WO2015110949A1 - Imatinib as cholesterol decreasing agent - Google Patents
Imatinib as cholesterol decreasing agent Download PDFInfo
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- WO2015110949A1 WO2015110949A1 PCT/IB2015/050395 IB2015050395W WO2015110949A1 WO 2015110949 A1 WO2015110949 A1 WO 2015110949A1 IB 2015050395 W IB2015050395 W IB 2015050395W WO 2015110949 A1 WO2015110949 A1 WO 2015110949A1
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- imatinib
- cholesterol
- treatment
- pharmaceutically acceptable
- acceptable salt
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- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 title claims abstract description 306
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- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 1
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- AZQWKYJCGOJGHM-UHFFFAOYSA-N para-benzoquinone Natural products O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
- the present invention relates to methods of treatment of hyperlipidemia.
- it relates to the treatment of human patients diagnosed with hypercholesterolemia and/or hypertriglyceridemia.
- Hyperlipidemic patients typically show high blood levels of total cholesterol due to high levels of the "bad” low density lipoprotein cholesterol (LDL-C) and high levels of the "bad” triglycerides. If at the same time those patients have low levels of the "good” high density lipoprotein cholesterol (HDL-C) they have a high risk to suffer from cardiovascular or cerebrovascular diseases.
- LDL-C low density lipoprotein cholesterol
- HDL-C high density lipoprotein cholesterol
- the LDL-C may deposit together with other substances at the inner walls of the arteries forming a thick and hard plaque which narrows those blood vessels and makes them less flexible.
- the arteries are narrowed and lost their flexibility (a condition which is called atherosclerosis) there is a risk that they are entirely blocked by clot formation and that the heart and the brain is not any longer feeded with blood resulting the patient being affected by heart attack or stroke. Due to the cardio- and cerebrovascular risks associated with high blood levels of LDL-C, this type of cholesterol is often colloquially referred to as "bad" cholesterol.
- HDL-C in contrast, is often called the "good” cholesterol as it is believed to remove excess of cholesterol from the arteries and to transport it to the liver where the cholesterol is cleared from the human body (a process also referred to as reverse cholesterol transport, RCT). By doing so, the HDL-C may prevent the formation of further arterial plaque and, thus, acts as cardioprotective agent. This is why the HDL-C is often colloquially referred to as "good” cholesterol.
- HDL-C promotes angiogenesis and promotes endothelial repair processes, acts as anti-thrombotic, anti-oxidant and anti-diabetic, inhibits vascular inflammation and enhances endothelial repair.
- High blood levels of triglycerides (TG) especially combined with high levels of LDL-C and low levels of HDL-C, seem to accelerate the formation of arterial plaque and are therefore seen as another cardio- and cerebrovascular risk factor.
- total cholesterol which includes all types of cholesterol in the blood of a patient, e.g. HDL-C, LDL-C, VeryLDL-C (VLDL-C).
- TC total cholesterol
- LDL-C Low-density lipoprotein
- VLDL-C VeryLDL-C
- the ratio of TC / HDL-C total cholesterol divided by HDL cholesterol
- Choesterol ratio is generally and herein referred to as “cholesterol ratio" and is also used as parameter for guidance in treatment of hyperlipidemia.
- the ENESTnd study was a clinical trial that evaluated patients with chronic myelogenous leukemia in chronic phase, previously untreated.
- 283 patients were treated with imatinib at the dose of 400 mg, orally, daily administered in an outpatient setting.
- patients treated with imatinib were found to increase high density lipoprotein cholesterol (HDL-C), decrease total cholesterol (TC) and triglycerides (TG), and slightly decrease low density lipoprotein cholesterol (LDL-C) and hemoglobin A1 c (HbA1 c). These changes occurred over the first 6 months of treatment with imatinib. These changes are predicted to reduce cardiovascular risks.
- HDL-C high density lipoprotein cholesterol
- TC decrease total cholesterol
- TG triglycerides
- LDL-C low density lipoprotein cholesterol
- HbA1 c hemoglobin A1 c
- cardiovascular events or arterial occlusive events consisting of ischemic cardiac events, ischemic cerebrovascular events, and peripheral arterial occlusive disease: after 5 years, only 6 patients developed cardiovascular events (5 patients developed ischemic cardiac events, and 1 developed an ischemic cerebrovascular event).
- the number of cardiovascular events occurring after 5 years of observation in the patients treated with imatinib appears to be lower than the background number of events expected in patients with similar demographic characteristics and cardiovascular risk factors over that time period.
- the increase in HDL-C without a concurrent increase of TC means that the TC/HDL-C ratio decreases.
- the increase in HDL-C, the decrease in LDL-C triglyceride concentration, and in addition, a slight decrease in HbA1 C may explain the notably low incidence of cardiovascular events (CVEs) in the patients treated with imatinib.
- CVEs cardiovascular events
- the present invention provides imatinib or any pharmaceutically acceptable salt thereof for use as cholesterol ratio (total cholesterol / HDL cholesterol) decreasing agent.
- the present invention provides imatinib or any pharmaceutically acceptable salt thereof for use as cholesterol ratio (total cholesterol / HDL cholesterol) decreasing agent in the treatment of hyperlipidemia, hypercholesterolemia or
- the present invention provides imatinib or any pharmaceutically acceptable salt thereof for use according to the first or second aspect wherein Imatinib is used as cholesterol ratio (total cholesterol / HDL cholesterol) decreasing agent and as HDL cholesterol increasing agent.
- the present invention provides imatinib or any pharmaceutically acceptable salt thereof for use according to the first or second aspect wherein Imatinib is used as cholesterol ratio (total cholesterol / HDL cholesterol) decreasing agent and as HDL cholesterol increasing agent and as triglycerides decreasing agent.
- the present invention further provides imatinib or any pharmaceutically acceptable salt thereof for use according to any of the above mentioned aspects wherein the cholesterol ratio (total cholesterol / HDL cholesterol) latest after 12 months, preferably latest after 6 months, from start of treatment with imatinib is decreased by at least by 10%, preferably by at least 20%, compared to the cholesterol ratio at start of the treatment with imatinib.
- the cholesterol ratio total cholesterol / HDL cholesterol
- the present invention further provides imatinib or any pharmaceutically acceptable salt thereof for use according to any of the above mentioned aspects wherein the cholesterol ratio decrease is further characterized by an increased level of the HDL cholesterol and by unchanged or decreased levels of LDL, triglycerides, and total cholesterol latest after 12 months, preferably latest after 6 months, from start of the treatment with imatinib compared to the levels at start of the treatment with imatinib.
- the drug substance Imatinib is present in its free form or in the form of any pharmaceutically acceptable salt salt, complex, co-crystal, hydrate or solvate thereof.
- imatinib is present in its free base form.
- Imatinib is present as mesylate salt; in yet another embodiment as mono-mesylate salt; in yet another embodiments as mono-mesylate salt in its amorphous form as described in WO2008/154262 and US 2010/0178336 which are incorporated herein as references or in its crystalline alpha form or crystalline beta form as described in WO 99/03854 and US 7,151 ,106 which are incorporated herein as references, preferably in the crystalline beta form.
- Imatinib is known to act as a tyrosine-kinase inhibitor and used in the treatment of cancers, particularly of Philadelphia chromosome-positive (Ph+) chronic myelogeous leukemia (CML) and gastrointestinal stromal tumors (GIST).
