WO2018165120A1 - Effet de carboxyalkyléthers sur les symptômes de l'obésité et la lipodystropie - Google Patents

Effet de carboxyalkyléthers sur les symptômes de l'obésité et la lipodystropie Download PDF

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WO2018165120A1
WO2018165120A1 PCT/US2018/021093 US2018021093W WO2018165120A1 WO 2018165120 A1 WO2018165120 A1 WO 2018165120A1 US 2018021093 W US2018021093 W US 2018021093W WO 2018165120 A1 WO2018165120 A1 WO 2018165120A1
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patient
compound
fpl
formula
insulin
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PCT/US2018/021093
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Rebecca BAKKER-ARKEMA
Charles L. Bisgaier
Seth Channing RENO
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Gemphire Therapeutics Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

Definitions

  • lipid lowering agent to lower apoC-II, apoC-III, modulate apoE, improve insulin sensitivy, improve obesity symptoms, and to treat subjects with congenital or acquired lipodystrophy.
  • Lipodystrophic (also known as lipoatrophy) syndromes encompass a
  • Metabolic abnormalities may also be associated with this condition.
  • Lipodystrophic syndromes are commonly associated with hypertriglyceridemia, hepatic steatosis, and severe insulin resistance.
  • the fact that insulin resistance and the consequent progression to diabetes can result from either obesity or lipodystrophy reflects the crucial role of adipose tissue in carbohydrate and lipid metabolism.
  • excess calories cannot be diverted to their normal storage depot; instead they accumulate as increased triglyceride stores in liver, in skeletal and cardiac muscle, and in the pancreatic ⁇ cell.
  • This extra- adipose lipid accumulation, through as-yet unclear means, is associated with impaired insulin action and, often, diabetes.
  • Lipodystrophies are associated with partial or complete leptin deficiency. Leptin replacement therapy dramatically improves dyslipidemia, total cholesterol, insulin sensitivity, reduction in HbAlc, and intrahepatic fat content. In patients not fully responsive to anti- hyperglycemic medications or high dose insulin, leptin reduces fasting blood glucose and HbAlc levels. Studies have shown that a synthetic human leptin analogue administered over a three year period demonstrated a durable responses including reduction of glucose , triglycerides, and liver enzymes to reduce some of the abnormalities associated with lipodystrophy Ficarella et al., (Curr Diab Rep Vol.
  • United States Patent No. 7, 183,254 discloses leptin, leptin analogs, and leptin derivative and methods of treating patients with lipoatrophy. United States Patent No. 7,183,254 is herein incorporated by reference in its entirety. Use of a recombinant form of leptin analog, metreleptin, was approved in 2014 as a replacement therapy to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy. In some cases, immunogenicity (e.g., formation of neutralizing antibodies) can develop to metreleptin, reducing its effectiveness in continued treatment.
  • immunogenicity e.g., formation of neutralizing antibodies
  • Obesity is a term that has been precisely defined by the National Institutes of
  • the BMI Body Mass Index
  • the BMI a key index for relating body weight to height, is a person's weight in kilograms (kg) divided by their height in meters (m) squared. Since the BMI describes the body weight relative to height, it correlates strongly (in adults) with the total body fat content. Insulin sensitivity describes how sensitive the body is to the effects of insulin. Someone said to be insulin sensitive will require smaller amounts of insulin to lower blood glucose levels than someone who has low sensitivity. Low insulin sensitivity, or insulin resistance, is associated with type 2 diabetes and obesity. The insulin resistance of obesity and type 2 diabetes is often associated with a metabolic dyslipidemia that increases cardiovascular risk. Insulin resistance can impair the ability to metabolize glucose for fuel, prompting a switch from fat storage that promotes free fatty acid flux, hepatic triglyceride synthesis and increased VLDL production.
  • the inventors have disclosed methods for treating subjects with negative biological effects of obesity (other than weight) and in subjects with lipodystrophy.
  • a first aspect of the present invention provides methods for increasing insulin sensitivity in a patient in need thereof comprising administering to the patient an effective amount of a compound of formula (I):
  • n and m are each independently the integer 3, 4, 5, or 6.
  • a second aspect of the present invention provides methods for decreasing blood glucose levels in a patient in need thereof comprising administering to the patient an effective amount of a compound of formula (I):
  • n and m are each independently the integer 3, 4, 5, or 6.
  • a third aspect of the present invention provides methods for decreasing HbAlc levels in a patient in need thereof comprising administering to the patient an effective amount of a compound of formula (I):
  • n and m are each independently the integer 3, 4, 5, or 6
  • a fourth aspect of the present invention provides methods for increasing the glucose disposal rate in a patient in need thereof comprising administering to the patient an effective amount of a compound of formula (I):
  • n and m are each independently the integer 3, 4, 5, or 6.
  • a fifth aspect of the present invention provides methods for treating
  • n, and m independently are integers from 2 to 9; each occurrence of Ri, R 2 , R 3 , and R 4 is independently Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or Ri and R 2 taken together with the carbon to which they are attached form a carbocyclic ring having from 3 to 6 carbons, or R 3 and R 4 together with the carbon to which they are attached, form a carbocyclic ring having from 3 to 6 carbons; Yi and Y 2 independently are -COOH, -CHO, tetrazole, and -COOR5; R5 is Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl; or an ester, or a hydrate, or a salt thereof.
  • the method comprises administering the compound.
  • the method comprises administering the monocalcium salt of gemcabene (gemcabene, calcium).
  • Figures 1 A Geneetic Models
  • IB Chargeles River Laboratories
  • Figures 2A (Genetic Models) and 2B (Charles River Laboratories) show the decrease in plasma triglycerides levels, over the 32 day sampling period.
  • Figures 3 A and 3B show the changes in plasma non-HDL-cholesterol levels, over the 32 day sampling period.
  • Figures 4A and 4B show the increase in plasma HDL-cholesterol levels over the 32 day sampling period.
  • Figures 5A (Genetic Models) and 5B (Charles River Laboratories) show the increased ratio of plasma HDL-C to plasma non-HDL-C over the 32 day sampling period.
