peptide, or pharmaceutically acceptable salt thereof, present in the aqueous compositions described herein ranges from 4.0 mg/mL to 6.5 mg/mL, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment. In another alternative, the concentration of ApoE mimicking peptide, or pharmaceutically acceptable salt thereof, present in the aqueous compositions described herein ranges from 5.0 mg/mL to 6.0 mg/mL, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment. In another alternative, the concentration of ApoE mimicking peptide, or pharmaceutically acceptable salt thereof, present in the aqueous compositions described herein is 1 mg/mL, 2.5 mg/mL, or 5 mg/mL, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment. In another alternative, the concentration of ApoE mimicking peptide, or pharmaceutically acceptable salt thereof, present in the aqueous compositions described herein is 5 mg/mL, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment.

[0036] In a thirteenth embodiment, the ApoE mimicking peptide and polyoxyethylene sorbitan fatty acid ester in the aqueous compositions described herein form particles, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment.

[0037] In a fourteenth embodiment, the ApoE mimicking peptide and polyoxyethylene sorbitan fatty acid ester in the aqueous compositions described herein form particles having an average particle size of less than 20 nm, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment. Alternatively, the ApoE mimicking peptide and polyoxyethylene sorbitan fatty acid ester in the aqueous compositions described herein form particles having an average particle size ranging from 2 nm to 17 nm, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment. In another alternative, the ApoE mimicking peptide and polyoxyethylene sorbitan fatty acid ester in the aqueous compositions described herein form particles having an average particle size ranging from 5 nm to 15 nm, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment. In another alternative, the ApoE mimicking peptide and

polyoxyethylene sorbitan fatty acid ester in the aqueous compositions described herein form particles having an average particle size ranging from 5 nm to 12 nm, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment. In another alternative, the ApoE mimicking peptide and polyoxyethylene sorbitan fatty acid ester in the aqueous compositions described herein form particles having an average particle size ranging from 6 nm to 10 nm, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment. [0038] In a fifteenth embodiment, the ApoE mimicking peptide and polyoxyethylene sorbitan fatty acid ester in the aqueous compositions described herein form particles that are micelles, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or fourteenth embodiment.

[0039] In a sixteenth embodiment, the ApoE mimicking peptide and polyoxyethylene sorbitan fatty acid ester in the aqueous compositions described herein form particles that are micelles homogenously distributed throughout the aqueous composition, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, fourteenth, or fifteenth embodiment.

[0040] Other examples of compositions, including independent components of the peptides and/or phospholipids described herein, are provided in the EXEMPLIFICATION. In certain embodiment, the compositions described herein encompass all of the disclosed peptides and phospholipids, and combinations and variations thereof, as further set forth in the EXEMPLIFICATION.

D. Uses and Administration

[0041] Disclosed herein are methods for affecting plasma LDL, plasma very Low Density Lipoproteins (VLDL), or both, comprising administering a composition comprising i) a synthetic apo lipoprotein E (ApoE) mimicking peptide of the formula CH₃(CH₂)_xC(0)- LRY¹LRY²RLLR-DWLKAFYDKVAEKLKEAF-NH₂, or a pharmaceutically acceptable salt thereof, wherein x is an integer from 1 to 20 and Y¹ and Y² are each independently lysine or arginine; ii) a phospholipid as described herein; and iii) a cationic amino acid. In one aspect, the plasma LDL, plasma VLDL, or both, are affected. In another aspect, binding of LDL to a cell of the subject is enhanced. In another aspect, degradation of LDL by a cell of the subject is increased. In another aspect, LDL cholesterol in the subject is lowered. In another aspect, binding of VLDL to a cell of the subject is enhanced. In another aspect, degradation of VLDL by a cell of the subject is increased. In another aspect, VLDL cholesterol in the subject is lowered. In another aspect, total plasma concentration of cholesterol in the subject is lowered. In one aspect, in the methods of affecting plasma LDL, plasma VLDL, or both, the disclosed synthetic apo lipoprotein E (ApoE)-mimicking peptides are administered in an amount of about 0.1 mg/kg to about 20 mg/kg, e.g., 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 mg/kg, or any range in between.

