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`UNITED STATES DEPARTMENT OF COMMERCE
`UNITED STATES DEPARTMENT OF COMMERCE
`United States Patent and Trademark Office
`United States Patent and Trademark Office
`
`June 16, 2015
`Jnne 16, 2015
`
`THIS IS TO CERTIFY THAT ANNEXED IS A TRUE COPY FROM THE
`THIS IS TO CERTIFY THAT ANNEXED IS A TRUE COPY FROM THE
`RECORDS OF THIS OFFICE OF THE FILE WRAPPER AND CONTENTS
`RECORDS OF THIS OFFICE OF THE FILE WRAPPER AND CONTENTS
`OF:
`OF:
`
`APPLICATION NUMBER: 60/550,915
`APPLICATION NUMBER: 601550,915
`FILING DATE: March 05, 2004
`FILING DATE: March 05, 2004
`
`By Authority of the
`By Authority of the
`Under Secretary of Commerce for Intellectual Property
`and Director of the United States Patent and Trademark Office
`Under Secretary of Commerce for Intellectual Property
`and Director of the United States Patent and Trademark Office
`
`_»
`
`~
`
`-
`
`'
`
`‘”
`
`i
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`r
`
`4:’;
`
`4;.’
`
`:;§§; w~%;4;:£:g2M~ «V
`
`AL ACE
`
`Certifying Officer
`
`Certifying Officer
`
`

`
`PTO/SB/16 (08-03)
`Approved for use through 07131/2006. OMB 0651-0032
`U.S. Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE
`-o Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it displays a valid OMB control number.
`*3
`PROVISIONAL APPLICATION FOR PATENT COVER SHEET
`This is a request for filing a PROVISIONAL APPLICATION FOR PATENT under 37 CFR 1.53 (c).
`I Express Mail Label No. EL964555135US
`
`I
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`INVENTOR($)
`
`Given Name (first and middle [if any))
`
`Family Name or Surname
`
`DANIELJ.
`
`RADER
`
`Residence
`(City and either State or Foreian Country)
`Philadelphia, Pennsylvania
`
`0 Additional inventors are being named on the separately numbered sheets attached hereto
`TITLE OF THE INVENTION (500 characters max)
`METHODS FOR TREATING HYPERLIPIDEMIA AND
`HYPERCHOLESTEROLEMIA WHILE MINIMIZING SIDE~EFFECTS
`CORRESPONDENCE ADDRESS
`Direct all correspondence to:
`t8l Customer Number:
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`0 Application Data Sheet. See 37 CFR 1. 76
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`return Postcard
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`METHOD OF PAYMENT OF FILING FEES FOR THIS PROVISIONAL APPLICATION FOR PATENT
`[8J Applicant claims small entity status. See 37 CFR 1.27.
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`fees or credit any overpayment to Deposit Account Number:
`D Payment by credit card. Form PT0-2038 is attached.
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`The invention was made by an agency of the United States Government or under a contract with an agency of
`the United States Government.
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`[Page 1 of 1)
`Respectfully su~itted, ~ 1 t rfl jjJ
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`TYPED or PRINTE NA E
`Gwilym J.O. Attwell
`
`SIGNATURE
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`Date
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`March 5, 2004
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`(if appropriate)
`Docket Number.
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`UPN0026 001<03474!
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`USE ONLY FOR FlUNG A PROVISIONAL APPUCATION FOR PATENT
`This collection of information is required by 37 CFR 1.51. The information is required to obtain or retain a benefit by the public which is to file (and by the USPTO to process)
`an application. Confidentiality is govemed by 35 U.S.C. 122 and 37 CFR 1.14. This collection is estimated to take 8 hours to complete, induding gathering, preparing, and
`submitting the completed application form to the USPTO. Time wiU vary depending upon the individual case. Any comments on the amount of time you require to complete this
`form and/or suggestions for reducing this burden, should be sent to the Chief Information Officer, U.S. Patent and Trademark Office, U.S. Department of Commerce, P.O. Box
`1450, Alexandria, VA 22313-1450. DO NOT SEND FEES OR COMPLETED FORMS TO THIS ADDRESS. SEND TO: Mall Stop Provisional Application, Commissioner
`for Patents, P.O. Box 1460, Alexandria, VA 22313-1450.
`If you need assistance in completing lh11 form, can 1-8lJO.PT0.9199 and select option 2.
`
`

