(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World .. !=.~: o,..m...uon .1m11m111u11011111111rn11111111111n111111111l11lllllHI
`
`(43) International Publication Date
`15 June 2006 (15.06.2006)
`
`PCT
`
`(10) International Publication Number
`WO 2006/062748 A2
`
`(51) InternatlonaJ Patent CtmmlfJcaUon:
`A61K 311426 (2006.01)
`A61K 311202 (2006.01)
`
`(21) Internatlonal Appllcatlon Number:
`PCT/US200S/042648
`
`(22) International Flllng Date:
`22 November 2005 (22.11.2005)
`
`(25) Filing Langwige:
`
`(26) Publlcatlon Language:
`
`English
`
`English
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AB, AG, AL, AM,
`AT, AU, AZ, BA, BB, BO, BR, BW, BY, BZ. CA, CH, CN,
`CO, CR. CU, CZ. DE, DK, DM, OZ. EC, EE, EO, ES, Fl,
`GB, OD, OE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE,
`KG, KM, KN, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV,
`LY, MA, MD, MG, MK, MN, MW, MX, MZ, NA, NG, NI,
`NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG,
`SK, SL, SM, SY, TJ, TM, TN, TR, TI. TZ, UA, UG, US,
`UZ. VC, VN, YU, ZA, ZM, 'ZW.
`
`(30) Priority Data:
`60/633,125
`60/659,099
`60/699,866
`
`6 December 2004 (06.12.2004)
`8 March 2005 (08.03.2005)
`18 Jnly 2005 (18.07.2005)
`
`us
`us
`us
`(71) Appllcant (for all designaled States except US): RE·
`LIANT PHARMACEUTICALS, INC. [US/US]; 110
`Allen Road, Liberty Comer, NJ 07938 (US).
`
`(75) lnventors.IAppDcaots (for US only): RONGEN, Roelof',
`M., L [Nl.JUS]; 131 Fairmount Road, East, Caliton, NJ
`07930 (US). BOBOTAS, George [USIUS]; 1245 North
`Florida Avenue, Tarpon Springs, Fl... 34689 (US).
`(74) Agents: BERMAN, Richard, J. et al.; ARENT FOX,
`PLLC, 1050 Connecticut Avenue NW, Washington, DC
`20036 (US).
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`OM, KE, LS, MW,MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY. KG, KZ, MD, RU, TJ, TM).
`Enropean (AT, BE, BO, CH, CY, CZ. DE, DK, EE, ES, FL
`FR. GB, OR, HU, IE, IS, IT, LT, LU, LV, MC, NL, PL, PT,
`RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CO, Cl, CM, GA,
`GN, GQ, GW, ML, MR, NE, SN, TD, TO).
`
`Published:
`-
`without inlemational search repon and to be republished
`upon receipt of that repon
`
`For two-letter codes and other abbreviations, ref er to the "Guid(cid:173)
`ance Notes on Codes andAbb~iations" appearing at the begin(cid:173)
`·ning of each ~gular issue of the PCT Gazene.
`
`= (72) Inventors; and
`
`-
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`-
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`-
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`-
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`-iiiiiiii --
`iiiiiiii ----
`--iiiiiiii
`---
`M <
`QC
`~ r(cid:173)
`M
`\C ________________________________________________________________________ ~
`~ (54) TIUe: OMEOA-3 FATIY ACIDS AND DYSLIPIDEMIC AGENT FOR LIPID THERAPY
`= = (57) Abstract: A method and composition for blood lipid therapy by administering to the subject an effective amount of a dyslipi-
`M demic agent and omega-3 fatty acids. The method utilius a single adminis1I11tion or a unit dosage of a combination of dyslipidemic
`0 agent and omega-3 fatty acids for the treatment of patients with hypertriglyceridemia, h)'percholesterolemia, mixed dyslipidemia,
`:> coronary heart disease (CHD), vascular disease, artherosclerotic disease and related conditions, and the prevention or reduction of
`~ cl!Idiovascular and vascular events.
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`OMEGA-3 FATTY ACIDS AND DYSLIPIDEMIC AGENT
`FOR LIPID THERAPY
`
`[0001) The present application claims priority from provisional patent
`
`application Serial No. 60/633, 125, filed December 6, 2004, Serial No.
