WO2017120568A1 - Compositions de peptides mimétiques de l'apoe - Google Patents

Compositions de peptides mimétiques de l'apoe Download PDF

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Publication number
WO2017120568A1
WO2017120568A1 PCT/US2017/012678 US2017012678W WO2017120568A1 WO 2017120568 A1 WO2017120568 A1 WO 2017120568A1 US 2017012678 W US2017012678 W US 2017012678W WO 2017120568 A1 WO2017120568 A1 WO 2017120568A1
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Prior art keywords
pharmaceutical composition
aqueous pharmaceutical
fatty acid
acid ester
polyoxyethylene sorbitan
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PCT/US2017/012678
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English (en)
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WO2017120568A8 (fr
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Dennis I Goldberg
Phillip M FRIDEN
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Lipimetix Development, Inc.
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Publication of WO2017120568A1 publication Critical patent/WO2017120568A1/fr
Publication of WO2017120568A8 publication Critical patent/WO2017120568A8/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/775—Apolipopeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • Apo lipoprotein E plays an important role in the metabolism of triglyceride rich lipoproteins, such as very low density lipoprotein (VLDL) and chylomicrons.
  • VLDL very low density lipoprotein
  • chylomicrons triglyceride rich lipoproteins
  • 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).
  • LDL low density lipoprotein
  • VLDLR very low density lipoprotein receptor
  • apoE2R apoE2 receptor
  • ApoE peptides e.g., AEM-28
  • MTDs maximum tolerated dose levels
  • NOAELs low no-observed adverse effect levels
  • polyoxyethylene sorbitan fatty acid ester to the aqueous formulations comprising these synthetic ApoE mimetic peptides.
  • AEM-28- 14 and AEM-28-8 were formulated in 2% polysorbate 80 (e.g., TweenTM 80) in PBS, complete dissolution occurred and the NOAELs for both peptides were up to 15 mg/kg, with minimal effects observed at 25 mg/kg. See Examples 2 and 3.
  • polyoxyethylene sorbitan fatty acid ester increased the NOAEL dose from ⁇ 5 mg/kg to 10 mg/kg. See Example 3.
  • compositions comprising certain longer-chain mimetic ApoE peptides (e.g., AEM-28- 14 and AEM-28-8) and a polyoxyethylene sorbitan fatty acid exhibit no adverse effects and elicit superior reductions in plasma cholesterol.
  • AEM-28- 14 formulated in 0.8% polysorbate 80 e.g., TweenTM 80
  • 0.8% polysorbate 80 reduced cholesterol from 450 mg/dl to zero in some animals, thereby essentially removing all circulating cholesterol for at least 6 hours post-dose from the initial dose of 4 mg/kg.
  • AEM-28-8 formulated in 0.8% polysorbate 80 e.g., TweenTM 80
  • at a dose of 4 mg/kg showed a change of total cholesterol to 9% of baseline. See e.g., Figure 1 and
  • FIG. 1 illustrates the change in cholesterol (mg/dL) vs time for AEM-28-8, AEM- 28- 14, and AEM-28 at concentrations of 0.4 or 4 mg/kg, where a) represents total cholesterol and b) represents percent (%) change in total cholesterol.
  • FIG. 2 illustrates the change in cholesterol (mg/dL) vs time for AEM-28-8, AEM- 28- 14, and AEM-28 at concentrations of 1 or 2 mg/kg, where a) represents total cholesterol and b) represents percent (%) change in total cholesterol.
  • FIG. 3 shows the effect of AEM-28- 14 in 2% Tween® 20/PBS in
  • hypercholesterolemic cynomolgus monkeys hypercholesterolemic cynomolgus monkeys.
  • aqueous formulations comprising i) a synthetic apolipoprotein E (ApoE)-mimicking peptide and ii) a polyethylene sorbitan ester.
  • aqueous pharmaceutical compositions comprising i) a synthetic apolipoprotein E (ApoE) mimicking peptide of the formula (CH 3 )(CH 2 ) x C(0)NH(CH 2 ) y C(0)-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF- NH 2 , wherein x is an integer from 0 to 6; and y is an integer from 1 to 20; or a
  • Ac-hE18A-NH 2 as used herein means a synthetic apolipoprotein E (ApoE)- mimicking peptide where "Ac” is acetyl, such that the synthetic apolipoprotein E (ApoE)- mimicking peptide has the structure H 3 C(CO)-LRKLRKRLLR-
  • Ac-MyrA[R]hE18A-NH 2 as used herein means a synthetic apolipoprotein E (ApoE)-mimicking peptide where "Ac” is acetyl and "MyrA” is myristic acid, such that the synthetic apolipoprotein E (ApoE)-mimicking peptide has the structure H 3 C(CO)- NH(CH 2 )i 3 (CO)-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH 2 .
