UNITED STATES DEPARTMENT OF COMMERCE
`United States Patent and Trademark Office
`
`May26, 2015
`
`THIS IS TO CERTIFY THAT ANNEXED HERETO IS A TRUE COPY FROM
`THE RECORDS OF THIS OFFICE OF:
`
`U.S. PATENT: 8,618,135
`ISSUE DATE: December 31, 2013
`
`By Authority of the
`Under Secretary of Commerce for I~ellectual Property
`tes ~. 'tent and }:tadyna. rk Office
`and Director of the U nit7d. S
`1,// ~t;::
`I ;/i
`I jl
`f' ~?'~
`/J~:E:_f 87 'f~
`
`Certifying Officer
`
`

`
`111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US008618135B2
`
`(12J United States Patent
`Rader
`
`(!OJ Patent No.:
`(45) Date of Patent:
`
`US 8,618,135 B2
`*Dec. 31, 2013
`
`(54) METHODS FOR TREATING DISORDERS OR
`DISEASES ASSOCIATED WITH
`HYPERLIPIDEMIA AND
`HYPERCHOLESTEROLEMIA WHILE
`MINIMIZING SIDE EFFECTS
`Inventor: Daniel J. Rader, Plriladelpbia, PA (US)
`(75)
`(73) Assignee: The Trustees of the University of
`Pennsylvania, Philadelphia, PA (US)
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`This patent is subject to a terminal disM
`claimer.
`(21) Appl. No.: 13/046,118
`(22) Filed:
`Mar. 11, 2011
`Prior Publication Data
`(65)
`
`( *) Notice:
`
`US 2012/0010243 AI
`
`Jan. 12, 2012
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 10/591,923, filed as
`application No. PCT/US2005/007435 on Mar. 7,
`2005, now Pat. No. 7,932,268.
`
`(60)
`
`(51)
`
`(52)
`
`(58)
`
`Provisional application No. 60/550,915, filed on Mar.
`5, 2004.
`Int. Cl.
`A61K31/445
`A61K31/501
`A61K31152
`U.S.Cl.
`USPC . 514/321; 514/325; 514/252.03; 514/255.03;
`514/263.22
`
`(2006.01)
`(2006.01)
`(2006.01)
`
`Field of Classification Search
`USPC .......... 514/321, 325, 252.03, 255.03, 263.22,
`514/824,210.02
`See application file for complete search history.
`
`(56)
`
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`(Continued)
`
`Primary Examiner- Kevin E 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)
`fying compounds.
`
`10 Claims, No Drawings
`
`Copy provided by USPTO from the PIRS Image Database on 05/21/2015
`
`

`
`US 8,618,135 B2
`Page2
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`
`

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`* cited by examiner
`
`Copy provided by USPTO from the PIRS Image Database on 05/21/2015
`
`