`
`60/659,099, filed March 8, 2005, and Serial No. 60/699,866, filed July 18,
`
`2005. The disclosure of the provisional applications Is hereby incorporated by
`
`reference.
`
`FIELD OF THE INVENTION
`
`[0002] The present Invention relates to a method utilizing a single
`
`administration or a unit dosage of a combination of a dyslipidemic agent and
`
`omega-3 fatty acids for the treatment of patients With hypertriglyceridemia,
`
`coronary heart disease (CHO), vascular disease, artherosclerotic disease and
`
`related conditions, and the prevention or reduction of cardiovascular and
`
`vascular events.
`
`BACKGROUND OF THE INVENTION
`
`[0003)
`
`. In humans, cholesterol and triglycerides are part of lipoprotein
`
`complexes In the bloodstream, and can be separated via ultracentrifugation
`
`into high-density lipoprotein (HDL), intermediate-density lipoprotein (JDL), low(cid:173)
`
`density lipoprotein (LDL) and very-low-density llpoprotein {VLDL) fractions.
`
`Cholesterol and triglycerides are synthesized in the liver, incorporated Into
`
`VLDL, and released into the plasma. High levels of total cholesterol (total-C).
`
`LDL-C, and apollpoprotein B (a membrane complex for LDL-C and VLDL-C)
`
`promote human atherosclerosis and decreased levels of HDL-C and Its
`
`transport complex, apolipoprotein A, which are associated with the
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`development of atherosclerosis. Further, cardiovascular morbidity and
`
`mortality in humans can vary directly with the level of total-C and LDL-C and
`
`inversely with the level of HDL-C. In addition, researchers have found that
`
`non-HDL cholesterol is an important indicator of hypertriglyceridemla,
`
`vascular disease, artherosclerotic disease and related conditl.ons. In fact,
`
`recenUy non-HDL cholesterol reduction has been specified as a treatment
`
`objective in NCEP ATP Ill.
`
`[0004] Agents, such as dyslipidemic agents and omega-3 fatty acids, have
`
`been used to treat post-myocardial infarction (Ml) and adult endogenous
`
`hyperllpldemlas of hypercholesterolemlas and of hypertriglyceridemlas1whlch
`
`are generally categorized as "cardiovascular events".
`
`[0005] Dysllpldemlc agents commonly Include HMG CoA inhibitors (statins),
`
`cholesterol absorption inhibitors, niacin and derivatives such as nlcotlnamlde,
`
`fibrates, bile acid sequestrants, MTP inhibitors, LXR agonists and/or
`
`antagonists and PPAR agonists and/or antagonists ..
`
`[0006] Statins, which are 3-hydroxy-3-methyl glutaryl coenzyme A (HMG(cid:173)
`
`CoA) reductase inhibitors, have been used to treat hyperlipldemia and
`
`arthrosclerosis, for example. Typically, statln monotherapy has been used to
`
`treat cholesterol levels, particularly when a patient is not at an acceptable
`
`LDL-C level. Statins inhibit the enzyme HMG-CoA reductase, which controls
`
`the rate of cholesterol production in the body. Stalins lower cholesterol by
`
`slowing down the production of cholesterol and by increasing the liver's ability
`
`to remove the LDL-cholesterol already in the blood. Accordingly, the major
`
`effect of the statlns Is to lower LDL-cholesterol levels. Statlns have been
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`shown to decrease CHO risk by about one.:.thlrd. However, statins only
`
`appear to have a modest effect on the TG-HDL axis.
`
`;
`
`[0007] Cholesterol absorption inhibitors, such as ezetlmibe and MD-0727,
`
`are a class of lipid-lowering compounds that s~lectively inhibit the intestinal
`
`absorption of cholesterol. Ezetimibe acts on brush border of the small
`
`intestine and decreases biliary and dietary cholesterol from the small intestine
`
`uptake into the enterocytes.
`
`[0008] Cholesteryl ester transfer protein (CETP) inhibitors, such as
`
`torcetraplb, Inhibit the CETP molecule which, among other things, moves
`
`cholesterol from the HDL form to the LDL form. Inhibiting this molecule is,
`
`therefore, a promising approach to increasing HDL cholesterol levels.
