111111111111111111111111111111111111111111111111111111111111111111111111111
`US007932268B2
`
`c12) United States Patent
`Rader
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 7,932,268 B2
`Apr. 26, 2011
`
`(54) METHODS FOR TREATING DISORDERS OR
`DISEASES ASSOCIATED WITH
`HYPERLIPIDEMIA AND
`HYPERCHOLESTEROLEMIA WHILE
`MINIMIZING SIDE EFFECTS
`
`(75)
`
`Inventor: Daniel J. Rader, Philadelphia, PA (US)
`
`(73) Assignee: The Trustees of the University of
`Pennsylvania, Philadelphia, PA (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 895 days.
`
`(21) Appl. No.:
`
`10/591,923
`
`(22) PCTFiled:
`
`Mar. 7, 2005
`
`(86) PCTNo.:
`
`PCT /US2005/007 435
`
`§ 371 (c)(l),
`(2), ( 4) Date:
`
`Jun.21,2007
`
`(87) PCT Pub. No.: W02005/087234
`
`PCT Pub. Date: Sep. 22, 2005
`
`(65)
`
`Prior Publication Data
`
`AU
`
`5,767,115 A *
`5,786,361 A
`5,789,197 A
`5,811,429 A
`5,827,875 A
`5,883,109 A *
`5,885,983 A
`5,952,498 A
`5,990,110 A
`6,034,115 A
`6,057,339 A
`6,066,650 A
`6,066,653 A
`6,114,341 A
`6,121,283 A
`6,140,343 A
`6,194,454 B1 *
`6,245,775 B1
`6,265,431 B1
`6,297,233 B1
`6,344,450 B1
`6,479,503 B2
`6,492,365 B1
`6,498,156 B2
`6,620,821 B2
`6,627,636 B2
`6,720,351 B2
`6,774,236 B1
`
`6/1998 Rosenblumetal. ..... 514/210.02
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`9/1999 Lenfers eta!.
`1111999 Firestone
`3/2000 Connell et a!.
`5/2000 Gregg
`5/2000 Biller eta!.
`5/2000 Gregg eta!.
`9/2000 Muller eta!.
`9/2000 Chang eta!.
`10/2000 DeNinno et al.
`2/2001 Dow ............................ 514/522
`6/2001 Muller eta!.
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`10/2001 Stein et a!.
`212002 Bisacchi eta!.
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`9/2003 Rob!
`9/2003 Rob!
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`(Continued)
`
`FOREIGN PATENT DOCUMENTS
`727895
`7/1998
`(Continued)
`
`OTHER PUBLICATIONS
`
`US 2009/0042941 Al
`
`Feb. 12, 2009
`
`Related U.S. Application Data
`
`(60) Provisional application No. 60/550,915, filed on Mar.
`5, 2004.
`
`(51)
`
`Int. Cl.
`A61K 311445
`(2006.01)
`(52) U.S. Cl. ........................................ 514/321; 514/325
`(58) Field of Classification Search ............. 514/252.03,
`514/255.03, 263.22, 321, 325, 824, 210.02
`See application file for complete search history.
`
`(56)
`
`References Cited
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`(Continued)
`
`Primary Examiner- Kevin Weddington
`(74) Attorney, Agent, or Firm- Goodwin Procter LLP
`
`(57)
`
`ABSTRACT
`
`The present invention provides methods and compositions for
`treating hyperlipidemia and/or hypercholesterolemia com(cid:173)
`prising administering to the subject an effective amount of an
`MTP inhibitor to inhibit hyperlipidemia and/or hypercholes(cid:173)
`terolemia in said subject, wherein said administration com(cid:173)
`prises an escalating series of doses of the MTP inhibitor. In
`some embodiments the method comprises administering at
`least three step-wise, increasing dosages of the MTP inhibitor
`to the subject. In some embodiments, the method further
`comprises the administration of one or more other lipid modi(cid:173)
`:tying compounds.
`
`8 Claims, No Drawings
`
`CFAD Ex. 1007 (1 of 14)
`
`

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`CFAD Ex. 1007 (3 of 14)
`
`

`
`US 7,932,268 B2
`
`1
`METHODS FOR TREATING DISORDERS OR
`DISEASES ASSOCIATED WITH
`HYPERLIPIDEMIA AND
`HYPERCHOLESTEROLEMIA WHILE
`MINIMIZING SIDE EFFECTS
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a national phase application under 35
`U.S.C. §371 ofPCT/US05/007435 filed Mar. 7, 2005 which
`in turn claims priority benefit of U.S. Ser. No. 60/550,915,
`filed Mar. 5, 2004, all of which are hereby incorporated by
`reference in their entireties.