  • Figures 6A Genetic Models
  • E E
  • C-II C-III
  • Figures 6A and 6 show the changes in plasma apolipoprotein A-I, E, C-II and C-III on the 32nd day of sampling.
  • Figures 7A (Genetic Models) and 7B (Charles River Laboratories) show the changes in fasted blood glucose levels over the 32 day sampling period.
  • Figures 8A (Genetic Models) and 8B (Charles River Laboratories) show the changes in fasted plasma insulin levels over the 32 day sampling period.
  • Figures 9A (Genetic Models) and 9B (Charles River Laboratories) show the ratio of blood fasted glucose levels/ fasted insulin levels on day 32nd day of sampling.
  • Figures 10A (Genetic Models) and 10B (Charles River Laboratories) show the changes in body weight over the 32 day sampling period.
  • Figures 11 A (Genetic Models) and 1 IB (Charles River Laboratories) show the changes in liver weight on day 32nd day of sampling.
  • Figures 12A (Genetic Models) and 12B (Charles River Laboratories) show the percent liver weight to body weight on day 32nd day of sampling.
  • Figures 13 A shows that gemcabene significantly lowered total cholesterol (TC) by a mean percentage of 27.1% (p ⁇ 0.0001) versus placebo (0.3%) in obese human subjects after 4 weeks in treatment.
  • Figures 13B shows that gemcabene significantly lowered LDL-C by a mean percentage of 39.6% (p ⁇ 0.0001) versus placebo ( +0.9%) in obese human subjects after 4 weeks in treatment.
  • Figures 13C shows that gemcabene lowered TGs by a mean percentage of 3.2% versus placebo (2.5%) in obese human subjects after 4 weeks in treatment.
  • Figures 13D shows that gemcabene significantly increased percent glucose disposal rate change by mean percentage of 13.1% (p ⁇ 0.0178) versus placebo (6.3%) in obese human subjects after 4 weeks in treatment.
  • Dose or dosing amounts refer to the amount of the parent compound even when the compound is administered as a salt, an ester or a hydrate.
  • ACC1 is an abbreviation for acetylCoA carboxylase I.
  • apoB is an abbreviation for apolipoprotein B.
  • apoE is an abbreviation for apolipoprotein E.
  • apoC-II is an abbreviation for apolipoprotein C-II.
  • apoC-III is an abbreviation for apolipoprotein C-III.
  • CRP is an abbreviation for c-reactive protein.
  • hsCRP is an abbreviation for high sensitivity CRP.
  • CGL is an abbreviation for congenital generalized lipodystrophy.
  • FPL is an abbreviation for familial partial lipodystropy.
  • AGL is an apreviation for acquired generalized lipodystrophy.
  • GDR is an abbreviation for average glucose disposal rate.
  • HDL is an abbreviation for high-density lipoprotein.
  • HDL-C is an abbreviation for high-density lipoprotein cholesterol.
  • Non-HDL-C is comprised of VLDL-C plus LDL-C, and can be calculated as
  • HbAlc is an abbreviation for glycated hemoglobin.
  • LDL is an abbreviation for low-density lipoprotein.
  • LDL-C is an abbreviation for low-density lipoprotein cholesterol.
  • An obese person has a BMI (Body Mass Index) of 30 and above.
  • BMI Body Mass Index
  • a person with obesity is the same as an obese person.
  • TC is an abbreviation for total cholesterol.
  • TG is an abbreviation for triglyceride.
  • treatment or “treating” include therapeutic treatment and prophylactic treatment.
  • Therapeutic treatment is treatment of a subject that has signs or symptoms of the disease, condition or disorder to be treated.
  • Prophylactic treatments refers to treatment of a subject that is predisposed to the disease, condition or disorder that does not show overt signs of the disease, condition or disorder.
  • alkyl refers to a saturated aliphatic hydrocarbon containing 1-6 carbon atoms. An alkyl can be straight or branched.
  • alkenyl refers to an aliphatic carbon that contains 2-6 carbon atoms and at least one double bond. Like an alkyl, an alkenyl can be straight or branched.
  • alkynyl refers to an aliphatic carbon that contains 2-6 carbon atoms and at least one triple bond. Like an alkyl, an alkynyl can be straight or branched.
  • Carbocyclic ring encompasses cycloalkyl and cycloalkenyl rings having 3-7 carbons. Carbocyclic rings can be optionally substituted with one or more
  • substituents such as aliphatic (e.g., alkyl, alkenyl, or alkynyl).
  • VLDL is an abbreviation for very low-density lipoprotein.
  • VLDL-C is an abbreviation for very low-density lipoprotein cholesterol.
  • Gemcabene has the formula:
  • Gamcabene, calcium monocalcium salt, (gemcabene, calcium).
  • the term "Gemcabene, calcium” has been shortened to gemcabene when used in various publications describing clinical trials or data.
  • “Gemcabene, calcium” is also known as gemcabene and PD72953-0038.
  • PD72953 is also known as PD72953-0000, and is the diacid form of "Gemcabene, calcium”.
  • Gemcabene has a dual mechanism of action that involves: (1) enhancing the clearance of VLDL; and (2) blocking the overall production of hepatic TG and cholesterol synthesis.
  • gemcabene may have an effect on inflammation by reducing CRP mRNA production and decreasing high sensitivity CRP (hsCRP).
  • Gemcabene decreases the expression level of apolipoprotein C-III (apoC-III) mRNA likely resulting in decreased apoC-III protein production.
  • Gemcabene reduction in apoC-III increases VLDL-remnant clearance and enhances lipoprotein lipase activity, with the overall effect of reducing VLDL particle number and production of low-density lipoprotein (LDL).
  • apoC-III apolipoprotein C-III
  • apoC-II Reduction of apoC-II is also associated with increase clearance of TG-rich lipoproteins, however its reduction is also associated with decreased activation of lipoprotein lipase. Therefore, some reduction in apoC-II is expected to decrease plasma TG, however, too much reduction in apoC-II is expected to inhibit activation of lipoprotein lipase and impede the reduction of plasma TG. In primary rat hepatocytes, gemcabene markedly blocked radiolabeled acetate incorporation into both TG and cholesterol. Cytoplasmic acetylCoA carboxylase (ACC1) is the rate-limiting step in de novo fatty acid synthesis that catalyzes the conversion of acetylCoA to malonylCoA.