`
`[0009] Niacin (nlcotinic acid or 3-pyridinecarboxyllc acid) has previously been
`
`used to treat hyperlipidemia and atherosclerosis! Niacin Is known to reduce
`
`total cholesterol, LDL-C and triglycerides and increase HDL-C. Niacin therapy
`
`·is also known to decrease serum levels of apolipoprotein B (Apo B), the major ..
`
`protein component of VLDL-C and LDL-C fractions. However, the magnitude
`
`of the individual lipid and lipoprotein response from niacin therapy may be
`
`influenced by the severity and type of underlying lipid abnormality.
`
`[00010] Fibrates such as fenofibrate, bezafibrate, clofibrate and gemfibrozil,
`
`are PPAR-alpha agonists and are used in patients to decrease lipoproteins
`
`rich in triglycerides, to increase HDL and to decrease atherogenlc-dense LDL.
`
`Fibrates are typically orally administered to such patients.
`
`[00011] Fenofibrate or 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic
`
`acid, 1-methylethyl ester, which belongs to the fibrate family, has been known
`
`for many years as a medicinal active principle because. of its efficacy in
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`lowering blood triglyceride and cholesterol levels: Fenofibrate is an active
`
`principle which is very poorly soluble In water and the absorption of
`
`fenofibrate In the digestive tract is limited. A treatment of 40 to 300 mg of
`
`fenofibrate per day enables a 20 to 25% reduction of cholesterolemia and a
`
`40 to 50% reduction of triglyceridemia to be obtained.
`
`[00012] Bile acid sequestrants, such as cholestyi'amine, colestipol and
`
`colesevelam, are a class of drugs that binds bile acids, prevents their
`
`reabsorption from the digestive system, and reduces cholesterol levels. The
`
`usual effect of bile acid sequestrants Is to lower LDL-cholesterol by about 1 O
`
`to 20 percent. Small doses of sequestrants can produce useful reductions in
`
`LDL-cholesterol.
`
`[00013] MTP Inhibitors, such as implltaplde, are known to inhibit the
`
`secretion of cholesterol and triglyceride.
`
`[00014] Liver X receptors (LXRs) are ncholesterol sensorsn that regulate the
`
`expression of genes involved in lipid metabolism In response to specific
`
`oxysterol ligands (Repa et al., Annu. Rev. Cell Dev. Biol. 16: 459-481 (2000)).
`
`LXR agonlsts and antagonists are potential therapeutic agents for
`
`dyslipidemla and atherosclerosis.
`
`(00015] PPAR-gamma agonists, such as the thlazolidlnediones pioglitazone
`
`and rosiglitazone, have been shown to improve surrogate markers of
`
`cardiovascular risk and atherosclerosis. For example, thiazolidlnediones
`
`decrease C-reactive protein and carotid intlma-medla thickness. Non(cid:173)
`
`thlazolidinediones, such a$ tesaglltazar, navlglltizar and muraglitazar, are
`
`dual alpha/gamma PPAR agonlsts. These compounds are used for lowering
`
`glucose, insulin, triglycerides and free fatty acids.
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`[00016] Partial PPAR-gamma agonist/antagonists, such as metaglidasen,
`
`are used for the treatment of type 11 diabetes.
`
`[00017] Marine oils, also commonly referred to as fish oils, are a good source
`
`of two omega-3 fatty acids, eicosapentaenoic acid (EPA} and
`
`docosahexaenolc acid (DHA}, which have been found to regulate lipid
`
`metabolism. Omega-3 fatty acids have been found to have beneficial effects
`
`on the risk factors for cardiovascular diseases, especially mild hypertension,
`
`hypertrigiyceridemia and on the coagulation factor Vil phospholipld complex
`
`activity. Omega-3 fatty acids lower serum triglycerides, increase serum HDL(cid:173)
`
`cholesterol, lower systolic and diastolic blood pressure and the pulse rate, and
`
`lower the activity of the blood coagulation factor Vll-phosphollpid.complex.
`
`Further, omega-3 fatty acids seem to be well tolerated, without giving rise to
`
`any severe side effects.
`
`[00018) One such form of omega-3 fatty acid is a concentrate of omega-3,
`
`long chain, polyunsaturated fatty acids from fish oil containing DHA and EPA
`
`and Is sold under the trademark Omacor®. Such a form of omega-3 fatty acid ·
`
`Is described, for example, in U.S. Patent N0s. 5,502,077, 5,656,667 and
`
`5,698,594, each incorporated herein by reference.