`
`US 8,618,135 B2
`
`1
`METHODS FOR TREATING DISORDERS OR
`DISEASES ASSOCIATED WITH
`HYPERLIPIDEMIA AND
`HYPERCHOLESTEROLEMIA WHILE
`MINIMIZING SIDE EFFECTS
`
`5
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`FIELD OF THE INVENTION
`
`The present invention generally relates to therapy for
`hypercholesterolemia and hyperlipidemia.
`
`BACKGROUND OF THE INVENTION
`
`This application is a continuation of U.S. Ser. No. 10/591,
`923, which is a national phase application under 35 U.S.C.
`§371 ofPCTIUS05/007435 filed Mar. 7, 2005 which in turn
`claims priority benefit ofU.S. Ser. No. 60/550,915, filed Mar.
`5, 2004, all of which are hereby incorporated by reference in
`their entireties.
`
`2
`lesterolemia, familial combined hyperlipidemia, familial
`hypercholesterolemia, remnant hyperlipidemia, chylomi(cid:173)
`cronemia syndrome and familial hypertriglyceridemia.
`A number of treatments are currently available for lower~
`ing serum cholesterol and triglycerides. However, each has its
`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.,
`10 cholestyramine (Questran Light®, Bristol~Myers Squibb),
`and colestipol hydrochloride (Colestid®, The Upjohn Com(cid:173)
`pany). When taken ora1ly, these positively~charged resins
`bind to the negatively charged bile acids in the intestine.
`Because the resins cannot be absorbed from the intestine, they
`15 are excreted carrying the bile acids with them. The use of such
`resins, however, at best only lowers serum cholesterol levels
`by about 200/o, 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
`20 medications must be taken at least one hour before or four to
`six hours subsequent to ingestion of the resin; thus, compli ~
`eating heart patient's drug regimens.
`The statins are cholesterol-lowering agents that block cho(cid:173)
`Hypercholesterolemia is a well-known risk factor for
`lesterol synthesis by inhibiting HMGCoA reductase-the
`ASCVD, the major cause of mortality in the Western world.
`25 key enzymeinvolvedin the cholesterol biosyntheticpathway.
`Numerous epidemiological studies have clearly demon(cid:173)
`The statins, e.g., lovastatin (Mevacof(ID, Merck & Co., Inc.),
`simvastatin (Zocor®, Merck & Co., Inc.), atorvastatin (Lipi~
`strated that pharmacological lowering of total cholesterol
`(TC) and Low-density Lipoprotein (LDL) Cholesterol (LDL-
`tor®, Pfizer), rosuva (Crestof(ID, Astra Zeneca) and pravasta(cid:173)
`C) is associated with a significant reduction in clinical car(cid:173)
`tin (Pravachol®, Bristol~ Myers Squibb Co.), and combina~
`diovascular events. Hypercholesterolemia is often caused by 30 tions thereof are sometimes used in combination with bile~
`a polygenic disorder in the majority of cases and modifica~
`acid~binding resins. Statins significantly reduce serum
`cholesterol and LDL~serum levels, and slow progression of
`tions in lifestyle and conventional drug treatment are usua1ly
`successful in reducing cholesterol levels. However, in few
`coronary atherosclerosis. However, serum HDL cholesterol
`levels are only moderately increased. The mechanism of the
`cases, as in familial hypercholesterolemia (FH), the cause is a
`LDL lowering effect may involve both reduction ofVLDL
`monogenic defect and the available treatment in homozygous 35
`concentration and induction of cellular expression of LDL-
`patients can be much more challenging and far from optimal
`receptor, leading to reduced production and/or increased
`because LDL~C levels remain extremely elevated despite
`catabolism ofLDLs. Side effects, including liver and kidney
`aggressive use of combination therapy. Therefore, for this
`dysfunction are associated with the use of these drugs (Phy~
`group of high~risk patients, effective medical therapy is
`40 sicians Desk Reference, Medical Economics Co., Inc.,
`urgently needed.
`Triglycerides are common types of fats (lipids) that are
`Montvale, N.J., 2004; hereinafter ''PDR"). The FDA has
`essential for good health when present in normal amounts.
`approved atorvastatin to treat rare but urgent cases of familial
`hypercholesterolemia.
`They account for about 95 percent of the body's fatty tissue.
`Abnormally high triglyceride levels may be an indication of
`Ezetimibe is a cholesterol absorption inhibitor which
`such conditions as cirrhosis of the liver, underactive thyroid 45
`reduces the amount of cholesterol absorbed by the body.
`Ezetimibe is used to reduce the amount of total cholesterol,
`(hypothyroidism), poorly controlled diabetes, or pancreatitis
`LDL cholesterol (by about 18%), and apolipoprotein B.
`(inflammation of the pancreas). Researchers have identified
`triglycerides as an independent risk factor for heart disease.
`Ezetimibe is often used with a low cholesterol diet and, in
`Higher~than~normal triglyceride levels are often associ~
`some cases, other cholesterol lowering medications.
`Niacin, or nicotinic acid, is a water soluble vitaminB~com­
`ated with known risk factors for heart disease, such as low 50
`levels of HDL ("good") cholesterol, high levels of WL
`plex used as a dietary supplement and antihyperlipidemic
`agent. Niacin diminishes production ofVLDL and is effective
`(''bad") cholesterol and obesity. Triglycerides may also con(cid:173)
`at lowering LDL. In some cases, it is used in combination
`tribute to thickening of artery walls-a physical change
`believed to be a predictor of atherosclerosis.
`with bilewacid binding resins. NIASPAN® has been approved
`Therefore, high triglyceride levels are at least a warning 55
`to prevent recurrent heart attacks in patients with high cho~
`sign that a patient's heart liealth may be at risk. In response,
`lesterol. Niacin can increase HDL when used at adequate
`doses, however, its usefulness is limited by serious side
`physicians may be more likely to stress the importance of
`losing weight, getting enough exercise, quitting smoking,
`effects when used at such high doses.
`controlling diabetes and other strategies that patients can use
`Fibric acid derivatives ("fibrates") are a class of lipid-
`to protect their own cardiovascular health.
`60 lowering drugs used to treat various forms of hyperlipidemia
`A large number of genetic and acquired diseases can result
`(i.e., elevated serum triglycerides) which may also be associ(cid:173)
`in hyperlipidemia. They can be classified into primary and
`ated with hypercholesterolemia. Fibrates appear to reduce the
`VLDL fraction and modestly increase HDL. However, the
`secondary hyperlipidemic states. The most common causes
`effects of these drugs on serum cholesterol is variable.
`ofthe secondary hyperlipidemias are diabetes mellitus, alco(cid:173)
`Fibrates are mainly used to lower high triglyceride levels.
`hol abuse, drugs, hypothyroidism, chronic renal failure, 65
`nephrotic syndrome, cholestasis and bulimia. Primary hyper~
`Although fibrates typically do not appear as effective as
`statins in lowering total cholesterol andLDL cholesterol lev~
`lipidemias have also been classified into common hypercho-
`
`Copy provided by USPTO from the PIRS Image Database on 05/21/2015
`
`