- the present invention provides Imatinib or any pharmaceutically acceptable salt thereof for use in the treatment of hyperlipidemia, hypercholesterolemia or hypertriglyceridemia.
- the present invention provides Imatinib or any pharmaceutically acceptable salt thereof for use in a method of treatment of hyperlipidemia, hypercholesterolemia or
- the present invention provides Imatinib or any pharmaceutically acceptable salt thereof for treating hyperlipidemia, hypercholesterolemia or hypertriglyceridemia.
- the present invention provides a method for the treatment of hyperlipidemia, hypercholesterolemia or hypertriglyceridemia in human patients in need of such treatment which comprises administering an effective amount of Imatinib or any pharmaceutically acceptable salt thereof.
- the present invention provides the use of Imatinib or any pharmaceutically acceptable salt thereof.
- hypercholesterolemia or hypertriglyceridemia are hypercholesterolemia or hypertriglyceridemia.
- the present invention provides a use comprising Imatinib or any pharmaceutically acceptable salt thereof for treating hyperlipidemia, hypercholesterolemia or hypertriglyceridemia patients.
- the present invention provides the use of Imatinib or any combination thereof.
- the present invention provides a medicament for the treatment of hyperlipidemia, hypercholesterolemia or hypertriglyceridemia comprising Imatinib or any pharmaceutically acceptable salt thereof.
- the present invention provides Imatinib or any pharmaceutically acceptable salt thereof for use in the treatment of hyperlipidemia, hypercholesterolemia or
- hypertriglyceridemia characterized in that the cholesterol ratio (total cholesterol / HDL cholesterol) latest after 12 months, preferably latest after 6 months, from start of treatment with imatinib is decreased by at least 10%, preferably by at least 20%, compared to the cholesterol ratio at start of said treatment.
- the present invention further provides Imatinib or any pharmaceutically acceptable salt thereof for use in a method of treatment of hyperlipidemia, hypercholesterolemia or hypertriglyceridemia, characterized in that the cholesterol ratio (total cholesterol / HDL cholesterol) latest after 12 months, preferably latest after 6 months, from start of treatment with imatinib is decreased by at least 10%, preferably by at least 20%, compared to the cholesterol ratio at start of said treatment.
- the cholesterol ratio total cholesterol / HDL cholesterol
- the present invention further provides Imatinib or any pharmaceutically acceptable salt thereof for treating hyperlipidemia, hypercholesterolemia or hypertriglyceridemia, characterized in that the cholesterol ratio (total cholesterol / HDL cholesterol) latest after 12 months, preferably latest after 6 months, from start of treatment with imatinib is decreased by at least 10%, preferably by at least 20%, compared to the cholesterol ratio at start of said treatment.
- the cholesterol ratio total cholesterol / HDL cholesterol
- the present invention provides a method for the treatment of hyperlipidemia, hypercholesterolemia or hypertriglyceridemia in human patients in need of such treatment which comprises administering an effective amount of Imatinib or any pharmaceutically acceptable salt thereof, wherein said treatment is characterized in that the cholesterol ratio (total cholesterol / HDL cholesterol) latest after 12 months, preferably latest after 6 months, from start is decreased by at least 10%, preferably by at least 20%, compared to the cholesterol ratio at start of said treatment.
- the present invention provides the use of Imatinib or any pharmaceutically acceptable salt thereof, wherein said treatment is characterized in that the cholesterol ratio (total cholesterol / HDL cholesterol) latest after 12 months, preferably latest after 6 months, from start is decreased by at least 10%, preferably by at least 20%, compared to the cholesterol ratio at start of said treatment.
- the present invention provides the use of Imatinib or any
- hypercholesterolemia or hypertriglyceridemia wherein said use decreases the cholesterol ratio (total cholesterol / HDL cholesterol) latest after 12 months, preferably latest after 6 months, from start of use with imatinib by at least 10%, preferably by at least 20%, compared to the cholesterol ratio at start of said use.
- the present invention provides a use comprising Imatinib or any pharmaceutically acceptable salt thereof for treating hyperlipidemia, hypercholesterolemia or hypertriglyceridemia patients, wherein said use decreases the cholesterol ratio (total cholesterol / HDL cholesterol) latest after 12 months, preferably latest after 6 months, from start of use with imatinib by at least 10%, preferably by at least 20%, compared to the cholesterol ratio at start of said use.
- a use comprising Imatinib or any pharmaceutically acceptable salt thereof for treating hyperlipidemia, hypercholesterolemia or hypertriglyceridemia patients, wherein said use decreases the cholesterol ratio (total cholesterol / HDL cholesterol) latest after 12 months, preferably latest after 6 months, from start of use with imatinib by at least 10%, preferably by at least 20%, compared to the cholesterol ratio at start of said use.
- the present invention provides the use of Imatinib or any combination thereof.
- a medicament for the treatment of hyperlipidemia, hypercholesterolemia or hypertriglyceridemia said medicament decreases the cholesterol ratio (total cholesterol / HDL cholesterol) latest after 12 months, preferably latest after 6 months, from start of treatment with imatinib by at least 10%, preferably by at least 20%, compared to the cholesterol ratio at start of said treatment with said medicament.
- the present invention provides a medicament for the treatment of hyperlipidemia, hypercholesterolemia or hypertriglyceridemia comprising Imatinib or any pharmaceutically acceptable salt thereof, said medicament decreases the cholesterol ratio (total cholesterol / HDL cholesterol) latest after 12 months, preferably latest after 6 month, from start of treatment with imatinib by at least 10%, preferably by at least 20%, compared to the cholesterol ratio at start of the treatment with said medicament.
- the cholesterol ratio decrease mentioned in the aspects of the present invention above is characterized by an increased level of the HDL cholesterol and by unchanged or decreased levels of LDL, triglycerides, and total cholesterol latest after 12 months, preferably latest after 6 months, from start of the treatment with imatinib compared to the levels at start of said treatment.
- said cholesterol ratio decrease is characterized by an increased level of the HDL cholesterol, by an decreased level of triglycerides, and by unchanged or decreased levels of LDL and total cholesterol latest after 12 months, preferably latest after 6 months, from start of the treatment with imatinib compared to the levels at start of said treatment.
- said HDL cholesterol level increase is of at least 10%, more preferably at least 20%;
- said triglycerides level decrease is of at least 10%, more preferably at least 20%, even more preferably at least 30%, even more preferably at least 35%;
- said LDL cholesterol level is decreased by at least 5%
- said total cholesterol level is decreased by at least 4%.
- hypercholesterolemia is defined by cholesterol ratios (total cholesterol / HDL cholesterol) of 5 or higher before starting with the treatment of imatinib. ln another preferred embodiment of the present invention the hyperlipidemia or
- hypercholesterolemia is defined by total cholesterol levels of 200 mg/dL or higher, more particularly 240 mg/dL or higher, before starting with the treatment of imatinib.
- the hyperlipidemia or hypercholesterolemia is defined by HDL cholesterol levels of 50 mg/dL or lower, more particularly 40 mg/dL or lower, before starting with the treatment of imatinib.
- the hyperlipidemia or hypercholesterolemia is defined by LDL cholesterol levels of 130 mg/dL or higher, more particularly 160 mg/dL or higher, before starting with the treatment of imatinib.
- the hyperlipidemia or hypertriglyceridemia is defined by triglycerides levels of 150 mg/dL or higher, more particularly 200 mg/dL or higher, before starting with the treatment of imatinib.