`
`[00019] Patients with mixed dyslipidemia or hypercholesteremla often
`
`present with blood levels of LDL cholesterol greater than 190 mg/di and
`
`triglyceride levels of 200 mg/di or higher. The use of diet and single-drug
`
`therapy does not always decrease LDL cholesterol and triglycerides
`
`adequately enough to reach targeted values in patients with mixed
`
`dysllpidemla or hypercholesterolemia with or without a concomitant increase
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`in triglycerides. In these patients~ a complementary combination therapy of a
`
`dyslipidemlc agent and omega-3 fatty acids may be desirable.
`
`[00020] Studies have examined the effects of fish oil and statln therapy. One
`
`study found that fish oil and lovastatin increases plasma LDL cholesterol and
`
`VLDL cholesterol. Satfy et al., Pakistan J. of Pharm. Sci. (2003) 16(2): 1-8.
`
`Nakamura et al. investigated the effeCts of purified EPA and statlns on
`
`patients with hyperllpldemla. Patients having baseline triglyceride levels of
`
`2.07 mmol/I (about 182 mg/di) and already treated with 5-20 mg/day
`
`pravastatin or 5 mg/day simvastatin were additionally treated for 3 months
`
`with 900or1800 mg/day purified (>90%) EPA ethyl ester. It was reported that
`
`combination treatment significantly reduced triglyceride levels, and
`
`significantly Increased HDL-C levels, as compared to baseline monotherapy.
`
`LDL-C levels were not reported. Nakamura etal., Int. J. Clin. Lab Res. 29:22-
`
`25 (1999).
`
`[00021] Davidson et al. Investigated the effects of marine oil and simvastatln
`
`in patients with combined hyperlipidemla. Patients having baseline
`
`triglyceride levels of 274.7 mg/di to 336.8 mg/di were treated for"12 weeks
`
`with 10 mg/day simvastatin and placebo, 7.2 g/day marine oil (SuperEPA9
`
`1200) and placebo, or a combination of slmvastatin and SuperEPA9 . The
`
`content of omega-3 fatty acids In 7.2 g of marine oil used In the study was 3.6
`
`g, with an EPA/DHA ratio of 1.5. Combination treatment was shown to
`
`significantly Increase HDL-C levels, as compared to marine oil alone. In
`
`addition, triglyceride and non-HDL-C levels were significantly reduced with
`
`combination treatment. However, non-HDL-C levels were reported to be
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`reduced less with combination treatment than with simvastatin alone.
`
`Davidson et al., Am J Cardlol (1997) 80: 797-798.
`
`[00022] Hong et. al. investigated the effects of fish oil and simvastatin in
`
`patients with coronary heart disease and mixed dyslipidemia. Patients having
`
`baseline triglyceride levels of 292.8 mg/di or 269.5 mg/di were initially treated
`
`with 10-20 mg/day simvastatin for 6-12 weeks. Thereafter the patients were
`
`treated with simvastatln and placebo or simvastatin and 3 g/day fish oil
`
`(Meilekang™). Combined treatment significantly reduced triglyceride levels,
`
`as compared to baseline and placebo. In addition, com.bined treatment
`
`numerically increased HDL-C levels, and numerically reduced LDL-C levels,
`
`as compared to baseline. However, the changes In HDL-C levels and LDL-C
`
`levels were not statistically significant. Hong et al., Chin. Med. Sci. J. 19:145-
`
`49 (2004).
`
`[00023] Contacos et al. investigated the effects of fish oil and pravastatin on
`
`patients with mixed hyperllpldemia. Patients having baseline triglyceride
`
`leveis of 4.6 to 5.5 mmol/I (404 to 483 mg/di) were initially treated for 6 weeks
`
`with 40 mg/day pravastatin, 6 g/day fish oil (Himega™, containing 3 g of
`
`omega-3 fatty acids, with an EPA/DHA ratio of 2:1 ), or placebo. Thereafter,
`
`all patients were treated with pravastatln and fish oil for an additional 12
`
`weeks. Initial treatment with pravastatin significantly reduced LDL-C levels.