[0042] Also disclosed herein are methods of treating atherosclerosis comprising administering to a subject in need thereof i) a synthetic apo lipoprotein E(ApoE) mimicking peptide of the formula CH₃(CH₂)_xC(0)-LRY¹LRY²RLLR-DWLKAFYDKVAEKLKEAF- NH₂, or a pharmaceutically acceptable salt thereof, wherein x is an integer from 1 to 20 and Y¹ and Y² are each independently lysine or arginine; and iii) a cationic amino acid. In one aspect in the methods of treating atherosclerosis, the disclosed synthetic apolipoprotein E (ApoE)-mimicking peptides are administered in an amount of about 0.01 mg/kg to about 20 mg/kg, e.g., 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 mg/kg, or any range in between.

[0043] Also disclosed are methods of treating a subject with a lipid disorder comprising administering to a subject in need thereof i) a synthetic apolipoprotein E (ApoE) mimicking peptide of the formula CH₃(CH₂)_XC(0)-LRY¹LRY²RLLR-DWLKAFYDKVAEKLKEAF- NH₂, or a pharmaceutically acceptable salt thereof, wherein x is an integer from 1 to 20 and Y¹ and Y² are each independently lysine or arginine; and iii) a cationic amino acid. In one aspect, the lipid disorder is selected from coronary artery disease, rheumatoid arthritis, systemic lupus, diabetes, Alzheimer’s disease, peripheral artery disease (PAD), diabetes- derived cardiovascular diseases, macular degeneration, hypertriglyceridemic pancreatitis, sepsis, and congestive heart failure. In one aspect in the methods of treating a lipid disorder, the disclosed synthetic apolipoprotein E (ApoE)-mimicking peptides are administered in an amount of about 0.01 mg/kg to about 20 mg/kg, e.g., 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,

13, 14, 15, 16, 17, 18, 19 mg/kg, or any range in between.

[0044] Also disclosed are methods of treating acute coronary syndrome (ACS) comprising administering to a subject in need thereof i) a synthetic apolipoprotein E(ApoE) mimicking peptide of the formula CH₃(CH₂)_XC(0)-LRY¹LRY²RLLR- DWLKAFYDKVAEKLKEAF-NH₂, or a pharmaceutically acceptable salt thereof, wherein x is an integer from 1 to 20 and Y¹ and Y² are each independently lysine or arginine; ii) a phospholipid as described herein; and iii) a cationic amino acid. In one aspect in the methods of treating ACS, the disclosed synthetic apolipoprotein E (ApoE)-mimicking peptides are administered in an amount of about 0.01 mg/kg to about 20 mg/kg, e.g., 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 mg/kg, or any range in between.

[0045] The dose or dosage of the compositions described herein can vary depending on many factors, such as but not limited to, age, condition, sex and extent of the disease in the patient, route of administration, length of treatment cycle, or whether other drugs are included in the regimen, and can be determined by one of skill in the art.

[0046] Effective dosages can be determined empirically, and making such determinations is within the skill in the art. The dosage ranges for the administration of the compositions are those large enough to produce the desired effect in which the disease is treated. For example, the dosage can be an amount effective to provide therapeutic effects and provide or allow for sustained therapeutic effects even after the treatment is withdrawn. The therapeutic effects can be, but are not limited to, a reduction in atherosclerotic lesions, decrease in arterial stiffness, decrease in isolated systolic hypertension, increase in vasoresponsiveness or improvement in cardiac function. The therapeutic effects can be measured by markers of arterial inflammation such as, but not limited to, C-reactive protein. The therapeutic effects can be measured by atherosclerosis imaging techniques, including MRI, intravascular ultrasound, ultrafast imaging CT scans, B-mode ultrasonography, virtual histology intravascular ultrasound, optical coherence tomography, or other known methods.