- the hyperlipidemia in further preferred embodiments of the present invention the hyperlipidemia
- hypercholesterolemia or hypertriglyceridemia is defined by any combination of the above mentioned levels.
- the hyperlipidemia, hypercholesterolemia, or hypertriglyceridemia is defined by the combination of total cholesterol levels of 200 mg/dL or higher, more particularly 240 mg/dL or higher, and HDL cholesterol levels of 50 mg/dL or lower, more particularly 40 mg/dL or lower, before starting with the treatment of imatinib.
- the hyperlipidemia, hypercholesterolemia, or hypertriglyceridemia is defined by the combination of total cholesterol levels of 200 mg/dL or higher, more particularly 240 mg/dL or higher, and HDL cholesterol levels of 50 mg/dL or lower, more particularly 40 mg/dL or lower and triglycerides levels of 150 mg/dL or higher, more particularly 200 mg/dL or higher, before starting with the treatment of imatinib.
- level used herein in the context of TC, LDL-C, HDL-C, TG is referred to as blood level or concentration in the blood of the human patient and expressed e.g. as mmol/L or mg/dL. Those levels can be determined by established clinical laboratory test methods which are standard in the field.
- Imatinib or any pharmaceutically acceptable salt thereof for use in the treatment of hyperlipidemia, hypercholesterolemia or hypertriglyceridemia characterized in that the glycolisated hemoglobin A1 c (HbA1 c) value latest after 12 months from start of treatment with imatinib is decreased by at least 3%, preferably by at least 5 %, compared to the cholesterol ratio at start of said treatment.
- HbA1 c glycolisated hemoglobin A1 c
- the HbA1 c value can be determined by established clinical laboratory test methods which are standard in the field.
- the terms TC, HDL-C, TG and HbA1 C as used herein are referred to as those values determined according to established clinical laboratory test methods applied to blood samples taken according to current good laboratory and clinical procedures (cGLP, cGCP) which are standardized and routine in the filed.
- the TC is measured directly.
- the cholesterol ratio (TC/HDL-C) as used herein is referred to the value which is calculated based on the directly measured TC and HDL-C values.
- the total cholesterol (TC) or cholesterol (high performance) herein is determined as independent and direct measurement of the blood sample taked according to cGCP from patients.
- a routine total cholesterol assay is performed using e.g. the calibrated Roche Modular Analyzer. All cholesterol esters present in blood serum are hydrolyzed quantitatively into free cholesterol and fatty acids by microbial cholesterol esterase: Cholesterol esters + H 2 0 cholesterol esterase> cholesterol + fatty acids ln the presence of oxygen, free cholesterol is oxidized by cholesterol oxidase to cholest-4- en-3-one: Cholesterol + 0 2 cholesterol oxidase> cholest-4-en-3-one + H 2 0 2
- the H 2 0 2 reacts in the presence of peroxidase (POD) with phenol and 4-aminophenazone to form an o-quinone imine dye: 2H 2 0 2 + 4-aminophenazone + phenol POD> 4-(p-benzoquinone monoamino)-phenazone + 4 H 2 0
- the intensity of the color formed is proportional to the cholesterol concentration and is measured photometrically.
- the HDL cholesterol (HDL-C) level herein is determined also by a direct measurement of the high density portion of the cholesterol.
- the high-density lipoprotein (HDL) cholesterol assay is performed on a blood serum sample by chemical precipitation.
- a polyanion dextran sulfate and divalent cation Mg++ solution interact with the low density lipoprotein (LDL) and very low density lipoprotein (VLDL) to form an insoluble complex which is precipitated by low speed centrifugation.
- LDL low density lipoprotein
- VLDL very low density lipoprotein
- the supernatant, which contains HDL is then assayed for cholesterol on e.g. a Roche Hitachi analyzers, using the method described for total cholesterol.
- the Friedewald calculation is used to estimate LDL cholesterol:
- LDL Cholesterol (Total Cholesterol) - (HDL Cholesterol) - (Triglycerides X 0.2)
- TG triglycerides
- the Triglycerides assay is performed on a blood serum sample by using e.g. a Roche Modular Analyzer.
- Lipase hydrolyzes triglycerides to glycerol and fatty acids.
- the glycerol is then oxidized to dihydroxyacetone phosphate and hydrogen peroxide.
- the peroxide reacts with 4-aminophenazone and 4-chlorophenol in a Trinder reaction to a colorimetric endpoint.
- the LDL and VLDL herein are estimates derived from calculations.
- the LDL is derived via the Friedwald Methodology by using the directly measured total cholesterol and HDL Cholesterol and Triglycerides according to the following formula: Estimation of LDL Cholesterol (Friedwald methodology):
- LDL-C Total Cholesterol - HDL-C - (Triglycerides / 5)
- LDL-C Total Cholesterol - HDL Cholesterol - (Triglycerides x 0.458)
- VLDL is calculated via Friedwald Methodology and is based on the directly measured triglycerides result in the following formula:
- VLDL-C Triglycerides x 0.20
- VLDL-C Triglycerides x 0.458
- the treatment comprises a daily dose of imatinib of 400 mg.
- Drug products with said nominal dose are commercially available.
- imatinib is marketed by Novartis under the brand names Gleevec or Glivec and is available in the dosage strengths of 100 mg and 400 mg in the form of tablets for oral administration.
- imatinib may be used for the treatment of
- hyperlipoproteinemia hyperlipidemia, hypercholesterolemia, dyslipidemia,
- hypertriglyceridemia or lipid disorders, preferably hyperlipidemis, more preferably hypercholesterolemia and/or hypertriglyceridemia.
- imatinib may be used for the treatment of patients with conditions such as high cholesterol, elevated cholesterol, abnormal cholesterol, high triglycerides, elevated tryglicerides, abnormal blood cholesterol, increased blood cholesterol, abnormal Total cholesterol/HDL ratio, increased Total cholesterol/HDL ratio, or increased non-high-density lipoprotein cholesterol.
- Imatinib Due to its HDL-C and cholesterol ratio modifying function Imatinib further may be useful as therapeutic drug in the context of cardiovascular risks, ischemic heart disease (myocardial infarction, coronary arterial disease, angina pectoris, coronary artery stenosis, coronary artery occlusion, cardiac ischemia, myocardial ischemia), peripheral arterial disease (also referred to as peripheral arterial occlusive disease, claudication, intermittent claudication, occlusive arterial disorders, vascular occlusive disorders, arterial thrombosis, arterial occlusion, arterial stenosis, peripheral artery stenosis, peripheral ischemia, poor peripheral circulation, peripheral arterial ischemia, vascular occlusion, vascular stenosis), ischemic cerebrovascular disease (including stoke, ischemic stroke, thrombotic stroke, transient ischemic attack, reversible ischemic neurologic disorder, cerebrovascular accident, brainstem ischemia, caroti
- Imatinib 400 mg orally, once daily (qd), or nilotinib 300 mg or 400 mg, orally, twice daily (bid).
- Imatinib was administered on an outpatient basis, and patients were instructed to take imatinib with food. Patients continued to take imatinib until progression of the leukemia, treatment failure, or the development of intolerance of treatment.