`
`Combined treatment of pravastatin and fish oil also signiflcantiy reduced
`
`trjg~yc~ri~e and ~DL~ ~eve~s~ tiowever, the addition of fish oil to pravastatin
`
`monotherapy resulted in only a numerical increase in LDL-C levels, which
`
`was not statistically significant. Treatment with fish oil alone significantly
`
`reduced triglyceride levels, but increased LDL-C levels. Combined treatment
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`for this group significantly reduced LDL-C levels, as compared to fish oil. alone
`
`(but not as compared to baseline). Contacos et al., Arterioscl. Thromb.
`
`13:1755-62 (1993).
`
`(00024] Singer investigated the effects of fish oil and fluvastatin on patients
`
`with combined hyper11pldemla. Patients having baseline triglyceride levels of
`
`· 258 mg/di were Initially treated.for two months with 40 mg/day fluvastatin, and
`
`thereafter were additionally treated for two months with 3 g/day fish oil (18%
`
`EPA and 12% DHA). Thereafter, the patients remained on fluvastatin therapy
`
`alone for a final two months. Fluvastatin monotherapy was shown to
`
`significantly reduce triglyceride and LDL-C levels, and significantly Increase
`
`HDL-C levels. Combination treatment significantly reduced triglyceride and
`
`LDL-C levels and resulted In an additional numerical reduction of triglyceride
`
`and LDL-C levels,. as compared to fluvastatln alone. Combination treatment
`
`numerically increased HDL-C levels, as compared to monotherapy, although
`
`the increase in HDL-C levels with combined treatment was not statistically·
`
`significant. Singer, Prost. Leukotr. Ess. Fatty Acids 72:379-80 (2005).
`
`[00025] Liu et al. investigated the effects of fish oil and simvastatin In patients
`
`with hyperlipidemia. Patients having baseline triglyceride levels of 1.54 to
`
`1.75 mmol/I (about 136to154 mg/di) were treated for 12 weeks with 10
`
`mg/day slmvastatln, 9.2 g/day fish oil (Eskimo-3), or a combination of
`
`slmvastatin and Eskimo-3. The fish oil cont.alned 18% EPA, 12% DHA, and a
`
`total of 38% omega-3 fatty acids. Combined treatment significantly reduced
`
`triglyceride and LDL-C levels, and significantly increased HDL-C levels, as
`
`compared to baseline, and significantly reduced triglycer1de levels as
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`compared to slmvastatin alone. Liu et al., Nutrition Research 23 (2003) 1027-
`
`1034.
`
`[00026] An additional study concluded that the combined treatment of low(cid:173)
`
`dose pravastatin and fish oil after dinner In post-renal transplantation
`
`dlsllpldemla is more effective to change the lipid profile after renal
`
`transplantation. Grekas et al., Nephron {2001) 88: 329-333. One article
`
`summarizes the combination drug therapies for dyslipldemia, including the
`
`combination of statlns and 3-7 mg fish oil per day. The study indicates that
`
`combination therapy may further augment the reduction of triglyceride, total
`
`cholesterol, and apollprotein E levels, as compared with patients on a statin
`
`alone. Alaswad et al., Curr. Atheroscler. Rep. (1999) 1: 44-49. In another
`
`study, It was found that the combination of dietary fish oil and lovastatln
`
`reduces both very low-density lipoprotein (VLOL) and low density lipoproteln
`
`(LOL). Huff et al., Arterosclerosls and Thrombosis, 12(8): 901-910 {August
`
`1992).
`
`[00027] Additional studies have examined the effects of statlns in
`
`combination with administration of omega-3 fatty acids and concluded that a
`
`diet rich in omega-3 fatty acids increased the cholesterol-lowering effect of
`
`simvastatln, counteracted the fasting Insulin-elevating effect of simvastatin
`
`and did not decrease serum levels of P-carotene and ubiquinol-10. Jula et al.,
`
`JAMA 287 (5) 598-605 (February 6, 2002). Another study showed an .
`
`increase in thiobarblturlc acld-malondialdehyde complex {TBA-MOA) by using
`
`EPA and DHA and statins {e.g., slmvastatin) did not affect this result. Grundt
`
`et al., Eur. J of Clin. NiJtr. {2003) 57: 793-800.