  • Ac-Myr A[R]hE 18 A- NH 2 and AEM-28- 14 are used interchangeably.
  • Ac-Octa[R]hE18A-NH 2 as used herein means a synthetic apolipoprotein E (ApoE)-mimicking peptide where "Ac” is acetyl and “Octa” is octanoic acid, such that the synthetic apolipoprotein E (ApoE)-mimicking peptide has the structure H 3 C(CO)- NH(CH 2 ) 7 (CO)-LRRLRRRLLR-DWLKAFYDKVAEKLKE AF-NH 2 .
  • Ac-Octa[R]hE 18 A- NH 2 and AEM-28-8 are used interchangeably.
  • the disclosed Apo E mimicking peptides disclosed herein comprise amino acids that contain basic groups (e.g., -NH 2 ) 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.
  • 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,
  • 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.
  • polyethylene sorbitan fatty acid esters are amphipathic, nonionic surfactants composed of fatty acid esters of polyoxyethylene sorbitan.
  • 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).
  • polysorbate 20 comprising polyoxyethylene (20) sorbitan monolaurate
  • TweenTM 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., TweenTM 40
  • polysorbate 60 comprising polyoxyethylene (20) sorbitan monostearate
  • polysorbate 80 comprising polyoxyethylene (20) sorbitan monooleate
  • TweenTM 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 TweenTM 80.
  • No observed adverse effect level refers to the highest tested dose of a peptide described in the compositons herein at which there is no biologically or statistically significant (e.g. alteration of morphology, functional capacity, growth, development or life span) increase in the frequency or severity of any adverse effects in the exposed subject when compared to a control subject or group.
  • the maximum tolerated dose is the highest dose of a drug (e.g., a composition as described herein) or treatment that does not cause unacceptable side effects.
  • Dose or “dosage” as used herein refers to a specific quantity of a therapeutic agent, such as an Apo E mimetic, that is taken at specific times.
  • average particle size means the average size of particles relative to the total amount the same particles in solution.
  • an effective amount is meant to mean a sufficient amount of the composition or Apo E mimetic to provide the desired effect.
  • 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 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.
  • sample is meant to mean an animal; a tissue or organ from an animal; a cell (either within a subject, taken directly from a subject, or a cell maintained in culture or from a cultured cell line); a cell lysate (or lysate fraction) or cell extract; or a solution containing one or more molecules derived from a cell or cellular material (e.g. a polypeptide or nucleic acid), which is assayed as described herein.
  • a sample may also be any body fluid or excretion (for example, but not limited to, blood, urine, stool, saliva, tears, bile) that contains cells or cell components.
  • subject refers to the target of administration, e.g. an animal.
  • the subject of the disclosed methods can be a vertebrate, such as a mammal.
  • 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”.
  • module is meant to mean to alter, by increasing or decreasing.
  • treatment refers 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.
  • treatment may be administered after one or more symptoms have developed, i.e., therapeutic treatment.
  • treatment may be administered in the absence of symptoms.
  • 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.
  • Susceptile individual being one who is at risk of developing one or more of the conditions recited herein.
  • lipoprotein or lipoproteins
  • lipoproteins is meant to mean a biochemical assembly that contains both proteins and lipids.
  • the lipids or their derivatives may be covalently or non-covalently bound to the proteins.
  • Many enzymes, transporters, structural proteins, antigens, adhesins, and toxins are lipoproteins. Examples include the high density and low density lipoproteins of the blood, the transmembrane proteins of the mitochondrion and the chloroplast, and bacterial lipoproteins
  • high-density lipoprotein is meant to mean a class of lipoproteins, varying somewhat in their size (8- 11 nm in diameter), that can transport cholesterol.
  • HDL cholesterol is cholesterol that is associated with HDLs. About one-fourth to one-third of blood cholesterol is carried by high-density lipoprotein (HDL).
  • HDL cholesterol is known as "good” cholesterol, because high levels of HDL seem to protect against heart attack.
  • Low levels of HDL (less than 40 mg/dL in men and less than 50 mg/dL in women) also increase the risk of heart disease. Medical experts think that HDL tends to carry cholesterol away from the arteries and back to the liver, where it is passed from the body. Some experts believe that that HDL removes excess cholesterol from arterial plaque, thus slowing its buildup
  • VLDL very Low Density Lipoproteins
  • LDL low density lipoprotein
  • low-density lipoprotein or “LDL” is meant to mean a lipoprotein that varies in size (approx. 22 nm) and can contain a changing number of triglycerides and cholesteryl esters they actually have a mass and size distribution.