[0047] The dosage should not be so large as to cause adverse side effects, such as unwanted cross-reactions, anaphylactic reactions, and the like. The dosage can be adjusted by the individual physician in the event of any counter-indications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products.

[0048] In the methods described herein, any suitable route of administration can be used for the disclosed compositions. Suitable routes of administration can, for example, include topical, enteral, local, systemic, or parenteral. For example, administration can be

epicutaneous, inhalational, enema, conjunctival, eye drops, ear drops, alveolar, nasal, intranasal, enteral, oral, intraoral, transoral, intestinal, rectal, intrarectal, transrectal, injection, infusion, intravenous, intraarterial, intramuscular, intracerebral, intraventricular,

intracerebroventricular, intracardiac, subcutaneous, intraosseous, intradermal, intrathecal, intraperitoneal, intravesical, intracavernosal, intramedullar, intraocular, intracranial, transdermal, transmucosal, transnasal, inhalational, intracistemal, epidural, peridural, intravitreal, etc. The disclosed compositions can be used in and with any other therapy.

[0049] In one aspect, the disclosed compositions are aqueous formulations that exists in e.g., H₂0 (e.g, water for injection (WFI)), PBS (e.g., sterile PBS), and the like.

[0050] The foregoing formulations and administration methods are intended to be illustrative and not limiting. It will be appreciated that, using the teaching provided herein, other suitable formulations and modes of administration can be readily devised. Examples

Example 1: General Peptide Synthesis

[0051] Peptides described herein were prepared via standard solid-phase synthetic procedures. AEM-28, AEM-28-08 and AEM-28-14 were prepared according to the procedures described in U.S. Patent No. 6,506,880 and WO 2016/018665, and following standard solid-phase synthetic procedures.

Example 2: Stock Solution Preparations

[0052] The following represent general methods for the preparation of 5.0 mg/mL AEM- 28-14 and AEM-28-8 stock formulations with Tween™ 80 and Arginine in PBS.

5.0 mg/mL AEM-28-14 Stock Formulation (with Tween™ 80 and Arginine in PBS)

Peptide:Tween™ 80 molar ratio 0.16

Peptide: Arginine molar ratio 1 :48

[0053] The stock formulation is a solution of 5.0 mg/mL AEM-28-14 (active basis) in vehicle. The vehicle is 11 mg/mL L- Arginine and 10.6 mg/mL Tween™ 80 in 1X-PBS (137 mM NaCl, 2.7 mM KC1, 9.5 mM Phosphate buffer. Does not contain magnesium or calcium. For example, VWR Phosphate Buffered Solution (PBS), product #97062-818) with pH adjusted to 7.0. The 5 mg/mL stock solution can be used to prepare any lower AEM-28-14 dosing formulation by volumetrically diluting the 5 mg/mL stock solution with the appropriate amount of PBS. Note: L- Arginine is very basic, and therefore a pH adjustment step is required after the Arginine addition to bring the vehicle pH to 7.0 - 7.4.

[0054] The vehicle is prepared from 1X-PBS by 1) adding 11.0 mg/mL L- Arginine to the PBS (the arginine should readily go into solution with gentle mixing), 2) adjusting the pH of the PBS/Arginine solution with 5N hydrochloric acid to pH 6.9 - 7.1, and 3) adding 10.6 mg/mL Tween™ 80 to the PBS/Arginine solution (the Tween™ 80 will go into solution with gentle mixing over 10-15 minutes). Note: Vortexing or excessive agitation will cause foaming of the Tween™ 80 in solution, therefore, use gentle mixing or sonication to avoid foaming.