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`[00028] U.S. Patent No. 6,720,001 discloses a stabilized pharmaceutical oil(cid:173)
`
`in-water emulsion for delivery of a polyfunctlonal drug having the drug, an
`
`aqueous phase, an oil phase and an emulsifier. Stalins are claimed among a
`
`list of possible polyfunctlonal drugs, and fish oil is claimed as one of seven
`
`optional components for the oil phase. Moreover, U.S. Patent Application
`
`_Publicati_o~ ~o. 20q2100~~317 claims compositions of statins and
`
`polyunsaturated fatty acids (PUFAs) (EPA and DHA), while U.S. Patent
`
`· Application Publication No. 2003/0170643 claims a method of treating a
`
`patient, by administering a therapeutic which lowers plasma concentrations of
`
`apoB and/or an apoB-containing lipoproteln and/or a component of an
`
`atherogenic lipoproteln by stimulating post-ER pre-secretory proteolysis
`
`(PERPP) using the combination of fish oils with statins, such as pravastatin,
`
`lovastatln, slmvastatin, atorvastatin, fluvastatin and cerivastatin.
`
`[00029] Studies have also investigated the effect of statins and concentrated
`
`omega-3 fatty acids, specifically the Omacor9 omega-3 acids. For example,
`
`Hansen et al. Investigated the effect of lovastatln (40 mg/day) in combination
`
`with fish oil concentrate (6 g/day Omaco.-6 omega-3 acids) in patients with
`
`hypercholesterolemia. Patients having baseline triglyceride levels of 1.66
`
`mmol/I (about 146 mg/di) were treated with 6 g/day Omacor® for 6 weeks,
`
`followed by 40 mg/day lovastatin for an additional 6 weeks, and a combination
`
`of both Omacor9 and lovastatln for a final 6 weeks. Lovastatln monotherapy
`
`resulted in ~igr:iifi~nt Increases in HDL-C levels, and significant decreases in
`
`triglyceride and LDL-C levels. After combination treatment. triglyceride and
`
`LDL-C levels were further significantly decreased. Hansen et al.,
`
`Arteriosclerosis and Thrombosis 14(2): 223-229(February1994).
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`[00030] Nordoy et al. Investigated the effect of atorvastatin and omega-3 fatty
`
`acids on patients with hyperlipemia. Patients having baseline triglyceride
`
`levels of 3.84 mmoVI (about 337 mg/di) or 4.22 mmoVI {about 371 mg/di) were
`
`treated with 10 mg/day. atorvastatln for 5 weeks. Thereafter, for an additional
`
`5 weeks, atorvastatin treatment was supplemented with 2 g/day Omacor® or.
`
`placebo. Atorvastatln monotherapy, significantly increased HDL-C levels, and
`
`triglyceride and LDL-C levels significantly decreased, as compared to
`
`baseline. Combination treatment furtherincreased HDL-C levels, as
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`compared to atorvastatin alone. Triglyceride and LDL-C levels numerically
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`further declined slightly with combination treatment, as compared to
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`atorvastatin monotherapy; however, the. decrease was insignificant, and the·
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`numerical reduction in triglyceride and LDL-C levels was less than with the
`
`reduction experienced by the 0 atorvastetln + placebo• group. The study
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`concluded that the addition of omega-3 fatty acids to statin (e.g., atorvastatin)
`
`treatment was an efficient alternative to treating combined hyperllpemla, as
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`the fatty aclds further increased HDL-C and reduced systolic blood pressure.
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`Nordoy et al., Nutr. Metab. Cardlovasc. Dis. '(2001) 11 :7-16.
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`[00031] Salvi et al. investigated the effects of Omaco~ and slmvastatin on
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`patients with familial hypercholesterolemia. Patients having baseline
`
`triglyceride levels of 1.355 mmol/I (about 119 mg/di) and already treated with
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`20-40 mg/day simvastatin were additionally treated with 6 g/day Omaco~ for
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`4 weeks. It was shown that combination treatment significantly decreased
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`triglyceride and LDL-C levels after 2 weeks, as qompared to baseline
`
`monotherapy. Salvi et al., Cun: Thar. Res. 53:717-21 (1993). Yet another
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`study investigated the effects of omega-3 fatty acids (2 g Omacor® omega-3
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`acids twice a day) for treating subjects with established CHO and type llb
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`hyperlipldemla who were already taking simvastatin. The study concluded
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`that the Omacor® omega-3 acids was effective In lowering serum triglyceride
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`levels In patients taking simvastatln. Bhatnagar et al., Eur. Heart J
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`Supplements (2001) 4 (Suppl. D): 053-058.