  • Each native LDL particle contains a single apolipoproteinB- 100 molecule (Apo B- 100, a protein with 4536 amino acid amino acid residues) and a phospholipid coat that circles the triglycerides and cholesteryl esters, keeping them soluble in the aqueous environment.
  • LDL is commonly referred to as bad cholesterol.
  • LDL cholesterol is cholesterol that is associated with LDLs.
  • LDL cholesterol When too much LDL cholesterol circulates in the blood, it can slowly build up in the inner walls of the arteries that feed the heart and brain. Together with other substances, it can form plaque, a thick, hard deposit that can narrow the arteries and make them less flexible. This condition is known as atherosclerosis. If a clot forms and blocks a narrowed artery, then heart attack or stroke can result.
  • 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 (1-palmitoyl 2-arachidonyl phophyatidyl choline). Oxidation of PAPC or PLPC, the lipid components of LDL, produce oxidized lipids. Having a lipid disorder can make you more likely to develop inflammatory disease such as atherosclerosis and hear 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, and systemic lupus.
  • 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
  • congestive heart failure and systemic lupus.
  • aqueous pharmaceutical compositions comprising i) a synthetic apo lipoprotein E (ApoE) mimicking peptide of the formula (CH 3 )(CH 2 ) x C(0)NH(CH 2 ) y C(0)-LRRLRRRLLR- DWLKAFYDKVAEKLKEAF-NH 2 , wherein x is an integer from 0 to 6; and y is an integer from 1 to 20; or a pharmaceutically acceptable salt thereof; and ii) a polyoxyethylene sorbitan fatty acid ester.
  • ApoE synthetic apo lipoprotein E
  • x in the peptides described herein is an integer from 0 to
  • y in the peptides described herein is an integer from 3 to
  • y is an integer from 4 to 16, wherein the remaining features are as described in the first or second embodiment. In another alternative, y is an integer from 6 to 13, wherein the remaining features are as described in the first or second embodiment.
  • compositions described herein is of the formula H 3 C(CO)-NH(CH 2 ) 6 (CO)-LRRLRRRLLR-
  • the ApoE mimicking peptide is of the formula H 3 C(CO)-NH(CH 2 ) 7 (CO)- LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH 2 , or a pharmaceutically acceptable salt thereof, wherein the remaining features are as described in the first, second, or third embodiment.
  • the ApoE mimicking peptide is of the formula H 3 C(CO)-NH(CH 2 )i 3 (CO)-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH 2 , or a pharmaceutically acceptable salt thereof, wherein the remaining features are as described in the first, second, or third 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, or fourth embodiment.
  • WFI sterile water for injection
  • PBS phosphate-buffered saline
  • the ApoE mimicking peptide and polyoxyethylene sorbitan fatty acid ester form particles, wherein the remaining features are as described in the first, second, third, fourth, or fifth embodiment.
  • the ApoE mimicking peptide and polyoxyethylene sorbitan fatty acid ester 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, or sixth embodiment.
  • the ApoE mimicking peptide and polyoxyethylene sorbitan fatty acid ester 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, or sixth embodiment.
  • the ApoE mimicking peptide and polyoxyethylene sorbitan fatty acid ester form particles having an average particle size ranging from 5 nm to
  • polyoxyethylene sorbitan fatty acid ester 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, or sixth embodiment.
  • the ApoE mimicking peptide and polyoxyethylene sorbitan fatty acid ester form particles having an average particle size ranging from 8 nm to 16 nm, wherein the remaining features are as described in the first, second, third, fourth, fifth, or sixth embodiment.
  • the ApoE mimicking peptide and polyoxyethylene sorbitan fatty acid ester 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, or sixth embodiment.
  • the ApoE mimicking peptide and polyoxyethylene sorbitan fatty acid ester 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, or sixth
  • the ApoE mimicking peptide and polyoxyethylene sorbitan fatty acid ester form particles having an average particle size ranging from 7 nm to 9 nm, wherein the remaining features are as described in the first, second, third, fourth, fifth, or sixth embodiment.
  • the ApoE mimicking peptide and polyoxyethylene sorbitan fatty acid ester form particles that are micelles, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, or seventh embodiment.
  • the ApoE mimicking peptide and polyoxyethylene sorbitan fatty acid ester form particles that are micelles, which are homogenously distributed throughout the aqueous formulation, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiment.