- lipid profiles which included routine assessment of total cholesterol (TC), HDL-C, LDL-C, and hemoglobin A1 c (HbA1 c) were assessed at baseline prior to initiation of therapy, at month 6, and yearly starting at month 12. As of the writing of this document, patients have been followed for five years on the study.
- HDL-C ( mmol/L ) Baseline Month 6 Month 12 Month 24 Month 36 Month 48 n 277 246 232 194 160 117 mean 1.06 1.31 1.31 1.32 1.32 1.29
- VLDL-C ( mmol/L ) Baseline Month 6 Month 12 Month 24 Month 36 Month 48 n 273 244 231 192 160 116 mean 0.90 0.58 0.60 0.59 0.60 0.63 s.d. 0.420 0.315 0.323 0.296 0.334 0.330 median 0.79 0.50 0.50 0.52 0.52 0.56
- hemoglobin HbA1c (%) Baseline Month 6 Month 12 Month 24 Month 36 Month 48 n 269 235 220 189 172 154 mean 5.61 5.42 5.33 5.41 5.38 5.43
- hyperlipidemia on statin therapy would initiate outpatient therapy with imatinib, at the dose of 400 mg daily, taken with food and a glass of water.
- imatinib Prior to starting imatinib therapy, the lipid profile would be established as a baseline to monitor the effects of the therapy. This would consist of routine standard clinical laboratory assessment of total cholesterol (TC), HDL-C, LDL-C, triglycerides (TG), and HbA1 c.
- TC total cholesterol
- TG triglycerides
- HbA1 c triglycerides
Abstract
The present invention relates to imatib for use in the treatment of hyperlipidemia, hypercholesterolemia or hypertriglyceridemia. Already after 6 months treatment, imatinib was found to sustainably decrease the cholesterol ratio (total cholesterol / HDL cholesterol), to sustainably increase HDL cholesterol blood levels, and to sustainably decrease LDL cholesterol and triglyceride blood levels. Thus, imatinib represents a new lipid-modifying drug that results in cardiovascular benefits.
Description
IMATINIB AS CHOLESTEROL DECREASING AGENT
Description FIELD OF THE INVENTION
The present invention relates to methods of treatment of hyperlipidemia. In particular it relates to the treatment of human patients diagnosed with hypercholesterolemia and/or hypertriglyceridemia.
BACKGROUND OF THE INVENTION
Hyperlipidemic patients typically show high blood levels of total cholesterol due to high levels of the "bad" low density lipoprotein cholesterol (LDL-C) and high levels of the "bad" triglycerides. If at the same time those patients have low levels of the "good" high density lipoprotein cholesterol (HDL-C) they have a high risk to suffer from cardiovascular or cerebrovascular diseases.
When the concentration of LDL-C in the blood is too high the LDL-C may deposit together with other substances at the inner walls of the arteries forming a thick and hard plaque which narrows those blood vessels and makes them less flexible. When the arteries are narrowed and lost their flexibility (a condition which is called atherosclerosis) there is a risk that they are entirely blocked by clot formation and that the heart and the brain is not any longer feeded with blood resulting the patient being affected by heart attack or stroke. Due to the cardio- and cerebrovascular risks associated with high blood levels of LDL-C, this type of cholesterol is often colloquially referred to as "bad" cholesterol.
HDL-C, in contrast, is often called the "good" cholesterol as it is believed to remove excess of cholesterol from the arteries and to transport it to the liver where the cholesterol is cleared from the human body (a process also referred to as reverse cholesterol transport, RCT). By doing so, the HDL-C may prevent the formation of further arterial plaque and, thus, acts as cardioprotective agent. This is why the HDL-C is often colloquially referred to as "good" cholesterol. As further positive effects, HDL-C promotes angiogenesis and promotes endothelial repair processes, acts as anti-thrombotic, anti-oxidant and anti-diabetic, inhibits vascular inflammation and enhances endothelial repair.
High blood levels of triglycerides (TG), especially combined with high levels of LDL-C and low levels of HDL-C, seem to accelerate the formation of arterial plaque and are therefore seen as another cardio- and cerebrovascular risk factor.
A further important parameter in the therapy of patients with hyperlipidemia is the "total cholesterol" (TC) which includes all types of cholesterol in the blood of a patient, e.g. HDL-C, LDL-C, VeryLDL-C (VLDL-C). The ratio of TC / HDL-C (total cholesterol divided by HDL cholesterol) is generally and herein referred to as "cholesterol ratio" and is also used as parameter for guidance in treatment of hyperlipidemia.
Basically, two distinct strategies to treat hyperlipidemia by medication have been suggested: Statins (HMG-CoA reductase inhibitors) have been already extensively used with the target to decrease the blood levels of LDL-C, whereas more recently cholesterol-ester transfer protein (CETP) inhibitors have been used in clinical trials with the aim to increase HDL-C blood levels in patients. However none of those CETP inhibitor drugs have so far reached the market. For the sake of providing physicians with a variety of treatment options it is highly desirable to further intensify exploration of the HDL-C increase strategy.
SUMMARY OF THE INVENTION The ENESTnd study was a clinical trial that evaluated patients with chronic myelogenous leukemia in chronic phase, previously untreated. In that study, 283 patients were treated with imatinib at the dose of 400 mg, orally, daily administered in an outpatient setting. In this trial, compared to baseline, patients treated with imatinib were found to increase high density lipoprotein cholesterol (HDL-C), decrease total cholesterol (TC) and triglycerides (TG), and slightly decrease low density lipoprotein cholesterol (LDL-C) and hemoglobin A1 c (HbA1 c). These changes occurred over the first 6 months of treatment with imatinib. These changes are predicted to reduce cardiovascular risks. After a period of 5 years, only very few patients treated with imatinib were found to develop cardiovascular events or arterial occlusive events, consisting of ischemic cardiac events, ischemic cerebrovascular events, and peripheral arterial occlusive disease: after 5 years, only 6 patients developed cardiovascular
events (5 patients developed ischemic cardiac events, and 1 developed an ischemic cerebrovascular event). The number of cardiovascular events occurring after 5 years of observation in the patients treated with imatinib appears to be lower than the background number of events expected in patients with similar demographic characteristics and cardiovascular risk factors over that time period.
The increase in HDL-C without a concurrent increase of TC, means that the TC/HDL-C ratio decreases. The increase in HDL-C, the decrease in LDL-C triglyceride concentration, and in addition, a slight decrease in HbA1 C may explain the notably low incidence of cardiovascular events (CVEs) in the patients treated with imatinib. Imatinib, which has thus been shown to decrease the TC/HDL-C ratio and increase HDL-C, appears to represent an HDL-modifying drug that results in cardiovascular benefits.
Based on these surprising findings, the inventors herewith provide the present invention in the following aspects:
In a first aspect, the present invention provides imatinib or any pharmaceutically acceptable salt thereof for use as cholesterol ratio (total cholesterol / HDL cholesterol) decreasing agent.
In a second aspect, the present invention provides imatinib or any pharmaceutically acceptable salt thereof for use as cholesterol ratio (total cholesterol / HDL cholesterol) decreasing agent in the treatment of hyperlipidemia, hypercholesterolemia or
hypertriglyceridemia
In a third aspect, the present invention provides imatinib or any pharmaceutically acceptable salt thereof for use according to the first or second aspect wherein Imatinib is used as cholesterol ratio (total cholesterol / HDL cholesterol) decreasing agent and as HDL cholesterol increasing agent.