`
`[00032) Chan et al. studied the combined treatment of atorvastatin (40
`
`mg/day) and fish oil (4 Omacc>r® omega-3 acid capsules orally at night, 4
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`g/day) on obese, Insulin-resistant men with dyslipldemia studied in a fasted
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`state. Patients having baseline triglyceride levels of 1. 7 to 2.0 mmol/I (about
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`150 to 170 mg/di) were treated for 6 weeks with: 40 mg/day atorvastatin and
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`placebo; 4 g/day Omacor® and placebo; a combination of atorvastatin and
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`Omacor®; or a combination of placebos. Combination treatment significantly
`
`decreased triglyceride, non-HDL-C and LDL-C levels, and significantly
`
`increased HDL-C, as compared to the placebo group. Chan et al., Diabetes,
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`51: 2377-2386 (Aug. 2002). An additional paper investigated the effects of
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`atorvastatln (40 mg/day) and fish oil (4 g/day Omacor® omega-3 acids at
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`night) on obese men with dyslipldemla and Insulin resistance. The treatment
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`groups received a placebo, atorvastatln, the Omacor® omega-3 acids, or a
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`combination thereof at night. The paper concluded that combination
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`treatment of statins and fish oil may be the optima! approach for correcting
`
`dyslipidemia in obese men. Chan et al., Eur. J of Clin. Invest. (2002) 32: 429-
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`436. Another paper Investigated the effects of atorvastatin (40 mg/day) and
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`fish oil (4 g/day Omacor® omega-3 acids at night) on plasma high-sensitivity
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`C-reactlve protein concentrations in obese individuals with dysllpldemla. The
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`paper concluded that although fish oil supplementation had no effect on
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`plasma hs-CRP. the addition of fish oil to statins may further optimize lipid(cid:173)
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`regulatlng effects by enhancing a decrease in plasma triglycerides and
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`increase in HDL-C. Chan et al., Clinical Chemistry (2002) 48(6): 877-883.
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`[00033) Nordoy et al. investigated the effect of omega-3 fatty acids (3.6 g/day
`
`via 4 g/day Omacor® omega-3 acids) and simvastatln (20 mg/day) on patients
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`with combined hyperlipemia. The study concluded that supplementation with
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`the fatty acids reduced hemostatic risk factors and significantly reduced
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`postprandial hyperllpemia. Nordoy et al., Arterloscler. Thromb. Vase. Bio/.
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`(2000) 20:259-265.
`
`(00034) Nordoy et al. also investigated the efficiency and the safety of
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`treatment with simvastatln and omega-3 fatty acids in patients with
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`hyperlipidemia. Nordoy et al., J. of Internal Medicine, 243:163-170 (1998).
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`Patients having baseline triglyceride levels of 2. 76 mmoVI (about 243 mg/di)
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`or 3.03 mmol/l (about 266 mg/di) were treated for 5 weeks with 20 mg/day
`
`simvastatin or placebo, then all patients were treated for an additional. 5
`
`weeks with 20 mg/day simvastatin. Thereafter, patients were additionally
`
`treated with 4 g/day Omacor® or placebo, for a further 5 weeks. The
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`administration of omega-3 fatty acids with simvastatin resulted in moderate
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`reductions in serum total cholesterol and reduction in triglycerol levels. HDL(cid:173)
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`C levels slightly decreased, and LDL-C levels slightly increased, with the
`
`addition of Omacor®, as compared to the baseline monotherapy.
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`(00035) Durrington et al. examined the effectiveness, safety, and tolerability
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`of a combination of Omacor® omega-3 acids and simvastatin in patients with
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`established coronary heart disease and persisting hypertriglycerldemla.
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`Patients having an average baseline triglyceride levels > 2.3 mmol/1 (average
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`patient serum triglyceride level was 4.6' mmol/I), were treated with 10-40
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`mg/day slmvastatln and 2 g/day Omacor® or placebo, for 24 weeks in a
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`double-blind trial, after which both groups were invited to receive Omacor® for
`
`a further 24 weeks in an open study. Combination treatment significantly
`
`decreased triglyceride levels within 12 weeks, as compared to baseline
`
`monotherapy. In particular, the serum triglyceride levels in patients receiving
`
`slmvastatin and Omacor® omega-3 acids decreased by 20-30%. In addition,
`
`the VLDL cholesterol levels In these patients decreased by 30-40%. LDL-C
`
`levels significantly decreased, as compared to baseline monotherapy, only
`
`after 48 weeks, although there was a numerical (statistically insignificant)
`
`decrease at 12 and 24 weeks. Ourrington et al., Heart, 85:544-548 (2001).