  • polyoxyethylene sorbitan fatty acid ester in the aqueous compositions described herein is less than 0.200, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment.
  • the molar ratio of ApoE mimicking peptide to polyoxyethylene sorbitan fatty acid ester in the aqueous compositions described herein is less than or equal to 0.170, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment.
  • the molar ratio of ApoE mimicking peptide to polyoxyethylene sorbitan fatty acid ester in the aqueous compositions described herein is less than 0.165, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment.
  • the molar ratio of ApoE mimicking peptide to polyoxyethylene sorbitan fatty acid ester in the aqueous compositions described herein ranges from 0.010 to 0.170, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment.
  • the molar ratio of ApoE mimicking peptide to polyoxyethylene sorbitan fatty acid ester in the aqueous compositions described herein ranges from 0.020 to 0.170, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment.
  • the molar ratio of ApoE mimicking peptide to polyoxyethylene sorbitan fatty acid ester in the aqueous compositions described herein ranges from 0.030 to 0.170, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment.
  • the molar ratio of ApoE mimicking peptide to polyoxyethylene sorbitan fatty acid ester in the aqueous compositions described herein ranges from 0.050 to 0.170, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment.
  • the molar ratio of ApoE mimicking peptide to polyoxyethylene sorbitan fatty acid ester in the aqueous compositions described herein ranges from 0.080 to 0.170, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment.
  • the molar ratio of ApoE mimicking peptide to polyoxyethylene sorbitan fatty acid ester in the aqueous compositions described herein ranges from 0.010 to 0.050, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment.
  • the molar ratio of ApoE mimicking peptide to polyoxyethylene sorbitan fatty acid ester in the aqueous compositions described herein ranges from 0.013 to 0.020, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment.
  • the molar ratio of ApoE mimicking peptide to polyoxyethylene sorbitan fatty acid ester in the aqueous compositions described herein ranges from 0.014 to 0.019, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment.
  • the polyoxyethylene sorbitan fatty acid ester 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, sixth, seventh, eighth, ninth, or tenth embodiment.
  • the polyoxyethylene sorbitan fatty acid ester is polysorbate 20 or polysorbate 80, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment.
  • the polyoxyethylene sorbitan fatty acid ester is polysorbate 80, wherein the remaining features are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment.
  • the ApoE mimicking peptide, or pharmaceutically acceptable salt thereof is present at a concentration ranging 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.
  • the ApoE mimicking peptide, or pharmaceutically acceptable salt thereof is present at a concentration ranging from 0.8 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.
  • the ApoE mimicking peptide, or pharmaceutically acceptable salt thereof is present at a concentration of 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.
  • compositions including independent components of the peptides and/or phospholipids described herein, are provided in the EXEMPLIFICATION.
  • the compositions described herein encompasses all of the disclosed peptides and phospholipids, and combinations and variations thereof, as further set fourth in the EXEMPLIFICATION.
  • a composition comprising i) a synthetic apolipoprotein E(ApoE)- mimicking peptide of the formula (CH 3 )(CH 2 ) x C(0)NH(CH 2 ) y C(0)-LRRLRRRLLR- DWLKAFYDKVAEKLKEAF-NH 2 , wherein x is an integer from 0 to 6; and y is an integer from 1 to 20; or a pharmaceutically acceptable salt thereof; and ii) a phospholipid as described herein.
  • the plasma LDL, plasma VLDL, or both are affected.
  • binding of LDL to a cell of the subject is enhanced.
  • degradation of LDL by a cell of the subject is increased.
  • LDL cholesterol in the subject is lowered.
  • binding of VLDL to a cell of the subject is enhanced.
  • degradation of VLDL by a cell of the subject is increased.
  • VLDL cholesterol in the subject is lowered.
  • total plasma concentration of cholesterol in the subject is lowered.
  • 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.
  • Also disclosed herein are methods of treating atherosclerosis comprising administering to a subject in need thereof i) a synthetic apolipoprotein E(ApoE)-mimicking peptide having the formula (CH 3 )(CH 2 ) x C(0)NH(CH 2 ) y C(0)-LRRLRRRLLR-
  • the disclosed synthetic apo lipoprotein 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.
  • Also disclosed are methods of treating a subject with a lipid disorder comprising administering to a subject in need thereof i) a synthetic apo lipoprotein E(ApoE)-mimicking peptide having the formula (CH 3 )(CH 2 ) x C(0)NH(CH 2 ) y C(0)-LRRLRRRLLR- DWLKAFYDKVAEKLKEAF-NH 2 , wherein x is an integer from 0 to 6; and y is an integer from 1 to 20; or a pharmaceutically acceptable salt thereof; and ii) a phospholipid as described herein.