`
`FIELD OF THE INVENTION
`
`The present invention generally relates to therapy for
`hypercholesterolemia and hyperlipidemia.
`
`BACKGROUND OF THE INVENTION
`
`Hypercholesterolemia is a well-known risk factor for
`ASCVD, the major cause of mortality in the Western world.
`Numerous epidemiological studies have clearly demon(cid:173)
`strated that pharmacological lowering of total cholesterol
`(TC) and Low-density Lipoprotein (LDL) Cholesterol (LDL(cid:173)
`C) is associated with a significant reduction in clinical car(cid:173)
`diovascular events. Hypercholesterolemia is often caused by
`a polygenic disorder in the majority of cases and modifica(cid:173)
`tions in lifestyle and conventional drug treatment are usually
`successful in reducing cholesterol levels. However, in few
`cases, as in familial hypercholesterolemia (FH), the cause is a
`monogenic defect and the available treatment in homozygous
`patients can be much more challenging and far from optimal
`because LDL-C levels remain extremely elevated despite
`aggressive use of combination therapy. Therefore, for this
`group of high-risk patients, effective medical therapy is
`urgently needed.
`Triglycerides are common types of fats (lipids) that are
`essential for good health when present in normal amounts.
`They account for about 95 percent of the body's fatty tissue.
`Abnormally high triglyceride levels may be an indication of
`such conditions as cirrhosis of the liver, underactive thyroid
`(hypothyroidism), poorly controlled diabetes, or pancreatitis
`(inflammation of the pancreas). Researchers have identified
`triglycerides as an independent risk factor for heart disease.
`Higher-than-normal triglyceride levels are often associ(cid:173)
`ated with known risk factors for heart disease, such as low
`levels of HDL ("good") cholesterol, high levels of LDL
`("bad") cholesterol and obesity. Triglycerides may also con(cid:173)
`tribute to thickening of artery walls-a physical change
`believed to be a predictor of atherosclerosis.
`Therefore, high triglyceride levels are at least a warning
`sign that a patient's heart health may be at risk. In response,
`physicians may be more likely to stress the importance of
`losing weight, getting enough exercise, quitting smoking,
`controlling diabetes and other strategies that patients can use
`to protect their own cardiovascular health.
`A large number of genetic and acquired diseases can result
`in hyperlipidemia. They can be classified into primary and
`secondary hyperlipidemic states. The most common causes
`of the secondary hyperlipidemias are diabetes mellitus, alco(cid:173)
`hol abuse, drugs, hypothyroidism, chronic renal failure,
`nephrotic syndrome, cholestasis and bulimia. Primary hyper(cid:173)
`lipidemias have also been classified into common hypercho(cid:173)
`lesterolemia, familial combined hyperlipidemia, familial
`
`2
`hypercholesterolemia, renmant hyperlipidemia, chylomi(cid:173)
`cronemia syndrome and familial hypertriglyceridemia.
`A number of treatments are currently available for lower(cid:173)
`ing serum cholesterol and triglycerides. However, each has its
`5 own drawbacks and limitations in terms of efficacy, side(cid:173)
`effects and qualifying patient population.
`Bile-acid-binding resins are a class of drugs that interrupt
`the recycling of bile acids from the intestine to the liver; e.g.,
`cholestyramine (Questran Light®, Bristol-Myers Squibb),
`10 and colestipol hydrochloride (Colestid®, The Upjohn Com(cid:173)
`pany). When taken orally, these positively-charged resins
`bind to the negatively charged bile acids in the intestine.
`Because the resins carmot be absorbed from the intestine, they
`are excreted carrying the bile acids with them. The use of such
`15 resins, however, at best only lowers serum cholcstcrollcvcls
`by about 20%, and is associated with gastrointestinal side(cid:173)
`effects, including constipation and certain vitamin deficien(cid:173)
`cies. Moreover, since the resins bind other drugs, other oral
`medications must be taken at least one hour before or four to
`20 six hours subsequent to ingestion of the resin; thus, compli(cid:173)
`cating heart patient's drug regimens.
`The statins are cholesterol-lowering agents that block cho(cid:173)
`lesterol synthesis by inhibiting HMGCoA reductase-the
`key enzyme involved in the cholesterol biosynthetic pathway.