`
`UPN0026-001 (Q3474)
`
`PROVISIONAL
`
`METHODS FOR TREATING HYPERLIPIDEMIA AND
`HYPERCHOLESTEROLEMIA WHILE MINIMIZING SIDE-EFFECTS
`
`FIELD OF THE INVENTION
`[0001] The present invention generally relates to therapy for hypercholesterolemia and
`
`hyperlipidemia.
`
`BACKGROUND OF THE INVENTION
`[0002] 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.
`[0003] Higher-than-normal triglyceride levels are often associated 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 contribute to thickening of artery walls -a
`
`physical change believed to be a predictor of atherosclerosis.
`[0004] 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.
`[0005) 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, alcohol abuse, drugs, hypothyroidism,
`
`chronic renal failure, nephrotic syndrome, cholestasis and bulimia. Primary hyperlipidemias
`
`have also been classified
`
`into common hypercholesterolaemia,
`
`familial combined
`
`hyperlipidaemia,
`
`familial
`
`hypercholesterolaemia,
`
`remnant
`
`hyperlipidaemia,
`
`chylomicronaemia syndrome and familial hypertriglyceridaemia.
`[0006] Hypercholesterolemia is a well-known risk factor for ASCVD, the major cause of
`
`mortality in the Western world. Numerous epidemiological studies have clearly demonstrated
`
`that pharmacological lowering of TC and LDL-C is associated with a significant reduction in
`
`-1-
`
`

`
`UPN0026-001 (Q3474)
`
`PROVISIONAL
`
`clinical cardiovascular events. Hypercholesterolemia is often caused by a polygenic disorder
`
`in the majority of cases and modifications 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.
`
`[0007] A number of treatments are currently available for lowering serum cholesterol and
`
`triglycerides. However, each has its own drawbacks and limitations in terms of efficacy, side(cid:173)
`
`effects and qualifying patient population.
`
`[0008] 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),
`
`and colestipol hydrochloride (Colestid®, The Upjohn Company). When taken orally, these
`
`positively-charged resins bind to the negatively charged bile acids in the intestine. Because
`
`the resins cannot be absorbed from the intestine, they are excreted carrying the bile acids with
`
`them. The use of such resins, however, at best only lowers serum cholesterol levels by about
`
`20%, and is associated with gastrointestinal side-effects, including constipation and certain
`
`vitamin deficiencies. Moreover, since the resins bind other drugs, other oral medications must
`
`be taken at least one hour before or four to six hours subsequent to ingestion of the resin;
`
`thus, complicating heart patient's drug regimens.
`
`[0009] The statins are cholesterol-lowering agents that block cholesterol synthesis by
`
`inhibiting HMGCoA reductase--the key enzyme involved in the cholesterol biosynthetic
`
`pathway. The statins, e.g., lovastatin (Mevacor®, Merck & Co., Inc.), and pravastatin
`
`(Pravachol®Bristol-Myers Squibb Co.) are sometimes used in combination with bile-acid(cid:173)
`
`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 of VLDL concentration and induction of cellular expression of LDL-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 (Physicians Desk
`
`Reference, Medical Economics Co., Inc., Montvale, N.J., 1997). The FDA has approved
`
`-2-
`
`

`
`UPN0026-001 (Q3474)
`
`PROVISIONAL
`
`atorvastatin (an HMGCoA reductase inhibitor developed by Parke-Davis) (Warner Lambert)
`
`for the market to treat rare but urgent cases of familial hypercholesterolemia.
`
`[0010] Niacin, or nicotinic acid, is a water soluble vitamin B-complex used as a dietary
`
`supplement and antihyperlipidemic agent. Niacin diminishes production of VLDL and is
`
`effective at lowering LDL. In some cases, it is used in combination with bile-acid binding
`
`resins. Niacin can increase HDL when used at adequate doses, however, its usefulness is
`
`limited by serious side effects when used at such high doses.
`
`[0011] Fibrates are a class of lipid-lowering drugs used to treat various forms of
`
`hyperlipidemia (i.e., elevated serum triglycerides) which may also be associated with
`
`hypercholesterolemia. Fibrates appear to reduce the VLDL fraction and modestly increase
`
`HDL--however the effects of these drugs on serum cholesterol is variable. 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(cid:173)
`
`Ayerst Laboratories) 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 always possible to
`
`predict which patients will obtain favorable 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-Davis) is a lipid regulating agent which moderately
`
`decreases serum triglycerides and VLDL cholesterol, and moderately increases HDL
`
`cholesterol--the HDL2 and HDL3 subfractions as well as both ApoA-1 and A-II (i.e., the
`All AII-HDL fraction). However, the lipid response is heterogeneous, especially among
`
`different patient populations. Moreover, while prevention of coronary heart disease was
`
`observed in male patients between 40-55 without history or symptoms of existing 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. Serious side-effects are associated with the
`
`use of fibrates including toxicity such as malignancy, (especially gastrointestinal cancer),
`
`gallbladder disease and an increased incidence in non-coronary mortality. These drugs are not
`
`indicated for the treatment of patients with high LDL or low HDL as their only lipid
`
`abnormality (Physician's Desk Reference, 1997, Medical Economics Co., Inc. Montvale,
`
`N.J.).
`
`-3-
`
`