`
`[00036) U.S. Patent No. 6,096,338, U.S. Patent No. 6,267,985, U.S. Patent
`
`No. 6,667,064, U.S. Patent No. 6,720,001, U.S. PatentAppllcation Publication
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`No. 2003/0082215, U.S. Patent Application Publication No. 2004/0052824,
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`WO 99/29300 and WO 2001/021154 disclose compositions, carrier systems
`
`and oil-In-water emulsions containing digestible oils or triglycerides with an
`
`active Ingredient, such as fenofibrate.
`
`[00037] U.S. Patent No. 6,284,268 is directed to self-emulsifying
`
`preconcentrate pharmaceutical compositions capable of forming oil-in-water
`
`microemulsions or emulsions upon dilution with an aqueous solution, and
`
`containing an omega-3 fatty acid oil and a poorly water soluble therapeutic
`
`agent, such as a cyclosporin. The '268 patent formulations use a large
`
`amount of surfactant (generally higher than 50% w/w, based on the weight of
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`the solvent system), and less than 10% w/w of a hydrophilic solvent system,
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`to achieve the self-emulsifying compositions. Formulation 19 discloses a self-
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`emulsifying preconcentrate product outside of the scope of the claims of the(cid:173)
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`'268. patent, containing 284 mg of fish oil (about 23% w/w based on the weight
`
`of the solvent system, including the fish oil), 663 mg of a surfactant system
`
`(about 55% w/w based on the weight of the solvent system), 273 mg of a
`
`hydrophilic solvent system (about 22% w/w based on the weight of the solvent
`
`system), and 100 mg of fenofibrate. There Is no disclosure or suggestion in
`
`the '268 patent of a fenofibrate formulation having a solvent systerri based
`
`mainly on fish oil, without the use of a large amount of surfactant. Nor is there
`
`any disclosure In the '268 patent regarding administration of the self(cid:173)
`
`emulsifylng preconcentrate fenofibrate product to subjects for any treatment.
`
`Rather, the '268 patent seemed to use fenofibrate simply to exemplify the
`
`solubilizing properties of the self-emulsifying compositions disclosed therein.
`
`[00038] Combinations of omega-3 fatty acids with other flbrates, such as
`
`gemflbrozil and clofibrate, have not been shown to produce any dramatic
`
`synergistic action in the treatment of hyperlipidemia and hyperlipoprotelnemia.
`
`See Salty et al., Pakistan J. of Phann. Si:i. (2003) 16(2): 1-8; Pennacchiotti et
`
`al., Lipids (2001) 26(2): 121-127; Wysynskl et al., Human and Experimental
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`Toxicology (1993) 12: 337-340.
`
`SUMMARY OF THE INVENTION
`
`[00039] There ls an unmet need in the art for combination products of
`
`dyslipldemlc agents and omega-3 fatty acids,· in particular a combination
`
`product that provides a single administration of concentrated amounts of
`
`omega-3 fatty acids and a dyslipidemic agent, for example, in a unit dosage.
`
`There is also an unmet need in the art for a method of administration of a
`
`single administration or unit dosage product.
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`[00040] The present invention meets these needs In the art, as well as
`
`others, by providing an administration of a unit dosage of a dysllpidemic agent
`
`and omega-3 fatty acids that can provide an effective pharmaceutical
`
`treatment of coronary heart disease, vascular disease, and related disorders,
`
`events, and/or symptoms.
`
`[@041] Some embodlm~mts ~f t~e pre~nt invention provide for a method of
`
`utilizing a combination of a dyslipidemic agent and omega-3 fatty acids in the
`
`treatment of hypertriglyceridemia, hypercholesterolemla,. mixed dyslipidemia,
`
`vascular disease, artherosclerotlc disease and related conditions, and the
`
`prevention or reduction of cardiovascular and vascular events.
`
`[00042) In a preferred embodiment, the present Invention includes methods
`
`of blood lipid therapy In a subject c0mprising administering to the subject an
`
`effective amount of a dyslipidemic agent