[0055] The stock formulation is then prepared by weighing the peptide in to a suitable glass bottle, and then volumetrically adding the appropriate amount of vehicle to result in a solution that is 5.0 mg/mL active AEM-28-14. The mixture should be sonicated in a room temperature sonication bath with gentle swirling until all peptide is fully in solution (about 5 minutes, but larger batch sizes may take longer). Peptide will initially form a slightly hazy mixture, but with more time and sonication the peptide should go fully into solution, resulting in a clear solution. Note: AEM-28-14 peptide is 86.4% active, so the peptide weighing step should account for the activity.

[0056] Final 5.0 mg/mL stock formulation should be a clear solution free of any solids or contaminants with a pH between 6.90 - 7.10. The dosing formulation may be sterile filtered (0.2 um polysulfone filter, or similar). Dosing formulation may be stored up to 24 hours at room temperature, or 72 hours at 2-8C. [Dosing formulation should be allowed to warm to room temperature prior to dosing or filtering].

[0057] As an example, to prepare 40 mL of the 5.0 mg/mL AEM-28-14 stock formulation (can be adjusted to other volumes as needed):

Prepare Vehicle

1) Add Arginine to 100.0 mL of PBS Solution.

a. Weigh 1.100 +/- 0.005 g of L- Arginine in to a clean glass jar (L- Arginine USP, Sigma Product #A4474 or similar)

b. Mix on stir-plate or by hand until clear solution (less than 1 minute). c. Add pH probe to monito pH, and dropwise add 5 N HC1 solution to bring the pH to 7.00 - 7.20. (Hydrochloric acid solution, 5. ON, VWR Product #

BDH7419, or similar). This will take approximately 0.8% addition by volume, or 0.6 - 1.0 mL 5 N HC1 for 100 mL of vehicle.

2) Add Tween™ 80 to PBS/Arginine solution

a. In a clean glass jar weigh 1.062 +/- 0.005 g Tween™ 80 (Polysorbate 80, Sigma Product #59924 or similar)

b. Add 100 mL of pH adjusted PBS/Arginine solution.

c. Mix on stir-plate until clear solution (10-15 minutes).

Active Stock Formulation

3) Prepare 40 mL of 5.0 mg/mL AEM-28-14 in vehicle (PBS/arginine/Tween™ 80). a. Weigh 231.50 +/- 0.20 mg of AEM-28-14 (equivalent to 200.0 mg active

peptide which is 86.4% active) into a clean glass bottle.

b. Volumetrically add 40.00 +/- 0.10 mL PBS/Arginine/Tween™ 80 vehicle to bottle. Cap bottle.

c. Sonicate bottle in a room temperature (15-25C) with gentle hand swirling until all peptide is fully dissolved (approximately 10 minutes). Do not shake or aggressively mix contents of bottle since it can lead to excessive foaming. d. Check pH is at 7.0 (6.85 - 7.15). If not, pH can be adjusted with 5N HC1 or 5N NaOH as long as not more than 0.8% total volume is required to adjust [for 40 mL total formulation, no more than 0.50 mL additional to adjust] e. Ensure a clear solution free of contaminants.

f. The 5.0 mg/mL AEM-28-14 Stock Formulation can be used to prepare any lower concentration formulation by a volumetric dilution with PBS:

g. Sterile filter solution (0.2 um polysulfone membrane).

h. Store refrigerated (2-8C) when not in use. Allow to warm to room temperature prior to dosing or filtering.

i. Formulated solution can be at room temperature up to 24 hours, or held

refrigerated for up to 72 hours.

[0058] AEM-28-8 formulation is prepared the same as AEM-28-14 formulation in all respects. The same PBS/Arginine/Tween™ 80 vehicle can be used for both preparations. Formulated solutions can be at room temperature up to 24 hours, or held refrigerated for up to 72 hours.

Example 3: Toxicity Studies

[0059] Studies were conducted to determine the potential toxicity of compositions comprising ApoE mimicking peptide (AEM-28-14 or AEM-28-08) and polyoxyethylene sorbitan fatty acid ester (Tween™ 20 or Tween™ 80) with and without the cationic amino acid L- Arginine. Study A: Toxicity of compositions comprising AEM-28-14 and Tween™ 20 in saline without L- Arginine when given as a single intravenous bolus injection to Sprague-Dawley rats

[0060] The experimental design for test material without L- Arginine is shown in Table 1.