In a fourth aspect, the present invention provides imatinib or any pharmaceutically acceptable salt thereof for use according to the first or second aspect wherein Imatinib is used as cholesterol ratio (total cholesterol / HDL cholesterol) decreasing agent and as HDL cholesterol increasing agent and as triglycerides decreasing agent.
The present invention further provides imatinib or any pharmaceutically acceptable salt thereof for use according to any of the above mentioned aspects wherein the cholesterol
ratio (total cholesterol / HDL cholesterol) latest after 12 months, preferably latest after 6 months, from start of treatment with imatinib is decreased by at least by 10%, preferably by at least 20%, compared to the cholesterol ratio at start of the treatment with imatinib. The present invention further provides imatinib or any pharmaceutically acceptable salt thereof for use according to any of the above mentioned aspects wherein the cholesterol ratio decrease is further characterized by an increased level of the HDL cholesterol and by unchanged or decreased levels of LDL, triglycerides, and total cholesterol latest after 12 months, preferably latest after 6 months, from start of the treatment with imatinib compared to the levels at start of the treatment with imatinib.
DETAILED DESCRIPTION OF THE INVENTION
Herein after, the present invention is described in further detail and is exemplified.
In the aspects of the present invention the drug substance Imatinib is present in its free form or in the form of any pharmaceutically acceptable salt salt, complex, co-crystal, hydrate or solvate thereof. In one embodiment imatinib is present in its free base form. In another embodiment Imatinib is present as mesylate salt; in yet another embodiment as mono-mesylate salt; in yet another embodiments as mono-mesylate salt in its amorphous form as described in WO2008/154262 and US 2010/0178336 which are incorporated herein as references or in its crystalline alpha form or crystalline beta form as described in WO 99/03854 and US 7,151 ,106 which are incorporated herein as references, preferably in the crystalline beta form.
Imatinib is known to act as a tyrosine-kinase inhibitor and used in the treatment of cancers, particularly of Philadelphia chromosome-positive (Ph+) chronic myelogeous leukemia (CML) and gastrointestinal stromal tumors (GIST). The present invention provides Imatinib or any pharmaceutically acceptable salt thereof for use in the treatment of hyperlipidemia, hypercholesterolemia or hypertriglyceridemia.
The present invention provides Imatinib or any pharmaceutically acceptable salt thereof for use in a method of treatment of hyperlipidemia, hypercholesterolemia or
hypertriglyceridemia.
The present invention provides Imatinib or any pharmaceutically acceptable salt thereof for treating hyperlipidemia, hypercholesterolemia or hypertriglyceridemia. Alternatively, the present invention provides a method for the treatment of hyperlipidemia, hypercholesterolemia or hypertriglyceridemia in human patients in need of such treatment which comprises administering an effective amount of Imatinib or any pharmaceutically acceptable salt thereof. As a further alternative, the present invention provides the use of Imatinib or any
pharmaceutically acceptable salt thereof for the treatment of hyperlipidemia,
hypercholesterolemia or hypertriglyceridemia.
As a further alternative, the present invention provides a use comprising Imatinib or any pharmaceutically acceptable salt thereof for treating hyperlipidemia, hypercholesterolemia or hypertriglyceridemia patients.
As a further alternative, the present invention provides the use of Imatinib or any
pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of hyperlipidemia, hypercholesterolemia or hypertriglyceridemia.
As a further alternative, the present invention provides a medicament for the treatment of hyperlipidemia, hypercholesterolemia or hypertriglyceridemia comprising Imatinib or any pharmaceutically acceptable salt thereof.
Even further, the present invention provides Imatinib or any pharmaceutically acceptable salt thereof for use in the treatment of hyperlipidemia, hypercholesterolemia or
hypertriglyceridemia, characterized in that the cholesterol ratio (total cholesterol / HDL cholesterol) latest after 12 months, preferably latest after 6 months, from start of treatment with imatinib is decreased by at least 10%, preferably by at least 20%, compared to the cholesterol ratio at start of said treatment.
The present invention further provides Imatinib or any pharmaceutically acceptable salt thereof for use in a method of treatment of hyperlipidemia, hypercholesterolemia or hypertriglyceridemia, characterized in that the cholesterol ratio (total cholesterol / HDL
cholesterol) latest after 12 months, preferably latest after 6 months, from start of treatment with imatinib is decreased by at least 10%, preferably by at least 20%, compared to the cholesterol ratio at start of said treatment. The present invention further provides Imatinib or any pharmaceutically acceptable salt thereof for treating hyperlipidemia, hypercholesterolemia or hypertriglyceridemia, characterized in that the cholesterol ratio (total cholesterol / HDL cholesterol) latest after 12 months, preferably latest after 6 months, from start of treatment with imatinib is decreased by at least 10%, preferably by at least 20%, compared to the cholesterol ratio at start of said treatment.
Alternatively, the present invention provides a method for the treatment of hyperlipidemia, hypercholesterolemia or hypertriglyceridemia in human patients in need of such treatment which comprises administering an effective amount of Imatinib or any pharmaceutically acceptable salt thereof, wherein said treatment is characterized in that the cholesterol ratio (total cholesterol / HDL cholesterol) latest after 12 months, preferably latest after 6 months, from start is decreased by at least 10%, preferably by at least 20%, compared to the cholesterol ratio at start of said treatment. As a further alternative, the present invention provides the use of Imatinib or any
pharmaceutically acceptable salt thereof for the treatment of hyperlipidemia,
hypercholesterolemia or hypertriglyceridemia, wherein said use decreases the cholesterol ratio (total cholesterol / HDL cholesterol) latest after 12 months, preferably latest after 6 months, from start of use with imatinib by at least 10%, preferably by at least 20%, compared to the cholesterol ratio at start of said use.
As a further alternative, the present invention provides a use comprising Imatinib or any pharmaceutically acceptable salt thereof for treating hyperlipidemia, hypercholesterolemia or hypertriglyceridemia patients, wherein said use decreases the cholesterol ratio (total cholesterol / HDL cholesterol) latest after 12 months, preferably latest after 6 months, from start of use with imatinib by at least 10%, preferably by at least 20%, compared to the cholesterol ratio at start of said use.
As a further alternative, the present invention provides the use of Imatinib or any
pharmaceutically acceptable salt thereof for the preparation (or manufacture) of a
medicament for the treatment of hyperlipidemia, hypercholesterolemia or hypertriglyceridemia, said medicament decreases the cholesterol ratio (total cholesterol / HDL cholesterol) latest after 12 months, preferably latest after 6 months, from start of treatment with imatinib by at least 10%, preferably by at least 20%, compared to the cholesterol ratio at start of said treatment with said medicament.
As a further alternative, the present invention provides a medicament for the treatment of hyperlipidemia, hypercholesterolemia or hypertriglyceridemia comprising Imatinib or any pharmaceutically acceptable salt thereof, said medicament decreases the cholesterol ratio (total cholesterol / HDL cholesterol) latest after 12 months, preferably latest after 6 month, from start of treatment with imatinib by at least 10%, preferably by at least 20%, compared to the cholesterol ratio at start of the treatment with said medicament.