  • a synthetic apo lipoprotein E(ApoE)-mimicking peptide having the formula (CH 3 )(CH 2 ) x C(0)NH(CH 2 ) y C(0)-LRRLRRRLLR- DWLKAFYDKVAEKLKEAF-NH 2 , wherein x is an integer from 0 to 6; and y is an integer from 1 to 20; or
  • 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, and congestive heart failure.
  • 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.
  • 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 having the formula (CH 3 )(CH 2 ) x C(0)NH(CH 2 ) y C(0)-LRRLRRRLLR- DWLKAFYDKVAEKLKEAF-NH 2 , wherein x is an integer from 0 to 6; and y is an integer from 1 to 20; or a pharmaceutically acceptable salt thereof; and ii) a phospholipid as described herein.
  • ACS acute coronary syndrome
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • administration can be
  • compositions can be used in and with any other therapy.
  • compositions are aqueous formulations that exists in e.g., H 2 0 (e.g, water for injection (WFI)), PBS (e.g., sterile PBS), and the like.
  • H 2 0 e.g, water for injection (WFI)
  • PBS e.g., sterile PBS
  • Peptides described herein were prepared via standard solid-phase synthetic procedures.
  • Ac-hE18A-NH 2 was prepared according to the procedures described in U.S. Patent No. 6,506,880 and U.S. Provisional No. 62/031,585, and following standard solid- phase synthetic procedures.
  • AEM-28 was found to readily dissolve in 0.9% saline, while AEM-28-08 and AEM-28-14 formed suspensions with rapid settling. To overcome this obstacle, the polyethylene sorbitan ester Tween was added. The addition of Tween to AEM-28-08 and AEM-28-14 was found to not only dissolve the peptides, but also formed small, uniform micelles, thereby producing smaller, more consistent API containing particles. Table 1 shows results from this study.
  • Table 1A shows the correlation between the molar ratio of AEM-28- 14/poly ethylene sorbitan ester and particle size. No visible particles were seen. [0062] Table 1A
  • the dose formulations for Groups 1-5 were formulated with Tween® 80 in PBS IX.
  • the dose formulation for Group 6 was formulated with Tween® 20 in PBS IX. All formulations for Sessions 1 and 2 were clear colorless solutions at the time of intravenous dose
  • Each animal in Sessions 1 and 2 received a single intravenous dose of prepared test article at the target dose levels and dose volumes indicated in the table above. Animals were monitored continuously for any adverse clinical signs for the first hour following dose administration, at which point tolerability and dose escalation were assessed. In addition, clinical observations were performed for all animals at 2, 3, 4, 5, 6, 7 and 24 hours post-dose. A summary of clinical observations are as follows. - Previously, data in mice with AEM-28 in saline/PBS generated a no observed adverse effect level (NOAEL) dose of ⁇ 5 mg/kg and an MTD of 10 mg/kg. However, with AEM-28 formulated in 2% Tween® 80/PBS, a higher NOAEL dose was observed at 10 mg/kg.
  • NOAEL no observed adverse effect level
  • AEM-28-08 and AEM-28- 14 in 5% Tween® 80/PBS generated a NOAEL up to 15 mg/kg, with minimal effects observed at 25 mg/kg.
  • both AEM-28-08 and AEM-28-14 elicit significant reductions in cholesterol levels with AEM-28-14 essentially removing all circulating cholesterol for at least 6 hours post-dose. See e.g., FIG. 1A for total cholesterol levels and Figure IB where AEM-28-8 and AEM-28-14 each elicit a dramatic reduction in % change of total cholesterol at 4 mg/kg (to 9% and 2% of baseline). This reduction is superior to AEM- 28, which exhibited a % change of total cholesterol to 38% of baseline. See e.g., FIG. IB.

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Abstract

L'invention concerne des compositions aqueuses comprenant un mélange de peptides synthétiques mimétiques de l'apolipoprotéine E (ApoE) et d'un ester de polyéthylène sorbitanne, et leur utilisation pour réduire le taux de cholestérol plasmatique.
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WO2019199976A1 (fr) * 2018-04-11 2019-10-17 Lipimetix Development, Inc. Compositions peptidiques mimétiques d'apoe

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018190896A1 (fr) * 2017-04-13 2018-10-18 Lipimetix Development, Inc. Compositions de peptides mimétiques de l'apoe
WO2019199976A1 (fr) * 2018-04-11 2019-10-17 Lipimetix Development, Inc. Compositions peptidiques mimétiques d'apoe

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