`25 The statins, e.g., lovastatin (Mevacor®, Merck & Co., Inc.),
`simvastatin (Zocor®, Merck & Co., Inc.), atorvastatin (Lipi(cid:173)
`tor®, Pfizer), rosuva (Crestor®, Astra Zeneca) and pravasta(cid:173)
`tin (Pravachol®, Bristol-Myers Squibb Co.), and combina(cid:173)
`tions thereof, are sometimes used in combination with bile-
`30 acid-binding resins. Statins significantly reduce serum
`cholesterol and LDL-serum levels, and slow progression of
`coronary atherosclerosis. However, serum HDL cholesterol
`levels are only moderately increased. The mechanism of the
`LDL lowering effect may involve both reduction ofVLDL
`35 concentration and induction of cellular expression of LDL(cid:173)
`receptor, leading to reduced production and/or increased
`catabolism of LDLs. Side effects, including liver and kidney
`dysfunction are associated with the use of these drugs (Phy(cid:173)
`sicians Desk Reference, Medical Economics Co., Inc.,
`40 Montvale, N.J., 2004; hereinafter "PDR"). The FDA has
`approved atorvastatin to treat rare but urgent cases of familial
`hypercholesterolemia.
`Ezetimibe is a cholesterol absorption inhibitor which
`reduces the amount of cholesterol absorbed by the body.
`45 Ezetimibe is used to reduce the amount of total cholesterol,
`LDL cholesterol (by about 18%), and apolipoprotein B.
`Ezetimibe is often used with a low cholesterol diet and, in
`some cases, other cholesterol lowering medications.
`Niacin, or nicotinic acid, is a water soluble vitamin B-com-
`50 plex used as a dietary supplement and antihyperlipidemic
`agent. Niacin diminishes production ofVLDL and is effective
`at lowering LDL. In some cases, it is used in combination
`with bile-acid binding resins. NIASPAN® has been approved
`to prevent recurrent heart attacks in patients with high cho-
`55 !estero!. Niacin can increase HDL when used at adequate
`doses, however, its usefulness is limited by serious side
`effects when used at such high doses.
`Fibric acid derivatives ("fibrates") are a class of lipid(cid:173)
`lowering drugs used to treat various forms of hyperlipidemia
`60 (i.e., elevated serum triglycerides) which may also be associ(cid:173)
`ated with hypercholesterolemia. Fibrates appear to reduce the
`VLDL fraction and modestly increase HDL. However, the
`effects of these drugs on serum cholesterol is variable.
`Fibrates are mainly used to lower high triglyceride levels.
`65 Although fibrates typically do not appear as effective as
`statins in lowering total cholesterol and LDL cholesterol lev(cid:173)
`els, they are sometimes used in combination with statins or
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`other medications to lower very high cholesterol levels. For
`example, fibrates are also sometimes added to statins to raise
`HDL cholesterol levels. In the United States, fibrates have
`been approved for use as antilipidemic drugs, but have not
`received approval as hypercholesterolemia agents. For
`example, clofibrate (Atromid-S®, Wyeth-Ayerst Laborato(cid:173)
`ries) is an antilipidemic agent which acts to lower serum
`triglycerides by reducing the VLDL fraction. Although serum
`cholesterol may be reduced in certain patient subpopulations,
`the biochemical response to the drug is variable, and is not 10
`always possible to predict which patients will obtain favor(cid:173)
`able results. Atromid-S® has not been shown to be effective
`for prevention of coronary heart disease. The chemically and
`pharmacologically related drug, gemfibrozil (Lopid®, Parke(cid:173)
`Davis) is a lipid regulating agent which moderately decreases
`serum triglycerides and VLDL cholesterol, and moderately
`increases HDL cholesterol-the HDL2 and HDL3 subfrac(cid:173)
`tions as well as both ApoA-I and A-II (i.e., the AIIAII-HDL
`fraction). However, the lipid response is heterogeneous, espe(cid:173)
`cially among different patient populations. Moreover, while
`prevention of coronary heart disease was observed in male
`patients between 40-55 without history or symptoms of exist(cid:173)
`ing coronary heart disease, it is not clear to what extent these
`findings can be extrapolated to other patient populations (e.g.,
`women, older and younger males). Indeed, no efficacy was
`observed in patients with established coronary heart disease.
`Fenofibrate (Tricor, Secalip) is also used to reduce levels of
`cholesterol and triglycerides. Serious side-effects have been
`associated with the use of several fibrates including toxicity
`such as malignancy, (especially gastrointestinal cancer), gall- 30
`bladder disease and an increased incidence in non-coronary
`mortality. Fibrates are often not indicated for the treatment of
`patients with high LDL or low HDL as their only lipid abnor(cid:173)
`mality (Physician's Desk Reference, 2004, Medical Econom(cid:173)
`ics Co., Inc. Montvale, N.J.).