In prefered embodiments of the present invention, the cholesterol ratio decrease mentioned in the aspects of the present invention above is characterized by an increased level of the HDL cholesterol and by unchanged or decreased levels of LDL, triglycerides, and total cholesterol latest after 12 months, preferably latest after 6 months, from start of the treatment with imatinib compared to the levels at start of said treatment. In more preferred embodiments of the present invention said cholesterol ratio decrease is characterized by an increased level of the HDL cholesterol, by an decreased level of triglycerides, and by unchanged or decreased levels of LDL and total cholesterol latest after 12 months, preferably latest after 6 months, from start of the treatment with imatinib compared to the levels at start of said treatment.
Even more preferably, said HDL cholesterol level increase is of at least 10%, more preferably at least 20%;
said triglycerides level decrease is of at least 10%, more preferably at least 20%, even more preferably at least 30%, even more preferably at least 35%;
said LDL cholesterol level is decreased by at least 5%; and
said total cholesterol level is decreased by at least 4%.
In preferred embodiments of the present invention the hyperlipidemia or
hypercholesterolemia is defined by cholesterol ratios (total cholesterol / HDL cholesterol) of 5 or higher before starting with the treatment of imatinib.
ln another preferred embodiment of the present invention the hyperlipidemia or
hypercholesterolemia is defined by total cholesterol levels of 200 mg/dL or higher, more particularly 240 mg/dL or higher, before starting with the treatment of imatinib.
In yet another preferred embodiment of the present invention the hyperlipidemia or hypercholesterolemia is defined by HDL cholesterol levels of 50 mg/dL or lower, more particularly 40 mg/dL or lower, before starting with the treatment of imatinib. In yet another preferred embodiment of the present invention the hyperlipidemia or hypercholesterolemia is defined by LDL cholesterol levels of 130 mg/dL or higher, more particularly 160 mg/dL or higher, before starting with the treatment of imatinib.
In yet another preferred embodiment of the present invention the hyperlipidemia or hypertriglyceridemia is defined by triglycerides levels of 150 mg/dL or higher, more particularly 200 mg/dL or higher, before starting with the treatment of imatinib.
In further preferred embodiments of the present invention the hyperlipidemia,
hypercholesterolemia, or hypertriglyceridemia is defined by any combination of the above mentioned levels.
In a particularly preferred embodiment of the present invention the hyperlipidemia, hypercholesterolemia, or hypertriglyceridemia is defined by the combination of total cholesterol levels of 200 mg/dL or higher, more particularly 240 mg/dL or higher, and HDL cholesterol levels of 50 mg/dL or lower, more particularly 40 mg/dL or lower, before starting with the treatment of imatinib.
In a more particularly preferred embodiment of the present invention the hyperlipidemia, hypercholesterolemia, or hypertriglyceridemia is defined by the combination of total cholesterol levels of 200 mg/dL or higher, more particularly 240 mg/dL or higher, and HDL cholesterol levels of 50 mg/dL or lower, more particularly 40 mg/dL or lower and triglycerides levels of 150 mg/dL or higher, more particularly 200 mg/dL or higher, before starting with the treatment of imatinib.
The term "level" used herein in the context of TC, LDL-C, HDL-C, TG is referred to as blood level or concentration in the blood of the human patient and expressed e.g. as mmol/L or mg/dL. Those levels can be determined by established clinical laboratory test methods which are standard in the field.
In another aspect of the present invention there is provided Imatinib or any pharmaceutically acceptable salt thereof for use in the treatment of hyperlipidemia, hypercholesterolemia or hypertriglyceridemia, characterized in that the glycolisated hemoglobin A1 c (HbA1 c) value latest after 12 months from start of treatment with imatinib is decreased by at least 3%, preferably by at least 5 %, compared to the cholesterol ratio at start of said treatment.
The HbA1 c value, e.g. expressed in %, can be determined by established clinical laboratory test methods which are standard in the field. The terms TC, HDL-C, TG and HbA1 C as used herein are referred to as those values determined according to established clinical laboratory test methods applied to blood samples taken according to current good laboratory and clinical procedures (cGLP, cGCP) which are standardized and routine in the filed. Alternatively, if the LDL-C, HDL-C and the TG are known, the TC may be calculated according to the following formula: TC = HDL-C + LDL-C + (20% of TG). Preferably, the TC is measured directly.
The cholesterol ratio (TC/HDL-C) as used herein is referred to the value which is calculated based on the directly measured TC and HDL-C values.
The total cholesterol (TC) or cholesterol (high performance) herein is determined as independent and direct measurement of the blood sample taked according to cGCP from patients.
For example, a routine total cholesterol assay is performed using e.g. the calibrated Roche Modular Analyzer. All cholesterol esters present in blood serum are hydrolyzed quantitatively into free cholesterol and fatty acids by microbial cholesterol esterase: Cholesterol esters + H20 cholesterol esterase> cholesterol + fatty acids
ln the presence of oxygen, free cholesterol is oxidized by cholesterol oxidase to cholest-4- en-3-one: Cholesterol + 02 cholesterol oxidase> cholest-4-en-3-one + H202
The H202 reacts in the presence of peroxidase (POD) with phenol and 4-aminophenazone to form an o-quinone imine dye: 2H202 + 4-aminophenazone + phenol POD> 4-(p-benzoquinone monoamino)-phenazone + 4 H20
The intensity of the color formed is proportional to the cholesterol concentration and is measured photometrically. The HDL cholesterol (HDL-C) level herein is determined also by a direct measurement of the high density portion of the cholesterol.
For example, the high-density lipoprotein (HDL) cholesterol assay is performed on a blood serum sample by chemical precipitation. A polyanion dextran sulfate and divalent cation Mg++ solution interact with the low density lipoprotein (LDL) and very low density lipoprotein (VLDL) to form an insoluble complex which is precipitated by low speed centrifugation. The supernatant, which contains HDL, is then assayed for cholesterol on e.g. a Roche Hitachi analyzers, using the method described for total cholesterol. The Friedewald calculation is used to estimate LDL cholesterol:
LDL Cholesterol = (Total Cholesterol) - (HDL Cholesterol) - (Triglycerides X 0.2)
The triglycerides (TG) herein are also determined by direct measurement.
For example, the Triglycerides assay is performed on a blood serum sample by using e.g. a Roche Modular Analyzer. Lipase hydrolyzes triglycerides to glycerol and fatty acids. The glycerol is then oxidized to dihydroxyacetone phosphate and hydrogen peroxide. In the presence of peroxidase, the peroxide reacts with 4-aminophenazone and 4-chlorophenol in a Trinder reaction to a colorimetric endpoint. The LDL and VLDL herein are estimates derived from calculations.
The LDL is derived via the Friedwald Methodology by using the directly measured total cholesterol and HDL Cholesterol and Triglycerides according to the following formula: Estimation of LDL Cholesterol (Friedwald methodology):
In conventional units (Reported in mg/dL):
LDL-C = Total Cholesterol - HDL-C - (Triglycerides / 5)
In SI Units (Reported in mmol/L):
LDL-C = Total Cholesterol - HDL Cholesterol - (Triglycerides x 0.458)
The VLDL is calculated via Friedwald Methodology and is based on the directly measured triglycerides result in the following formula:
Estimation of VLDL Cholesterol (Friedwald methodology):
In conventional units (Reported in mg/dL):
VLDL-C = Triglycerides x 0.20
In SI Units (Reported in mmol/L):
VLDL-C = Triglycerides x 0.458 According to the present invention the treatment comprises a daily dose of imatinib of 400 mg. Drug products with said nominal dose are commercially available. For example, imatinib is marketed by Novartis under the brand names Gleevec or Glivec and is available in the dosage strengths of 100 mg and 400 mg in the form of tablets for oral administration. According to the present invention imatinib may be used for the treatment of
hyperlipoproteinemia, hyperlipidemia, hypercholesterolemia, dyslipidemia,
hypertriglyceridemia, or lipid disorders, preferably hyperlipidemis, more preferably hypercholesterolemia and/or hypertriglyceridemia. Furthermore, according to the present invention imatinib may be used for the treatment of patients with conditions such as high cholesterol, elevated cholesterol, abnormal cholesterol, high triglycerides, elevated tryglicerides, abnormal blood cholesterol, increased blood cholesterol, abnormal Total cholesterol/HDL ratio, increased Total cholesterol/HDL ratio, or increased non-high-density lipoprotein cholesterol.