  • ACC1 Cytoplasmic acetylCoA carboxylase
  • Gemcabene's inhibition of human recombinant ACC1 enzymatic activity suggests it may block this rate-limiting step of de novo fatty acid synthesis.
  • gemcabene reduced hepatic ACC1 mRNA levels.
  • gemcabene may have an effect on inflammation by reducing CRP mRNA production and decreasing CRP.
  • gemcabene's mechanism of action should lower several parameters (atherogenic particles [VLDL, VLDL remnants and LDL] and inflammation) associated with the pathology of metabolic syndrome.
  • Gemcabene targets multiple pathways and should be helpful in treating obesity symptoms and lipodystropy symptoms.
  • Lipodystrophy can generally be classified on the basis of the extent or pattern of fat loss (generalized or partial) as well as whether the disease is genetic (i.e. the tendency to lose fat is present at birth) or acquired (the loss of fat occurs later in life).
  • the major lipodystrophy subtypes are congenital generalized lipodystrophy (CGL), familial partial lipodystrophy (FPL), and acquired generalized lipodystrophy (AGL).
  • CGL congenital generalized lipodystrophy
  • FPL familial partial lipodystrophy
  • AGL acquired generalized lipodystrophy
  • Human immunodeficiency virus (HIV)- associated lipodystrophy has been categorized as a type of AGL. There is more than one genetic form of lipoatrophy.
  • LMNA lamin A/C
  • FPL familial partial lipodystrophy
  • Individuals with Dunnigan's FPL are born with a normal fat distribution, but at puberty, they develop progressive subcutaneous extremity and truncal fat loss, with sparing of visceral and head and neck adipose tissue.
  • a different chromosomal location (9q34) has also been linked to a disease gene for congenital generalized lipodystrophy).
  • Congenital generalized lipodystrophy is a recessive disorder characterized by a near complete absence of adipose tissue from birth, insulin resistance, hypertriglyceridemia and acanthosis nigricans.
  • HAART highly active antiretroviral therapy
  • thiazolidinediones which are PPARy (peroxisome proliferator activated receptor gamma) agonists. While thiazolidinediones are appealing because they promote both adipocyte differentiation and insulin sensitivity, patients receiving thiazolidinediones are usually managed with combination therapy, including high dose insulin, oral hypoglycemic agents (e.g. metformin and thiazolidinediones), and lipid-lowering drugs, (e.g., fibrates and statins).
  • PPARy peroxisome proliferator activated receptor gamma
  • statins rosiglitazone and pioglitazone
  • patients are also treated with fibrates, niacin and sometimes statins.
  • treatment of these patients with statins is usually not an option as they are generally intolerant of statins.
  • a variety of genetically engineered animal models for lipoatrophy have been developed and tested. These models, however, provide conflicting results as to the sensitivity of these animals to treatment with leptin. For example, in one transgenic mouse model, which expresses a truncated nuclear version of SREBP-1 c and mimics the features of congenital generalized lipodystrophy having insulin resistance and markedly low adipose tissue, continuous systemic infusion of leptin overcame the resistance of the mice to insulin.
  • transgenic mouse which expresses the A-ZIP/F-1 gene and characterized by lack of fat tissue, severe resistance to insulin, diabetes, and greatly reduced serum leptin levels, failed to respond to leptin at similar doses and were minimally effective at higher doses. Any efficacy with leptin also diminished with age of the animal. Furthermore, although insulin resistance was overcome with leptin in the SREBP-lc transgenic mice, reversal of lipodystrophy was not observed.
  • Familial partial lipodystrophy is a rare genetic disorder characterized by selective, progressive loss of body fat (adipose tissue) from various areas of the body.
  • Subcutaneous fat is the fatty or adipose tissue layer that lies directly beneath the skin. In most cases, adipose tissue loss begins during puberty. FPL can be associated with a variety of metabolic abnormalities. The extent of adipose tissue loss usually determines the severity of the associated metabolic complications.
  • FPL FPL type 1
  • FPL type 2 Unnigan lipodystropy
  • FPL type 3 FPL type 4
  • FPL type 5 FPL type 5.
  • the compound of formula I or formula II is administered at a dose from about 25 mg to about 900 mg daily.
  • the dose of gemcabene is 25 mg, 50 mg, 75 mg, 150 mg, 300 mg, 450 mg, 600 mg or 900 mg.
  • the dose of gemcabene is 150 mg, 300 mg, 600 mg or 900 mg.
  • the dose of gemcabene is 300 mg, 600 mg or 900 mg. In some embodiments the daily dose of gemcabene is 25 mg, 50 mg, 75 mg, 150 mg, 300 mg, 450 mg, 600 mg or 900 mg. In some embodiments the daily dose of gemcabene is 150 mg, 300 mg, 600 mg or 900 mg. In some embodiments the daily dose of gemcabene is 300 mg, 600 mg or 900 mg.
  • the compound of formula I or formula II may be administered 1, 2, 3, or 4 times per day.
  • the gemcabene is administered 1 or 2 times a day. More preferably gemcabene is administered 1 time per day.
  • the compound is for lower apoC-II, apoC-III, modulate apoE, improve insulin sensitivy, improve obesity symptoms, and to treat subjects with congenital or ac uired lipodystrophy, in particular FPL, is a compound of formula III
  • n is an integer from 0 to 5;
  • n is an integer from 3 to 7;
  • X is -(CH 2 )z-, -0-, -CH(OH)-, CH(CH 2 OH)-, -NH- or -S-, wherein z is an integer from
  • each occurrence of R 1 and R 2 is independently (Ci-C6)alkyl, (C 2 -C6)alkenyl, (C 2 - C 6 )alkynyl, phenyl, benzyl, or R 1 and R 2 and the carbon to which they are both attached are taken together to form a (C3-Cv)cycloakyl group;
  • each occurrence of R 11 and R 12 is independently (Ci-C 6 )alkyl, (C2-C 6 )alkenyl, (C 2 - C 6 )alkynyl, phenyl, benzyl, or R 11 and R 12 and the carbon to which they are both attached are taken together to form a (C3-Cv)cycloakyl group;
  • each occurrence of Y 1 and Y 2 is independently (Ci-C 6 )alkyl, OH, COOH, COOR 3 ;
  • R 3 is (Ci-C 6 )alkyl, (C2-C 6 )alkenyl, (C2-C 6 )alkynyl, phenyl, or benzyl and is
  • a first embodiment of the present invention provides a method for increasing insulin sensitivity in a patient in need thereof, the method comprising administering to the patient an effective amount of mpound of formula (I):
  • n and m are each independently the integer 3, 4, 5, or 6.