Table 1

a Test material was administered via bolus intravenous injection via the tail vein on day 1. ^b Test material was administered via slow bolus intravenous injection over 2-4 minutes via the tail vein on day 1.

[0061] Assessment of toxicity was based on mortality/moribundity, clinical observations, body weight changes, gross necropsy findings and histopathologic examinations. Males and females administered AEM-28-14 (Group 1) at 20 mg/kg via bolus intravenous injection were euthanized for humane reasons on Day 1 due to adverse clinical signs. Related clinical signs were noted in the surviving male and female animals dosed at 10 mg/kg (bolus Group 2 and slow bolus Group 4) and 15 mg/kg slow bolus (Group 3). The clinical signs included skin discoloration of the tail (pale, red, blue and/or black), swollen tail, scabbing of the tail, and/or red urine. Clinical signs associated with the tail (discoloration, swelling and scabbing) correlated with related histologic. Related gross necropsy findings (dark discoloration of the tail) were noted for males dosed at 10 mg/kg, slow bolus (Group 4). Tail discoloration was associated with hemorrhage that was identified microscopically in the soft tissue of the tail. Treatment-related and adverse histologic findings were noted in rats dosed with each of the 10 mg/kg (bolus Group 2 and slow bolus Group 4) and 15 mg/kg slow bolus (Group 3) experiments. The most severe finding, of full thickness necrosis (infarction) of the tails was seen in all tissues examined microscopically, with the highest incidence and severity in animals dosed via slow bolus injection at 15 mg/kg.

[0062] In conclusion, male and female rats dosed with AEM-28-14 at 20 mg/kg via bolus intravenous injection (Group 1) were euthanized for humane reasons due to moribund condition. When dosed via slow bolus injection, microscopic findings of the tail included acute hemorrhage, subcutaneous crystals (likely hemaotidin in males), epidermal necrosis (in males only at 10 mg/kg), perivascular inflammatory cell infiltrates and muscular atrophy. When dosed via bolus injection, microscopic findings of the tail included serocellular crust (males only) and atrophy of skeletal muscle. In addition, thrombosis was present in one or both tail veins and/or in the tail artery among all dose levels. Based on these results, administration of AEM-28-14 in 1% Tween™ 20 in saline by once daily intravenous injection (bolus or slow bolus) was not tolerated in rats at levels > 10 mg/kg.

Study B: Toxicity of compositions comprising AEM-28-14 and Tween™ 20 in saline with L- Arginine when given as a single intravenous bolus injection to Sprague-Dawlev rats

[0063] The experimental design for test material with L- Arginine is shown in Table 2. Experiments were performed using single intravenous bolus injection to Sprague-Dawley rats.

a The first Group 1 animal was dosed and monitored (cage side observations) for a minimum of 1 hour. As no significant adverse clinical signs were observed, the remaining Group 1 animals were dosed. ^b The first Group 2 animal was dosed following completion of Group 1 dosing. As significant adverse clinical signs were observed shortly after dosing, the remaining three Group 2 animals were not dosed and were released from the study.

[0064] Assessment of toxicity was based on the following endpoints in the study:

mortality checks and clinical observations. On Day 1, the rat dosed with AEM-28-14 / Arginine at 20 and 70 mg/kg respectively, was euthanized for humane reasons due to its moribund condition shortly after dosing. AEM-28-l4-related clinical observations in males dosed with AEM-28-14 / Arginine at 15 and 52.5 mg/kg respectively, however, included irregular breathing, which normalized within 30 minutes post dose with no further adverse clinical signs. Overall, the administration of AEM-28-14 when dosed in conjunction with arginine as a single intravenous bolus injection, was well tolerated in rats at levels of 15 and 52.5 mg/kg respectively. This data supports that formulations comprising arginine reduce toxicity.