Due to its HDL-C and cholesterol ratio modifying function Imatinib further may be useful as therapeutic drug in the context of cardiovascular risks, ischemic heart disease (myocardial infarction, coronary arterial disease, angina pectoris, coronary artery stenosis, coronary artery occlusion, cardiac ischemia, myocardial ischemia), peripheral arterial disease (also referred to as peripheral arterial occlusive disease, claudication, intermittent claudication, occlusive arterial disorders, vascular occlusive disorders, arterial thrombosis, arterial occlusion, arterial stenosis, peripheral artery stenosis, peripheral ischemia, poor peripheral circulation, peripheral arterial ischemia, vascular occlusion, vascular stenosis), ischemic cerebrovascular disease (including stoke, ischemic stroke, thrombotic stroke, transient ischemic attack, reversible ischemic neurologic disorder, cerebrovascular accident, brainstem ischemia, carotid artery stenosis, carotid artery narrowing, carotid artery occlusion, cerebral ischemia), arteriosclerosis, atherosclerosis.
EXAMPLES
Hereinafter, the present invention is described in more details and specifically with reference to the examples, which however are not intended to limit the present invention.
Example 1 :
Cholesterol related data of the Imatinib arm of the ENESTnd clinical study
Patients with chronic myelogenous leukemia were treated with imatinib in a study conducted to evaluate the safety and efficacy of nilotinib (ENESTnd, AMN107A2303).
Patients were randomized to receive imatinib 400 mg, orally, once daily (qd), or nilotinib 300 mg or 400 mg, orally, twice daily (bid). Imatinib was administered on an outpatient basis, and patients were instructed to take imatinib with food. Patients continued to take imatinib until progression of the leukemia, treatment failure, or the development of intolerance of treatment.
As part of the study, lipid profiles which included routine assessment of total cholesterol (TC), HDL-C, LDL-C, and hemoglobin A1 c (HbA1 c) were assessed at baseline prior to initiation of therapy, at month 6, and yearly starting at month 12. As of the writing of this document, patients have been followed for five years on the study.
Within the first 6 months of starting imatinib treatment, changes in the lipid profile were observed and by month 12, the following were seen (mean values from baseline to month 12): 1) total cholesterol decreased from 4.68 to 4.45 mmol/L, 2) HDL-C increased from 1 .06
to 1 .31 mmol/L, 3) LDL-C decreased from 2.69 to 2.53 mmol/L, 4) triglycerides decreased from 2.05 to 1 .33 mmol/L, 5) glycosylated hemoglobin (HbA1 c) decreased from 5.63% to 5.33%. These changes in the lipid profile and in HbA1 c continued to be sustained over 4 years and beyond (see Table 1).
Cardiac risk factors, medication usage and medical history of patients of the "Imatinib 400 mg qd" arm of the ENESTnd study (N=280) at start of the treatment (baseline) are indicated in Table 2 below.
Over the first 5 years of the ENESTnd study, as the HDL-C was found to increase, and the changes in the lipid profile was found to occur, only very few patients were found to have developed cardiovascular events: only 6 patients developed cardiovascular events, 5 of whom developed ischemic cardiac events, and 1 who an ischemic cerebrovascular event (see Table 3). No patient has developed a peripheral arterial occlusive event.
Table 1 : Data of laboratory parameters of Imatinib 400 mg qd arm of ENESTnd study (N=280) at start of the treatment (baseline) and at different time points after start of the treatment.
Total Cholesterol
TC ( mmol/L ) Baseline Month 6 Month 12 Month 24 Month 36 Month 48 n 277 246 232 195 161 117 mean 4.68 4.42 4.45 4.45 4.50 4.43
100.0% 94.4% 95.1%
-5.6% -4.9%
s.d. 1.138 0.993 0.992 1.038 0.990 0.895 median 4.60 4.33 4.34 4.33 4.43 4.35
25-27m percentiles 3.91-5.34 3.62-5.07 3.74-4.98 3.69-5.04 3.83-5.01 3.79-4.88
Minimum - maximum 2.3-8.6 2.5-7.8 2.3-7.6 2.3-7.9 2.5-8.7 2.9-7.1
HDL-Cholesterol
HDL-C ( mmol/L ) Baseline Month 6 Month 12 Month 24 Month 36 Month 48 n 277 246 232 194 160 117 mean 1.06 1.31 1.31 1.32 1.32 1.29
100% 123.6% 123.6%
+23.6% +23.6%
SD 0.330 0.361 0.373 0.374 0.358 0.313 median 0.99 1.27 1.27 1.29 1.28 1.22
25-27m percentiles 0.82-1.26 1.06-1.46 1.06-1.53 1.04-1.49 1.05-1.51 1.09-1.46
Minimum - maximum 0.5-2.3 0.7-2.7 0.6-2.6 0.7-2.6 0.7-2.5 0.7-2.2
Cholesterol Ratio
TC/HDL-C Baseline Month 6 Month 12
n 277 246 232
mean 4.66 3.55 3.59
100% 76.2% 77.0%
-23.8% -23.0%
SD 1.326 1.096 1.113
median 4.47 3.37 3.31
25-27m percentiles 3.72-5.56 2.70-4.12 2.72-4.21
Minimum - maximum 2.0-9.8 2.0-9.1 1.4-7.5
LDL-Cholesterol
LDL-C ( mmol/L ) Baseline Month 6 Month 12 Month 24 Month 36 Month 48 n 273 244 231 191 159 116
mean 2.69 2.52 2.53 2.53 2.57 2.50
100% 93.7% 94.1%
-6.3% -5.9%
s.d. 0.932 0.818 0.835 0.872 0.837 0.755 median 2.67 2.40 2.43 2.44 2.57 2.51
25-27m percentiles 2.04-3.23 1.85-3.10 1.94-3.01 1.88-3.01 1.97-3.03 2.03-2.85
Minimum - maximum 0.7-5.8 1.0-5.8 0.6-5.1 0.7-5.1 1.1-6.0 1.0-5.1
Cholesterol (VLDL)
VLDL-C ( mmol/L ) Baseline Month 6 Month 12 Month 24 Month 36 Month 48 n 273 244 231 192 160 116 mean 0.90 0.58 0.60 0.59 0.60 0.63 s.d. 0.420 0.315 0.323 0.296 0.334 0.330 median 0.79 0.50 0.50 0.52 0.52 0.56
25-27m percentiles 0.59-1.12 0.35-0.75 0.38-0.77 0.38-0.73 0.37-0.76 0.40-0.79
Minimum - maximum 0.3-3.1 0.1-1.9 0.1-1.7 0.2-1.7 0.2-1.8 0.2-1.9
Triglycerides
TG ( mmol/L ) Baseline Month 6 Month 12 Month 24 Month 36 Month 48 n 277 246 232 195 161 117 mean 2.05 1.30 1.33 1.36 1.34 1.38
100% 63.4% 64.9%
-36.6% -35.1%
s.d. 1.069 0.812 0.736 0.918 0.775 0.718 median 1.77 1.10 1.11 1.14 1.12 1.23
25-27m percentiles 1.31-2.48 0.77-1.64 0.84-1.69 0.82-1.61 0.80-1.66 0.86-1.67
Minimum - maximum 0.5-6.9 0.3-7.1 0.3-4.6 0.3-9.1 0.4-4.7 0.3-4.2
Glycosylated
hemoglobin HbA1c (%) Baseline Month 6 Month 12 Month 24 Month 36 Month 48 n 269 235 220 189 172 154 mean 5.61 5.42 5.33 5.41 5.38 5.43
100% 96.6% 95.0%
-3.4% -5%
s.d. 0.704 0.511 0.546 0.484 0.737 0.793 median 5.50 5.40 5.30 5.40 5.30 5.30
25-27m percentiles 5.20-5.90 5.10-5.70 5.05-5.50 5.20-5.60 5.10-5.50 5.10-5.50
Minimum - maximum 3.8-10.4 3.9-9.9 3.9-10.3 4.1-9.2 3.9-12.9 3.6-13.1
Table 2: Cardiac risk factors, medication usage and medical history of patients of the "Imatinib 400 mg qd" arm of the ENESTnd study (N=280) at start of the treatment (baseline)