  • a second embodiment of the present invention provides a method for decreasing blood glucose levels in a patient in need thereof, the method comprising administering to the patient an effective am nt of a compound of formula (I):
  • n and m are each independently the integer 3, 4, 5, or 6.
  • a third embodiment of the present invention provides a method for decreasing
  • HbAlc levels in a patient in need thereof comprising administering to the patient an effective amount of a c mpound of formula (I):
  • n and m are each independently the integer 3, 4, 5, or 6.
  • a fourth embodiment of the present invention provides a method for increasing the glucose disposal rate in a patient in need thereof, the method comprising administering to the patient an effective am nt of a compound of formula (I):
  • n and m are each independently the integer 3, 4, 5, or 6.
  • the fifth embodiment is the method according to any one of embodiments 1-4, wherein m and n are the same integer.
  • the sixth embodiment is the method according to any one of embodiments 1-4, wherein m and n are different integers.
  • the seventh embodiment is the method according to any one of embodiments 1-4, wherein m and n are each 5.
  • the eighth embodiment is the method according to any one of embodiments 1-4, wherein the compound of formula (I) is
  • the ninth embodiment is the method according to embodiment 8 wherein the compound is the calcium salt of gemcabene.
  • the tenth embodiment is the method according to embodiment 8 wherein the compound is gemcabene, calcium.
  • the eleventh embodiment is the method according to any one of embodiments 1-
  • the twelfth embodiment is the method of embodiment 11, wherein the dose is 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 300 mg, 450 mg, 600 mg, or 900 mg.
  • the thirteenth embodiment is the method of embodiment 12, wherein the dose is
  • the dose administered is 300 mg, 600 mg or 900 mg.
  • the fourteen embodiment is the method according to any one of embodiments 8-
  • the fifteenth embodiment is the method according to any one of embodiments 1-
  • the sixteenth embodiment is the method according to any one of embodiments 1-
  • the seventeenth embodiment is the method according to any one of embodiments
  • the eighteenth embodiment is the method according to any one of embodiments
  • the nineteenth embodiment is the method according to any one of embodiments
  • the twentieth embodiment is the method according to any one of embodiments.
  • the twenty-first embodiment is the method according to any one of embodiments
  • the twenty-second embodiment is the method according to embodiment 21, wherein the additional agent is a glycemic control agent.
  • the twenty-third embodiment is the method according to embodiment 22, wherein the glycemic control agent is administered orally.
  • the twenty-fourth embodiment is the method according to embodiment 22, wherein the glycemic control agent is administered subcutaneously.
  • the twenty-fifth embodiment is the method according to embodiment 22, wherein the glycemic control agent is administered intramuscularly.
  • the twenty-sixth embodiment is the method according to embodiment 22, wherein the glycemic control agent is administered intravenously.
  • the twenty-seventh embodiment is the method of embodiment 22, where the glycemic control agent comprises one of more of insulin, a modified insulin, a short acting insulin, a long acting insulin, a basal insulin, a bolus insulin, a glucagon-like protein 1 agonist, a meglitinide, a DPP-IV inhibitor, metformin, a sulfonylurea, an alpha-glucosidase inhibitor, a sodium glucose co-transporter 2 (SGLT2) inhibitor.
  • the glycemic control agent comprises one of more of insulin, a modified insulin, a short acting insulin, a long acting insulin, a basal insulin, a bolus insulin, a glucagon-like protein 1 agonist, a meglitinide, a DPP-IV inhibitor, metformin, a sulfonylurea, an alpha-glucosidase inhibitor, a sodium glucose co-transporter 2 (SGLT2) inhibitor.
  • the twenty-eighth embodiment is the method of embodiment 22, where the glycemic control agent is a thiazolidinedione.
  • the twenty-ninth embodiment is the method according to any one of
  • the thirtieth embodiment is the method of embodiment 22, wherein the dose of the glycemic control agent administered to a patient in combination with a compound of Formula (1) is lower than the dose of the glycemic control agent is administered without the compound of Formula (l)to achieve a similar dynamic, biological or glycemic control effect.
  • the thirty-first embodiment is the method for treating lipodystrophy, comprising administering to a patient in need thereof a compound of formula II
  • n, and m independently are integers from 2 to 9; each occurrence of Ri, R 2 , R 3 , and R 4 is independently Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or Ri and R 2 taken together with the carbon to which they are attached form a carbocyclic ring having from 3 to 6 carbons, or R 3 and R 4 together with the carbon to which they are attached, form a carbocyclic ring having from 3 to 6 carbons; Yi and Y 2 independently are -COOH, -CHO, tetrazole, and -COOR5; R5 is Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl; or an ester, or a hydrate, or a salt thereof.
  • the thirty-second embodiment is the method of embodiment 31, wherein the compound of formula II is
  • compound of formula II is or an ester, or a hydrate or a salt thereof.
  • the thirty-forth embodiment is the method of any one of embodiments 31-33, wherein the lipodystrophy is a familial partial lipodystrophy.
  • the thirty-fifth embodiment is the method of any one of embodiments 31-34, wherein the compound of formula II is administered with an additional agent.
  • the thirty-sixth embodiment is the method of embodiment 35, wherein the additional agent is leptin, a leptin analog, a leptin derivative, insulin, a fibrate, a
  • Eicosapentenoic acid a prodrug of Eicosapentanoic acid, metformin, a statin, an oral hypoglycemic agent, an injectable hypoglycemic agent, an apo C-III antisense molecule, an apoC-III DNAi, an apoC-III siRNA, fish oil, a PCSK9 inhibitor, a cholesterol absorption inhibitor, a bile acid sequestrant, an appetite suppressing agent, or an anti-hypertensive agent.