Example 4: Total Cholesterol Reduction

[0065] A comparative study between the efficacy of AEM-28-14 in test formulations for reducing total serum cholesterol (CHOL) versus negative (vehicle) control was performed. A summary of the test articles is shown below.

[0066] A total of fifteen naive female Apo-E (-/-) mice were assigned to the study based on acceptable health as determined by a staff veterinarian. All animals were fasted for 4 hours on study day beginning around 0800 hours with food returned after a five (5) hour post dose blood collection. Animals followed the same fasting regimen before the 24 hour collection. The study design was as follows.

[0067] Each animal received a single intravenous dose of prepared test article at the target dose levels and dose volumes indicated above. Whole blood samples were collected from each animal by puncture of a submandibular vein as outlined in the sample collection table below.

X = sample collected. ^a Sample collected following 4 hour fast. ^b Samples collected before dosing. ^c Food returned following sample collection.

1 [0068] All blood samples were collected into tubes without additive and allowed to sit at room temperature for a minimum of 30 minutes to permit clot formation. Following full clot retraction, samples were centrifuged at 2200 * g for 10 minutes at 22 °C to isolate serum. The resulting serum was transferred to individual polypropylene tubes in a 96-well plate format and immediately placed on dry ice until storage at nominally -70 °C. Upon completion of the study, serum samples were transferred to Charles River Immunology Laboratory, Shrewsbury MA for total cholesterol analysis using an ELISA Wako Kit (ID# 439-17501). The Total Cholesterol results are shown in FIG 1. As shown, the efficacy of AEM-28-14 with and without L- Arginine are nearly analogous.

Claims

Listing of Claims:

1. An aqueous pharmaceutical composition comprising

i) a synthetic apo lipoprotein E(ApoE) mimicking peptide of the formula

CH₃(CH₂)_XC(0)-LRY¹LRY²RLLR-DWLKAFYDKVAEKLKEAF-NH₂, or a

pharmaceutically acceptable salt thereof, wherein x is an integer from 1 to 20 and Y¹ and Y² are each independently lysine or arginine;

ii) a polyoxyethylene sorbitan fatty acid ester; and

iii) a cationic amino acid.

2. The aqueous pharmaceutical composition of Claim 1, wherein the cationic amino acid is selected from arginine, lysine, histidine, and ornithine.

3. The aqueous pharmaceutical composition of Claim 1 or 2, wherein the cationic amino acid is selected from arginine and lysine.

4 The aqueous pharmaceutical composition of any one of Claims 1 to 3, wherein the cationic amino acid is arginine.

5. The aqueous pharmaceutical composition of any one of Claims 1 to 4, wherein x is an integer from 3 to 18.

6. The aqueous pharmaceutical composition of any one of Claims 1 to 5, wherein x is an integer from 4 to 16.

7. The aqueous pharmaceutical composition of any one of Claims 1 to 6, wherein x is an integer from 5 to 14.

8. The aqueous pharmaceutical composition of any one of Claims 1 to 7, wherein x is an integer from 5 to 13.

9. The aqueous pharmaceutical composition of any one of Claims 1 to 8, wherein x is an integer from 6 to 12.

10. The aqueous pharmaceutical composition of any one of Claims 1 to 9, wherein the ApoE mimicking peptide is of the formula CH₃(CH₂)_l2C(0)-LRRLRRRLLR- DWLKAFYDKVAEKLKEAF-NH₂, or a pharmaceutically acceptable salt thereof.

11. The aqueous pharmaceutical composition of any one of Claims 1 to 9, wherein the ApoE mimicking peptide is of the formula CH₃(CH₂)_l2C(0)-LRKLRKRLLR- DWLKAFYDKVAEKLKEAF-NH₂, or a pharmaceutically acceptable salt thereof.