`Oral estrogen replacement therapy may be considered for
`moderate hypercholesterolemia in post-menopausal women.
`However, increases in HDL may be accompanied with an
`increase in triglycerides. Estrogen treatment is, of course,
`limited to a specific patient population (postmenopausal
`women) and is associated with serious side effects including
`induction of malignant neoplasms, gall bladder disease,
`thromboembolic disease, hepatic adenoma, elevated blood
`pressure, glucose intolerance, and hypercalcemia.
`Homozygous familial hypercholesterolemia (hoFH) is a
`serious life-threatening genetic disease caused by homozy(cid:173)
`gosity or compound heterozygosity for mutations in the low
`density lipoprotein (LDL) receptor. Total plasma cholesterol
`levels are generally over 500 mg/dl and markedly premature
`atherosclerotic vascular disease is the major consequence.
`Untreated, most patients develop atherosclerosis before age
`20 and generally do not survive past age 30. The primary goal
`of therapy consists of controlling the hypercholesterolemia to
`delay the development of atherosclerotic cardiovascular dis(cid:173)
`ease (ASCVD). However, patients diagnosed with hoFH are
`largely unresponsive to conventional drug therapy and have
`limited treatment options. A mean LDL-C reduction of only
`about 5.5% has been recently reported in patients with geno(cid:173)
`type-confirmed hoFH treated with the maximal dose of
`statins (atorvastatin or simvastatin 80 mg/day). The addition
`of ezetimibe 10 mg/day to this regimen resulted in a total
`reduction of LDL-C levels of 27%, which is still far from
`optimal. Several non-pharmacological options have also been
`tested. Surgical interventions, such as portacaval shunt and
`ileal bypass have resulted only in partial and transient LDL-C
`lowering. Orthotopic liver transplantation has been demon(cid:173)
`strated to substantially reduce LDL-C levels in hoFH
`
`4
`patients, but obvious disadvantages and risks are associated
`with this approach. Although hoFH could be an excellent
`model for gene therapy, this modality of treatment is not
`foreseeable in the near future due to the limitations on the
`availability of safe vectors that provide long-term expression
`of LDL receptor gene. Thus, the current standard of care in
`hoFH is LDL apheresis, a physical method of filtering the
`plasma of LDL-C which as monotherapy can transiently
`reduce LDL-C by about 50%. Apheresis uses affinity col(cid:173)
`unms to selectively remove apoB-containing lipoproteins.
`However, because of rapid re-accumulation of LDL-C in
`plasma, apheresis has to be repeated frequently (every 1-2
`weeks) and requires 2 separate sites for IV access. Although
`15 anecdotally this procedure may delay the onset of atheroscle(cid:173)
`rosis, it is laborious, expensive, and not readily available.
`Furthermore, although it is a procedure that is generally well
`tolerated, the fact that it needs frequent repetition and IV
`access can be challenging for many of these young patients.
`20 Therefore, there is a tremendous unmet medical need for new
`medical therapies for hoFH.
`Patients with heterozygous FH can usually be successfully
`treated with combination drug therapy to lower the LDL-C to
`acceptable levels. In contrast, hoFH is unresponsive to con-
`25 ventional drug therapy and thus there are limited treatment
`options. Specifically, treatment with statins, which reduce
`LDL-C by inhibiting cholesterol synthesis and upregulating
`the hepatic LDL receptor, have negligible effect in patients
`whose LDL receptors are non-existent or defective.
`In July 2004, the NCEP published a paper entitled "Impli-
`cations of Recent Clinical Trials for the National Cholesterol
`Education Program Adult Treatment Panel III Guidelines",
`updating certain elements of the "Adult Treatment Panel III
`(ATP III)" cholesterol guidelines released in 2001. For high-
`35 risk patients, individuals who have coronary heart disease
`(CHD) or disease of the blood vessels to the brain or extremi(cid:173)
`ties, or diabetes, or multiple (2 or more) risk factors that give
`them a greater than 20 percent chance of having a heart attack
`within 10 years, the ATP III update recommends that the
`40 overall goal for high-risk patients is still an LDL less than 100
`mg/dL with a therapeutic option to set the goal at an LDL less
`than 70 mg/dL for very high-risk patients, those who have had
`a recent heart attack, or those who have cardiovascular dis(cid:173)
`ease combined with either diabetes, or severe or poorly con-
`45 trolled risk factors (such as continued smoking), or metabolic
`syndrome (a cluster of risk factors associated with obesity
`that includes high triglycerides and low HDL cholesterol).