  • the thirty-seventh embodiment is the method of embodiment 36, wherein the fibrate is gemfibrozil, fenofibric acid, bezafibrate, or clofibrate.
  • the thirty-eigth embodiment is the method of embodiment 36, wherein the thiazolidinedione is rosiglitazone or pioglitazone.
  • the thirty-ninth embodiment is the method of embodiment 36, wherein the statin is atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, or pitavastatin.
  • the fortieth embodiment is the method of embodiment 36, wherein the cholesterol absorption inhibitor is ezetimibe.
  • the forty-first embodiment is the method of embodiment 36, wherein the leptin analog is metreleptin.
  • the forty-second embodiment is the method of embodiment 36, wherein the antihypertensive agent is a calcium channel blocker, an ACE inhibitor, a beta-blocker, an angiotensin II receptor blocker, an alpha-2 receptor agonist, a vasodilator or a diuretic.
  • the antihypertensive agent is a calcium channel blocker, an ACE inhibitor, a beta-blocker, an angiotensin II receptor blocker, an alpha-2 receptor agonist, a vasodilator or a diuretic.
  • the forty-third embodiment is the method of embodiment 36, wherein the additional agent is an oral hypoglycemic agent and the oral agent is a biguanide , a sulfonylurea, a thiazolidinedione, a meglitimide, a D-phenylalanine derivative, an alpha-glucosidase inhibitor, a bile acid sequestrant, an insulin secretagogue, a DPP-4 inhibitor, or a combination thereof.
  • the additional agent is an oral hypoglycemic agent and the oral agent is a biguanide , a sulfonylurea, a thiazolidinedione, a meglitimide, a D-phenylalanine derivative, an alpha-glucosidase inhibitor, a bile acid sequestrant, an insulin secretagogue, a DPP-4 inhibitor, or a combination thereof.
  • the forty-forth embodiment is the method of embodiment 36, wherein the additional agent is an injectable hypoglycemic agent and the injectable hypoglycemic agent is leptin, a leptin analogue, a leptin derivative, insulin, an insulin analog, an insulin derivative, amylin, a synthetic amylin, an amylin analogue, a glucagon-like peptide- 1 (GLP-1), a GLP-1 analog, or a GLP-1 derivative, or a combination thereof.
  • the additional agent is an injectable hypoglycemic agent and the injectable hypoglycemic agent is leptin, a leptin analogue, a leptin derivative, insulin, an insulin analog, an insulin derivative, amylin, a synthetic amylin, an amylin analogue, a glucagon-like peptide- 1 (GLP-1), a GLP-1 analog, or a GLP-1 derivative, or a combination thereof.
  • the forty-fifth embodiment is the method of embodiment 44, wherein the amylin analogue is pramlintide or exenatide.
  • the forty-sixth embodiment is the method of any one of 31-45, wherein the insulin sensitivity of the patient is increased.
  • the forty-seventh embodiment is the method of any one of 31-45, wherein the patient requires less insulin to maintain glycemic control after administration of the compound of formula II when compared with the amount of insulin required prior to administration of the compound of formula II or an ester, or a hydrate, or a salt thereof.
  • the forty-eighth embodiment is a method of lowering the level of plasma apoC-III in a patient with FPL comprising administering a compound of formula II or an ester, or a hydrate, or a salt thereof.
  • the forty-ninth embodiment is a method of lowering the level of plasma triglyceride in a patient with FPL comprising administering a compound of formula II or an ester, or a hydrate, or a salt thereof.
  • the fiftieth embodiment is a method of preventing pancreatitis in a patient with FPL comprising administering a compound of formula II or an ester, or a hydrate, or a salt thereof.
  • the fifty-first embodiment is the method of reducing the incidence of pancreatitis in a patient with FPL comprising administering a compound of formula II or an ester, or a hydrate, or a salt thereof.
  • the fifty-second embodiment is a method of lowering plasma VLDL-C in a patient with FPL comprising administering a compound of formula II or an ester, or a hydrate, or a salt thereof.
  • the fifty-third embodiment is a method of lowering plasma LDL-C in a patient with FPL comprising administering a compound of formula II or an ester, or a hydrate, or a salt thereof.
  • the fifty-fourth embodiment is a method of elevating plasma HDL-C in a patient with FPL comprising administering a compound of formula II or an ester, or a hydrate, or a salt thereof.
  • the fifty-fifth embodiment is a method of lowering non-HDL-C in a patient with
  • FPL comprising administering a compound of formula II or an ester, or a hydrate, or a salt thereof.
  • the fifty-sixth embodiment is a method of lowering inflammation in a patient with FPL comprising administering a compound of formula II or an ester, or a hydrate, or a salt thereof.
  • the fifty-seventh embodiment is a method of treating, reducing, and prevention of medical complications in a patient with FPL comprising administering a compound of formula II or an ester, or a hydrate, or a salt thereof.
  • the fifty-eighth embodiment is a method of treating, reducing, and prevention of cardiovascular disease in a patient with FPL comprising administering a compound of formula II or an ester, or a hydrate, or a salt thereof.
  • the fifty-ninth embodiment is a method of treating, reducing, and prevention of inflammatory conditions or disease in a patient with FPL comprising administering a compound of formula II or an ester, or a hydrate, or a salt thereof.
  • the sixtieth embodiment is a method of treating, reducing, and prevention of abnormal redistribution of body fat in a patient with FPL comprising administering a compound of formula II or an ester, or a hydrate, or a salt thereof.
  • the sixty-first embodiment is a method of treating, reducing, and prevention of body weight gain in a patient with FPL comprising administering a compound of formula II or an ester, or a hydrate, or a salt thereof.
  • the sixty-second embodiment is a method of treating, reducing, and prevention acanthosis nigricans in a patient with FPL comprising administering a compound of formula II or an ester, or a hydrate, or a salt thereof.
  • the sixty-third embodiment is a method of delaying the time of onset or the severity of symptoms of FPL in a patient with FPL comprising administering a compound of formula II or an ester, or a hydrate, or a salt thereof.