12. The aqueous pharmaceutical composition of any one of Claims 1 to 9, wherein the ApoE mimicking peptide is of the formula CH₃(CH₂)₆C(0)-LRRLRRRLLR- DWLKAFYDKVAEKLKEAF-NH₂, or a pharmaceutically acceptable salt thereof.

13. The aqueous pharmaceutical composition of any one of Claims 1 to 9, wherein the ApoE mimicking peptide is of the formula CH₃(CH₂)₆C(0)-LRKLRKRLLR- DWLKAFYDKVAEKLKEAF-NH₂, or a pharmaceutically acceptable salt thereof.

14. The aqueous pharmaceutical composition of any one of Claims 1 to 13, wherein the polyoxyethylene sorbitan fatty acid ester is selected from polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80.

15. The aqueous pharmaceutical composition of any one of Claims 1 to 14, wherein the polyoxyethylene sorbitan fatty acid ester is polysorbate 20 or polysorbate 80.

16. The aqueous pharmaceutical composition of any one of Claims 1 to 15, wherein the polyoxyethylene sorbitan fatty acid ester is polysorbate 80.

17. The aqueous pharmaceutical composition of any one of Claims 1 to 16, wherein the molar ratio of ApoE mimicking peptide to cationic amino acid present in the aqueous composition ranges from 1:1 to 1:90.

18. The aqueous pharmaceutical composition of any one of Claims 1 to 17, wherein the molar ratio of ApoE mimicking peptide to cationic amino acid present in the aqueous composition ranges from 1:45 to 1:55.

19. The aqueous pharmaceutical composition of any one of Claims 1 to 17, wherein the molar ratio of ApoE mimicking peptide to cationic amino acid present in the aqueous composition is 1 :48.

20. The aqueous pharmaceutical composition of any one of Claims 1 to 19, wherein the molar ratio of ApoE mimicking peptide to polyoxyethylene sorbitan fatty acid ester present in the aqueous composition is less than 0.20, is less than or equal to 0.17, or is less than or equal to 0.15.

21. The aqueous pharmaceutical composition of any one of Claims 1 to 19, wherein the molar ratio of ApoE mimicking peptide to polyoxyethylene sorbitan fatty acid ester present in the aqueous composition ranges from 0.01 to 0.17, ranges from 0.01 to 0.05, ranges from 0.01 to 0.02, ranges from 0.02 to 0.17, ranges from 0.03 to 0.17, or ranges from 0.05 to 0.17.

22. The aqueous pharmaceutical composition of any one of Claims 1 to 19, wherein the molar ratio of ApoE mimicking peptide to polyoxyethylene sorbitan fatty acid ester present in the aqueous composition is less than 0.20.

23. The aqueous pharmaceutical composition of any one of Claims 1 to 19, wherein the molar ratio of ApoE mimicking peptide to polyoxyethylene sorbitan fatty acid ester present in the aqueous composition ranges from 0.05 to 0.19.

24. The aqueous pharmaceutical composition of any one of Claims 1 to 19, wherein the molar ratio of ApoE mimicking peptide to polyoxyethylene sorbitan fatty acid ester present in the aqueous composition ranges from 0.10 to 0.19.

25. The aqueous pharmaceutical composition of any one of Claims 1 to 19, wherein the molar ratio of ApoE mimicking peptide to polyoxyethylene sorbitan fatty acid ester present in the aqueous composition ranges from 0.3 to 0.18.

26. The aqueous pharmaceutical composition of any one of Claims 1 to 19, wherein the molar ratio of ApoE mimicking peptide to polyoxyethylene sorbitan fatty acid ester present in the aqueous composition ranges from 0.5 to 0.17.

27. The aqueous pharmaceutical composition of any one of Claims 1 to 19, wherein the molar ratio of ApoE mimicking peptide to polyoxyethylene sorbitan fatty acid ester present in the aqueous composition is 0.16.