`The ATP III update also recommends consideration of drug
`treatment in addition to lifestyle therapy for LDL levels 100
`50 mg/dL or higher in high-risk patients, and characterizes drug
`treatment as optional for LDL less than 100 mg/dL. For
`moderately high-risk patients, individuals who have multiple
`(2 or more) CHD risk factors together with a 10-20 percent
`risk for a heart attack within 10 years, the ATP III update
`55 recommends the overall goal for moderately high-risk
`patients to be an LDL less than 130 mg/dL. There is a thera(cid:173)
`peutic option to set the treatment goal at anLDL less than 100
`mg/dL, and to use drug treatment ifLDL is 100-129 mg/dL.
`For high-risk and moderately high-risk patients, the ATP III
`60 update advises that the intensity ofLDL-lowering drug treat(cid:173)
`ment in high-risk and moderately high-risk patients be suffi(cid:173)
`cient to achieve at least a 30 percent reduction in LDL levels.
`Patients suffering from severe hypercholesterolemia may
`also be unable to reach the new goals for LDL and HDL
`65 described above. For example, a large number of patients may
`be unable to attain LDL levels less than 70 using maximally
`tolerated current methodologies.
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`Abetalipoproteinemia is a rare genetic disease character(cid:173)
`ized by extremely low cholesterol and TG levels, absent apo(cid:173)
`lipoprotein ( apo) B-containing lipoproteins in plasma, fat
`malabsorption, severe vitamin E deficiency, and progressive
`spinocerebellar and retinal degeneration. It has been deter-
`mined that mutations in the MTP were the genetic cause of
`abetalipoproteinemia. MTP is responsible for transferring
`lipids, particularly TG, onto the assembling chylomicron and
`VLDL particles in the intestine and the liver, respectively.
`Although the mechanisms by which lipoproteins are formed 10
`are not completely understood, it is currently believed that the
`assembly of apoB containing lipoproteins requires two steps.
`The first step occurs within the endoplasmic reticulum that
`involves the synthesis of particles that contain only a small
`fraction of the lipid core found in the secreted lipoprotein. A 15
`larger core oflipid is added to the nascent particle in a second
`step. MTP is thought to be essential for the transfer oflipid to
`the apoB during the first step of the process. In the absence of
`functional MTP, chylomicrons and VLDL are not effectively
`assembled or secreted in the circulation and apoB is likely 20
`targeted for degradation. VLDL serves as the metabolic pre(cid:173)
`cursor to LDL and the inability to secrete VLDL from the liver
`results in the absence ofLDL in the blood. The concept that
`MTP may regulate apoB lipoprotein assembly is supported
`by observations in mice models. In heterozygous knockout 25
`mice MTP mRNA, protein and activity have been reported
`approximately half of normal and the apoB plasma concen(cid:173)
`tration was reduced about 30%. Dramatic reduction of apoB-
`1 00 concentration in plasma was also seen in liver-specific
`MTP knockout mice. The finding that MTP is the genetic 30
`cause of abetaliproteinemia and that is involved in apoB(cid:173)
`containing particles assembly and secretion led to the concept
`that pharmacologic inhibition of MTP might be a successful
`strategy for reducing atherogenic lipoproteins levels in
`humans.
`Because of the tremendous impact on the treatment of
`atherosclerosis and cardiovascular disease that can be derived
`from the pharmacologic inhibition of hepatic secretion of
`apoB containing lipoproteins, several MTP inhibitors have
`been developed. Both in vitro and in vivo animal studies with 40
`these compounds support the concept that inhibition ofMTP
`results in inhibition of apoB containing lipoproteins secretion
`and consequent reduction of plasma cholesterol levels. Inter(cid:173)
`estingly, the animal studies cited above had been conducted in
`Watanabe-heritable hyperlipidemic (WHHL) rabbits and 45
`LDLR-/-mice, two models for hoFH.
`Bristol-Myers Squibb (BMS) developed a series of com(cid:173)
`pounds, including BMS-201 038, as potent inhibitors of
`MTP-mediated neutral lipid transfer activity. These com(cid:173)
`pounds are described, for example, in U.S. Pat. Nos. 5,789, 50
`197, 5,883,109, 6,066,653, and 6,492,365, each of which is
`incorp