  • the sixty-forth embodiment is a method of treating, reducing the incidence of, or preventing hyperphagia in a patient with FPL comprising administering a compound of formula II or an ester, or a hydrate, or a salt thereof.
  • the sixty-fifth embodiment is the method of any one of embodiments 48-64, wherein the compound of formula II is administered with an additional agent.
  • the sixty-sixth embodiment is the method of embodiment 65, wherein the additional agent is leptin, a leptin analog, a leptin derivative, insulin, a fibrate, a
  • Eicosapentenoic acid a prodrug of Eicosapentenoic acid, metformin, a statin, an oral hypoglycemic agent, an injectable hypoglycemic agent, an apo C-III antisense molecule, an apoC-III DNAi, an apoC-III siRNA, fish oil, a PCSK9 inhibitor, a cholesterol absorption inhibitor, a bile acid sequestrant, an appetite suppressing agent, or an anti-hypertensive agent.
  • the sixty-seventh embodiment is the method of embodiment 66, wherein the fibrate is gemfibrozil, fenofibric acid, bezafibrate, or clofibrate.
  • the sixty-eighth embodiment is the method of embodiment 66, wherein the thiazolidinedione is rosiglitazone or pioglitazone.
  • the sixty-ninth embodiment is the method of embodiment 66, wherein the statin is atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, or pitavastatin.
  • the seventieth embodiment is the method of embodiment 66, wherein the cholesterol absorption inhibitor is ezetimibe.
  • the seventy-first embodiment is the method of embodiment 66, wherein the leptin is metreleptin.
  • the seventy-second embodiment is the method of any one of embodiments 31 or
  • the compound is a compound of formula II, wherein n is 2, or n is 3, or n is 4, or n is 5, or n is 6, or n is 7, or n is 8, or n is 9.
  • m is 2, or n is 3, or m is 4, or m is 5, or m is 6, or m is 7, or m is 8, or m is 9.
  • n and m are both 2, or n and m are both 3, or n and m are both 4, or n and m are both 5, or n and m are both 6, or n and m are both 7, or n and m are both 8, or n and m are both 9.
  • the seventy-third embodiment is the method of any one of embodiments 31 or 34-
  • Ri, R 2 , R 3 , and R 4 independently are Ci-C 6 alkyl. In some embodiments Ri, R 2 , R 3 , and R 4 are all Ci-C 6 alkyl. In some embodiments Ri, R 2 , R 3 , and R 4 independently are C 2 -C 6 alkenyl. In some embodiments Ri, R 2 , R 3 , and R 4 independently are C 2 -C 6 alkynyl. In some embodiments Ri, R 2 , R 3 , and R 4 are -CH 3 . In some embodiments Ri, R 2 , R 3 , and R 4 are -CH 2 CH 3 . In some embodiments Ri, R 2 , R 3 , and R 4 are -CH 2 CH 2 CH 3 .
  • Ri, R 2 , R 3 , and R 4 are all C 2 -C 6 alkenyl. In some embodiments Ri, R 2 , R 3 , and R 4 are all C 2 -C 6 alkynyl. In some embodiments Ri and R 2 taken together with the carbon to which they are attached form a carbocyclic ring having from 3 to 6 carbons. In other embodiments R 3 and R 4 together with the carbon to which they are attached, form a carbocyclic ring having from 3 to 6 carbons.
  • the seventy-forth embodiment is the method of any one of embodiments 31 or
  • Yi and Y 2 are both -CHO. In some embodiments Yi and Y 2 are both - tetrazole. In some embodiments Yi and Y 2 are both CH 2 (OH). In some embodiments Yi and Y 2 are both -COOR5 and R5 is Ci-C 6 alkyl. In some embodiments Yi and Y 2 are both -COOR5 and
  • R5 is C 2 -C 6 alkenyl. In some embodiments Yi and Y 2 are both -COOR5 and R5 is C 2 -C 6 alkynyl.
  • the seventy-fifth embodiment is the method of any one of embodiments 31 or 34-
  • the compound is a compound formula II, wherein n an m are the same integer, and Ri, R 2 , R 3 , and R 4 independently are Ci-C 6 alkyl.
  • the compound is a compound of formula I, wherein Yi and Y 2 are the same and are -COOH or -COOR5, and R5 is Ci-C 6 alkyl.
  • the compound is a compound formula II, wherein Yi and Y 2 are
  • COOH, Ri, R 2 , R 3 , and R 4 are methyl, and n and m are the same and are an integer selected from
  • n and m are the same and are 4 or 5. Most preferably n and m are 4.
  • the compound is a compound of formula II, wherein Yi and Y 2 are -
  • the compound is a compound of formula II, wherein Yi and Y 2 are -COOH, n and m are 4, Ri, R 2 , R 3 , and R 4 are methyl.
  • the compound is a compound of formula II, wherein Yi and Y 2 are -COOH, n and m are 5, Ri, R 2 , R3, and R 4 are methyl.
  • the compound is a compound of formula II, wherein Yi and Y 2 are -
  • the compound is a compound of formula II, wherein Yi and Y 2 are -CH2OH, n and m are 4 and Ri, R 2 , R3, and R 4 are methyl.
  • the seventy-sixth embodiment is the method of any one of embodiments 31 or
  • the seventy-seventh embodiment is the method of any one of embodiments 31 or
  • the seventy-eighth embodiment is the method of any one of embodiments 31 or
  • compound of formula II is the hydrate of the monocalcium salt, as described in U.S. Patent No. 7,141,608 which is hereby incorporated in its entirety.
  • the structure of the hydrate of the monocalcium salt of gemcabene is:
  • x is an integer from 1 to 10.
  • the seventy-ninth embodiment is the method of any one of embodiments 31 or
  • the eightieth embodiment is the method according to any one of embodiments 31-
  • compound is administered to the patient in a dose from about 25 mg to about 900 mg.
  • the eight-first embodiment is the method of embodiment 80, wherein the dose is
  • the eight-second embodiment is the method of embodiment 80, wherein the dose is 100 mg, 300 mg, 450 mg, 600 mg, or 900 mg. Or the dose administered is 300 mg, 600 mg or 900 mg.