28. The aqueous pharmaceutical composition of any one of Claims 1 to 27, wherein the concentration of ApoE mimicking peptide, or pharmaceutically acceptable salt thereof, present in the aqueous composition ranges from 0.1 mg/mL to 10 mg/mL.

29. The aqueous pharmaceutical composition of any one of Claims 1 to 28, wherein the ApoE mimicking peptide, or pharmaceutically acceptable salt thereof, present in the aqueous composition ranges from 0.8 mg/mL to 8.0 mg/mL.

30. The aqueous pharmaceutical composition of any one of Claims 1 to 29, wherein the ApoE mimicking peptide, or pharmaceutically acceptable salt thereof, present in the aqueous composition ranges from 1.0 mg/mL to 5.5 mg/mL.

31. The aqueous pharmaceutical composition of any one of Claims 1 to 30, wherein the ApoE mimicking peptide, or pharmaceutically acceptable salt thereof, present in the aqueous composition is 1 mg/mL, 2.5 mg/mL, or 5 mg/mL.

32. The aqueous pharmaceutical composition of any one of Claims 1 to 31, wherein the ApoE mimicking peptide, or pharmaceutically acceptable salt thereof, present in the aqueous composition is 5 mg/mL.

33. The aqueous pharmaceutical composition of any one of Claims 1 to 32, wherein the ApoE mimicking peptide and polyoxyethylene sorbitan fatty acid ester form particles.

34. The aqueous pharmaceutical composition of any one of Claims 1 to 33, wherein the ApoE mimicking peptide and polyoxyethylene sorbitan fatty acid ester form particles having an average particle size of less than 20 nm.

35. The aqueous pharmaceutical composition of any one of Claims 1 to 34, wherein the ApoE mimicking peptide and polyoxyethylene sorbitan fatty acid ester form particles having an average particle size ranging from 2 nm to 17 nm.

36. The aqueous pharmaceutical composition of any one of Claims 1 to 35, wherein the ApoE mimicking peptide and polyoxyethylene sorbitan fatty acid ester form particles having an average particle size ranging from 5 nm to 15 nm.

37. The aqueous pharmaceutical composition of any one of Claims 1 to 36, wherein the ApoE mimicking peptide and polyoxyethylene sorbitan fatty acid ester form particles having an average particle size ranging from 5 nm to 12 nm.

38. The aqueous pharmaceutical composition of any one of Claims 1 to 37, wherein the ApoE mimicking peptide and polyoxyethylene sorbitan fatty acid ester form particles having an average particle size ranging from 6 nm to 10 nm.

39. The aqueous pharmaceutical composition of any one of Claims 1 to 38, wherein the ApoE mimicking peptide and polyoxyethylene sorbitan fatty acid ester form particles that are micelles.

40. The aqueous pharmaceutical composition of any one of Claims 1 to 39, wherein the ApoE mimicking peptide and polyoxyethylene sorbitan fatty acid ester form particles that are micelles homogenously distributed throughout the aqueous composition.

41. A method of reducing plasma cholesterol in a subject in need thereof comprising administering to the subject an effective amount of the aqueous pharmaceutical composition of any one of Claims 1 to 40.

42. A method of treating a subject with a condition selected from atherosclerosis, acute coronary syndrome (ACS), coronary artery disease, rheumatoid arthritis, diabetes,

Alzheimer's disease, peripheral arterial disease (PAD), cerebral vascular disease, diabetes derived cardiovascular diseases, macular degeneration, congestive heart failure,

hypertriglyceridemic pancreatitis, sepsis, and systemic lupus, comprising administering to a subject an effective amount of the aqueous pharmaceutical composition of any one of Claims 1 to 40.

43. The method of Claim 42, wherein the condition is atherosclerosis.

44. The method of any one of Claims 41 to 43, wherein the ApoE mimicking peptide is administered at a concentration ranging from 0.1 to 20 mg/kg.

45. The method of any one of Claims 41 to 44, wherein the ApoE mimicking peptide is administered at a concentration of 5 mg/kg.