`
`US 8,618,135 B2
`
`3
`els, they are sometimes used in combination with statins or
`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 s
`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, 10
`the biochemical response to the drug is variable, and is not
`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- 15
`Davis) is a lipid regulating agentwhichmoderately decreases
`serum triglycerides and VLDL cholesterol, and moderately
`increases HDL cholesterol-the HDL2 and HDL3 subfrac(cid:173)
`tions as well as bothApoA-1 and A-ll (i.e., theAJ/Ali-HDL
`fraction). However, the lipid response is heterogeneous, espe- 20
`dally 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., 25
`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 30
`such as malignancy, (especially gastrointestinal cancer), gall(cid:173)
`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- 35
`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, 40
`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 50
`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- 55
`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 60
`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 65
`ileal bypass have resulted only in partial and transient LDL-C
`lowering. Orthotopic liver transplantation has been demon-
`
`4
`strated to substantial1y reduce LDL-C levels in hoFH
`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)
`umns 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
`anecdota11y 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.
`Therefore, there is a tremendous unmet medical need for new
`medical therapies for hoFH.
`Patients with heterozygous PH can usually be successfully
`treated with combination drug therapy to lower the LDL-C to
`acceptable levels. In contrast, hoFH is unresponsive to con(cid:173)
`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(cid:173)
`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(cid:173)
`risk patients, individuals who have coronary heart disease
`(CHD) or disease of the blood vessels to the brain or extremi-
`ties, or diabetes, or multiple (2 or more) risk factors that give
`them a greater than 20 percent chance ofhaving a heart attack
`within 10 years, the ATP III update recommends that the
`overall goal for high-risk patients is still an LDL less than I 00
`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
`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