  • the eight-third embodiment is the method according to any one of embodiments
  • Metabolic syndrome associated with type 2 diabetes includes low HDL, elevated VLDL-C and TGs, insulin resistance and elevated glucose. As the metabolic syndrome condition develops temporally, a transition period is sustained whereby increasing amounts of insulin are produced to maintain baseline glucose levels. Animals were evaluated in two separate strains of female obse Zucker rats from separate vendors, Genetic Models and Charles River Laboratories. These rat models are deficient in the leptin receptor and develop age-dependent obesity and diabetes. Animals were treated once daily with either a carboxymethyl cellulose/Tween 20 vehicle or the indicated amounts of gemcabene in this vehicle. Gemcabene produced significant changes of the evaluated variables.
  • Plasma insulin was determined by a rat insulin radioimmunoassay (RI13K, Linco Co, St Louis, Missouri). Apolipoproteins were determined by electroimmuno assay. Grundy SM, Am J Cardiol 1998;81 : 18B-25B. Plasma triglycerides and cholesterol were determined enzymatically. Auerbach BJ, et al., J Lipid Res 1995;36:2541-51. Plasma lipoprotein cholesterol distributions were determined by high- performance gel-filtration chromatography with post-column detection. Kieft KA, et al., J Lipid Res 1991;32:859-66.
  • Figures 1 A (Genetic Models) and IB (Charles River Laboratories) show the increase in plasma total cholesterol levels, over the 32 day sampling period.
  • Figures 2A (Genetic Models) and 2B (Charles River Laboratories) show the decrease in plasma triglycerides levels, over the 32 day sampling period.
  • Figures 3 A (Genetic Models) and 3B (Charles River Laboratories) show the changes in plasma non-HDL-cholesterol levels, over the 32 day sampling period.
  • Figures 4A (Genetic Models) and 4B (Charles River Laboratories) show the increase in plasma FIDL-cholesterol levels over the 32 day sampling period.
  • Figures 5 A (Genetic Models) and 5B (Charles River Laboratories) show the increased ratio of plasma FIDL-C to plasma non-HDL-C over the 32 day sampling period.
  • Plasma levels of select apolipoproteins were evaluated at the end of 32 day treatment and compared to the levels in the control treated animals.
  • Figures 6A (Genetic Models) and 6B (Charles River Laboratories) show the changes in plasma apolipoprotein A-I, E, C-II and C-III on the 32nd day of sampling.
  • FIG. 10A (Genetic Models) and 10B (Charles River Laboratories) show the changes in body weight over the 32 day sampling period.
  • Figures 11 A (Genetic Models) and 1 IB (Charles River Laboratories) show the changes in liver weight on day 32nd day of sampling.
  • Figures 12A (Genetic Models) and 12B (Charles River Laboratories) show the percent liver weight to body weight on day 32nd day of sampling.
  • Gemcabene beneficially modified the lipoprotein profile in these models of NIDDM.
  • the insulin sensitizing effect of gemcabene was also evident in both Zucker rat models, but there was no change in the glucose tolerance.
  • the above studies are carried out in rats and do not directly provide evidence of the behavior of gemcabene in humans.
  • GDR glucose disposal rate
  • the euglycemic hyperinsulinemic clamp also known as a hyperinsulinemic clamp, requires acutely raising the insulin level by a continuous infusion of insulin. Meanwhile, the plasma glucose concentration is held constant at basal levels by a variable glucose infusion. When the steady-state is achieved, the glucose infusion rate equals glucose uptake by all the tissues in the body and is therefore a measure of tissue insulin sensitivity.
  • Subjects were enrolled in a double-blind, placebo-controlled, multiple-dose, multicenter study. Subjects of any race and either gender were required to meet the following criteria in order to be eligible to participate in the study: age >18 years; body mass index between 30 and 40 kg/m2; fasting glucose ⁇ 126 mg/dL; and be in good health. Fifty-three subjects (37 male, 16 female) ranging in age from 26 to 63 years entered the study and were randomized to receive either 900 mg gemcabene or placebo once daily on Day 2 through Week 4. A hyperinsulinemic clamp study was performed on Day 1 and one hour following the last dose of gemcabene at the end of the fourth week of treatment. Fifty subjects completed the study. Table 7
  • the criteria for evaluation were efficacy, pharmacokinetic/pharmacodynamics, and safety.
  • the primary efficacy measure was insulin sensitivity as defined by average glucose disposal rate during the last 30 minutes of a 3-hour euglycemic hyperinsulinemic clamp study.
  • Insulin sensitivity was measured with the 3-hour euglycemic hyperinsulinemic clamp technique. Before each clamp study, subjects are required to fast for 10 to 12 hours overnight. A polyethylene cannula was inserted into an antecubital vein for the infusion of test substances. A second catheter was inserted retrogradely into an ipsilateral wrist vein on the dorsum of the hand for blood sampling and the hand kept in a heated box at 65°C.
  • insulin is administered as a primed continuous infusion at the rate of 40 mU/m 2 /minute for 180 minutes.
  • the plasma glucose concentration was measured every five minutes after the start of the insulin infusion, and a variable infusion of 20% glucose was adjusted based on the negative feedback principle to maintain the plasma glucose level at 90 mg/dL.
  • Plasma samples were collected every 15 minutes from 0 to 150 minutes and every 5 to 10 minutes from 150 to 180 minutes for determination of plasma glucose.
  • a wash-out period was required for eligible subjects taking any lipid-regulating therapies or supplements, with the exception of atorvastatin (10, 20, 40, or 80 mg QD), rosuvastatin (5, 10, 20, or 40 mg QD), simvastatin (20 or 40 mg QD), or ezetimibe 10 mg QD.
  • atorvastatin 10, 20, 40, or 80 mg QD
  • rosuvastatin 5, 10, 20, or 40 mg QD
  • simvastatin (20 or 40 mg QD
  • ezetimibe 10 mg QD for subjects who required a wash-out period, the Pre-Screening Visit was their first study visit and occurred prior to the Screening Visit based on the duration of the wash-out period required. The duration of the wash-out period was dependent upon the status of the subject's current lipid- regulating therapy.