Table 3: Cardiovascular events (CVE) in the patient population of the "Imatinib 400 mg qd" arm of the ENESTnd study
Possible use of imatinib for the management of lipids and cardiovascular risks
Patients for example with significant cardiovascular risks such as patients with
hyperlipidemia on statin therapy would initiate outpatient therapy with imatinib, at the dose of 400 mg daily, taken with food and a glass of water. Prior to starting imatinib therapy, the lipid profile would be established as a baseline to monitor the effects of the therapy. This would consist of routine standard clinical laboratory assessment of total cholesterol (TC), HDL-C, LDL-C, triglycerides (TG), and HbA1 c. As patients continue therapy, this lipid profile would be monitored at month 6, and yearly starting at month 12 thereafter. Therapy would continue as long as the need to reduce cardiovascular risks is present, which may be life-long for patients with a history of prior significant cardiovascular disease such as a myocardial infarction for example.
Claims
Imatinib or any pharmaceutically acceptable salt thereof for use as cholesterol ratio (total cholesterol / HDL cholesterol) decreasing agent.
Imatinib or any pharmaceutically acceptable salt thereof for use as cholesterol ratio (total cholesterol / HDL cholesterol) decreasing agent in the treatment of
hyperlipidemia, hypercholesterolemia or hypertriglyceridemia
Imatinib or any pharmaceutically acceptable salt thereof for use according to claim 1 or 2 wherein Imatinib is used as cholesterol ratio (total cholesterol / HDL cholesterol) decreasing agent and as HDL cholesterol increasing agent.
Imatinib or any pharmaceutically acceptable salt thereof for use according to claim 1 or 2 wherein Imatinib is used as cholesterol ratio (total cholesterol / HDL cholesterol) decreasing agent and as HDL cholesterol increasing agent and as triglycerides decreasing agent.
Imatinib or any pharmaceutically acceptable salt thereof for use according to any of the preceding claims, wherein the cholesterol ratio (total cholesterol / HDL cholesterol) latest after 12 months, preferably latest after 6 months, from start of treatment with imatinib is decreased by at least by 10%, preferably by at least 20%, compared to the cholesterol ratio at start of the treatment with imatinib.
Imatinib or any pharmaceutically acceptable salt thereof for use according to any of the preceding claims wherein the cholesterol ratio decrease is further characterized by an increased level of the HDL cholesterol and by unchanged or decreased levels of LDL, triglycerides, and total cholesterol latest after 12 months, preferably latest after 6 months, from start of the treatment with imatinib compared to the levels at start of the treatment with imatinib.
Imatinib or any pharmaceutically acceptable salt thereof for use according to any of the preceding claims wherein the cholesterol ratio decrease is further characterized by an increased level of the HDL cholesterol, by an decreased level of triglycerides, and by unchanged or decreased levels of LDL and total cholesterol latest after 12 months,
preferably latest after 6 months, from start of the treatment with imatinib compared to the levels at start of said treatment.
8. Imatinib or any pharmaceutically acceptable salt thereof for use according to any of the preceding claims wherein the HDL cholesterol level increase is of at least 10%, preferably at least 20%.
9. Imatinib or any pharmaceutically acceptable salt thereof for use according to any of the preceding claims wherein the triglycerides level decrease is of at least 10%, preferably at least 20%, more preferably at least 30%.
10. Imatinib or any pharmaceutically acceptable salt thereof for use according to any of the preceding claims wherein the LDL cholesterol level is decreased by at least 5%.
1 1 . Imatinib or any pharmaceutically acceptable salt thereof for use according to any of the preceding claims wherein the total cholesterol level is decreased by at least 4%.
12. Imatinib or any pharmaceutically acceptable salt thereof for use according to any of the preceding claims wherein the hyperlipidemia or hypercholesterolemia is defined by cholesterol ratios (total cholesterol / HDL cholesterol) of 5 or higher before starting with the treatment of imatinib.
13. Imatinib or any pharmaceutically acceptable salt thereof for use according to any of the preceding claims wherein the hyperlipidemia or hypercholesterolemia is defined by total cholesterol levels of 200 mg/dL or higher, more particularly 240 mg/dL or higher, before starting with the treatment of imatinib.
14. Imatinib or any pharmaceutically acceptable salt thereof for use according to any of the preceding claims wherein the hyperlipidemia or hypercholesterolemia is defined by HDL cholesterol levels of 50 mg/dL or lower, more particularly 40 mg/dL or lower, before starting with the treatment of imatinib.
15. Imatinib or any pharmaceutically acceptable salt thereof for use according to any of the preceding claims wherein the hyperlipidemia or hypercholesterolemia is defined by LDL
cholesterol levels of 130 mg/dL or higher, more particularly 160 mg/dL or higher, before starting with the treatment of imatinib.
16. Imatinib or any pharmaceutically acceptable salt thereof for use according to any of the preceding claims wherein the hyperlipidemia or hypertriglyceridemia is defined by triglycerides levels of 150 mg/dL or higher, more particularly 200 mg/dL or higher, before starting with the treatment of imatinib.
17. Imatinib or any pharmaceutically acceptable salt thereof for use according to any of the preceding claims wherein the treatment comprises a daily dose of imatinib of 400 mg.
18. Imatinib or any pharmaceutically acceptable salt thereof for use according to any of the preceding claims wherein the imatinib is in the form of the mesylate salt.
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Citations (2)
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GOLOGAN R ET AL: "Hypolipemiant besides antileukemic effect of imatinib mesylate", LEUKEMIA RESEARCH, NEW YORK,NY, US, vol. 33, no. 9, September 2009 (2009-09-01), pages 1285 - 1287, XP026222040, ISSN: 0145-2126, [retrieved on 20090326], DOI: 10.1016/J.LEUKRES.2009.02.024 * |
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