  • PCSK9 inhibitors required an 8-week wash-out period
  • fibrates required a 6-week wash-out period
  • niacin or other lipid-regulating therapies such as bile acid sequestrants required a 4-week wash-out period prior to the Screening Visit.
  • Subjects were randomized on Day 1 in a 1 : 1 ratio to the following treatment groups placebo or gemcabene 600 mg. Subjects were stratified by statin intensity (high-intensity dosage; moderate-intensity dosage) and Type 2 diabetes (yes or no). The first dose of study drug was administered at the site on Day 1. On days with a scheduled office visit with blood sample collection, subjects remained fasted (at least 10 hours) and should not have taken gemcabene until after the blood samples were collected. For days when the subject self-dosed, subjects were instructed to take study drug at the same time in the morning with a full glass (8 ounces) of water either with or without food.
  • Post-randomization clinic visits occurred at Week 2, Week 4, Week 8, and Week 12.
  • the Follow-up Visit occurred 4 weeks ( ⁇ 3 days) after the last dose of study drug.
  • statin-intensity stratum (moderate and high), for diabetic subjects, and for subjects with and without mixed dyslipidemia. Explicitly, the following characteristics were summarized: 1) sex (male, female); 2) menopausal status for females, 3) race, 4) ethnicity; 5) age; 6) height; 7) weight; 8) and BMI.
  • Age integer ([Screening Visit date - date of birth]/365.25).
  • BMI was calculated using the following formula:
  • BMI (body weight in kilograms)/(height in meters) 2 .
  • the primary efficacy endpoint (percent change from baseline to Week 12 in LDL-C) was analyzed using analysis of covariance (ANCOVA) and the full analysis set (FAS) population.
  • ANCOVA analysis of covariance
  • FAS full analysis set
  • the null hypothesis tested was that there was no difference in the expected percent change from baseline to Week 12 in LDL-C between the active treatment (subjects treated with gemcabene 600 mg) and placebo (subjects treated with placebo) groups after adjusting for baseline statin-intensity stratum, baseline diabetes status, and baseline LDL-C.
  • LSM least-squares mean
  • CI 95% confidence interval
  • Baseline for TC non-HDL-C, HDL-C and VLDL-C were defined similarly to baseline for LDL-C.
  • Baseline for fasting lipoproteins, hsCRP, serum Amyloid A (SAA), fibrinogen, adiponectin, fasting plasma glucose (FPG), fasting insulin, and serum PCSK9 were defined as the value from pre-dose Day 1/Visit Tl .
  • Baseline for HbAlc was the value from the first visit (Pre-Screening or Screening Visit).
  • the secondary efficacy endpoints that were binary were analyzed using logistic regression.
  • the logistic regression model included the indicator for meeting the criteria (eg, achieving a LDL-C reduction from baseline of > 10% at Week 12) as the dependent variable; and randomized treatment group, baseline statin-intensity stratum, baseline diabetes status, and baseline LDL-C as independent factors.
  • the output from each logistic regression model included the odds ratio (OR), 95% CI, and the associated P-value.
  • GEM-301 was designed to determine the safety and additional LDL-C lowering of gemcabene 600 mg over 12 weeks in 105 subjects with LDL-C > 100 mg/dL and TG ⁇ 500 mg/dL while on high and moderate-intensity stable background statin therapy +/- ezetimibe.
  • a total of 105 subjects were randomized (55 subjects [52.4%] and 50 subjects [47.6%] in the moderate-intensity and high-intensity statin stratums, respectively) with a median age of 63.0 years, the majority female (53.3%) and white (77.1%), a mean BMI of 30.6 kg/rrn, and a mean baseline LDL-C of 130.2 mg/dL.
  • a post-hoc subpopulation analysis was conducted whereby the study population was segregated into two groups, subjects with BMI below 30 and subjects with BMI equal to or greater than 30.
  • the subject data was evaluated for select lipids, lipoproteins, apolipoprotein B, and high sensitivity C-reative protein, (hs-CRP) an indication of inflammation.

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Abstract

L'invention concerne des procédés de traitement de symptômes de l'obésité, de troubles métaboliques ou de la lipodystropie par administration de carboxyalkyléthers, en particulier de l'acide 6,6'-oxybis-(2,2'-diméthylhexanoïque) ou d'un ester, d'un hydrate ou d'un sel de celui-ci.
PCT/US2018/021093 2017-03-06 2018-03-06 Effet de carboxyalkyléthers sur les symptômes de l'obésité et la lipodystropie WO2018165120A1 (fr)

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Citations (4)

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US5648387A (en) * 1995-03-24 1997-07-15 Warner-Lambert Company Carboxyalkylethers, formulations, and treatment of vascular diseases
US20100048545A1 (en) * 2006-03-22 2010-02-25 Innodia Inc. Compounds and Compositions for Use in the Prevention and Treatment of Disorders of Fat Metabolism and Obesity
US20130116234A1 (en) * 2011-11-04 2013-05-09 Hoffmann-La Roche Inc. Aryl-quinoline derivatives
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US5648387A (en) * 1995-03-24 1997-07-15 Warner-Lambert Company Carboxyalkylethers, formulations, and treatment of vascular diseases
US20100048545A1 (en) * 2006-03-22 2010-02-25 Innodia Inc. Compounds and Compositions for Use in the Prevention and Treatment of Disorders of Fat Metabolism and Obesity
US20130116234A1 (en) * 2011-11-04 2013-05-09 Hoffmann-La Roche Inc. Aryl-quinoline derivatives
US20160137584A1 (en) * 2014-11-14 2016-05-19 Gemphire Therapeutics Inc. PROCESSES AND INTERMEDIATES FOR PREPARING a,w -DICARBOXYLIC ACID-TERMINATED DIALKANE ETHERS

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HAKEEM ET AL.: "HIV-associated lipodystrophy - a new metabolic syndrome", THE BRITISH JOURNAL OF DIABETES & VASCULAR DISEASE, vol. 8, 1 May 2008 (2008-05-01), pages 129 - 134, XP055559823 *
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