`
`UPN0026-001 (Q3474)
`
`PROVISIONAL
`
`[0012] 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.
`
`[0013] Homozygous familial hypercholesterolemia (hoFH) is a serious life-threatening
`
`genetic disease caused by homozygosity 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 disease (ASCVD). However,
`
`patients diagnosed with hoFH are unresponsive to conventional drug therapy and have
`
`limited treatment options. Current therapy includes several medications which together
`
`reduce LDL by up to 20% and a mechanical therapy, LDL apheresis, which is very effective
`
`but is not widely available and not well tolerated by patients. Thus, new therapies are needed
`
`to help control cholesterol and reduce the need for apheresis.
`
`[0014] 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
`
`conventional 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. A mean LDL-C reduction of only about 5.5% has
`
`been recently reported in patients with genotype-confirmed hoFH treated with the maximal
`
`dose of statins (atorvastatin or simvastatin 80 mg/day). The addition of ezetimibe (a
`
`cholesterol absorption inhibitor) 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 demonstrated to substantially reduce LDL-C levels in hoFH patients, but obvious
`
`disadvantages and risks are associated with this approach. Although hoFH could be an
`
`-4-
`
`

`
`UPN0026-001 (Q3474)
`
`PROVISIONAL
`
`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 columns 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 anecdotally this procedure may delay the onset of
`
`atherosclerosis, 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.
`
`[0015] Abetalipoproteinemia is a rare genetic disease characterized by extremely low
`
`cholesterol and TG levels, absent apolipoprotein (apo) B-containing lipoproteins in plasma,
`
`fat malabsorption, severe vitamin E deficiency, and progressive spinocerebellar and retinal
`
`degeneration. It has been determined 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 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 larger
`
`core of lipid is added to the nascent particle in a second step. MTP is thought to be essential
`
`for the transfer of lipid 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 targeted for degradation. VLDL serves as the metabolic
`
`precursor to LDL and the inability to secrete VLDL from the liver results in the absence of
`
`LDL in the blood. The concept that MTP may regulate apoB lipoprotein assembly is
`
`supported by observations in mice models. In heterozygous knockout mice MTP mRNA,
`
`protein and activity have been reported approximately half of normal and the apoB plasma
`
`concentration 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
`
`-5-
`
`

`
`UPN0026-001 (Q3474)
`
`PROVISIONAL
`
`genetic cause of abetaliproteinemia and that is involved in apoB-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.
`
`[0016] Because of the
`
`tremendous
`
`impact on the
`
`treatment of atherosclerosis and
`
`cardiovascular disease that can b~ 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 these compounds support the concept that inhibition
`
`of MTP results in inhibition of apoB containing lipoproteins secretion and consequent
`
`reduction of plasma cholesterol levels. Interestingly, the animal studies cited above had been
`
`conducted in Watanabe-heritable hyperlipidemic (WHHL) rabbits and LDLR-/- mice, two
`
`models for hoFH.
`
`· [0017] Bristol-Myers Squibb (BMS) developed a series of compounds, including BMS-
`
`201038, as potent inhibitors of MTP-mediated neutral lipid transfer activity. These
`
`compounds are described, for example, in U.S. Patents 5,789,197, 5,883,109, 6,066,653, and
`
`6,492,365, each of which is incorporated herein by reference in its entirety. In particular,
`
`MTP inhibitors are described throughout U.S. Patent 6,066,653, in particular in columns 3-
`
`28. In in vitro studies, BMS-201038 appears to inhibit lipid transfer by directly binding to
`
`MTP. In cell culture studies, the IC50 for inhibition of apoB secretion by BMS-20 1038 was
`much lower than that for apoAI secretion (0.8 nM vs 6.5 J..lM), indicating that the compound
`
`is a highly selective inhibitor of apoB secretion. The efficacy to inhibit accumulation of
`
`triglyceride-rich particles in plasma of rats after injection of Triton is similar in both fed and
`
`fasted states, suggesting that both intestinal and hepatic lipoprotein secretions are inhibited by
`
`this compound. Six-month toxicity studies were conducted by BMS in rats and dogs and their
`
`results are detailed in IND# 50,820. Doses tested were 0, 0.02, 0.2, 2.0, and 20 mg/kg in rats
`
`and 0, 0.01, 0.1, 1.0, and 10 mg/kg in dogs. Dose-related lipid accumulation in the liver and
`
`. small intestine correlated with decrease in serum TG and cholesterol levels. These changes
`
`are a consequence of the pharmacologic effects of BMS-201038. In rats, but not in dogs,
`
`doses of 0.2 mg/kg and higher were associated with subacute inflammation and single-cell
`
`necrosis of hepatocytes and histiocytosis (phospholipidosis) in the lungs. The hepatic
`
`accumulation of lipids was reversed in rats at the end of a 1-month washout period. Studies in
`
`animals indicated that BMS-201038 effectively reduced plasma cholesterol levels in a dose
`
`dependent manner. BMS-201038 was found to be effective in reducing cholesterol levels in
`
`-6-
`
`

`
`UPN0026-001 (Q3474)
`
`PROVISIONAL
`
`rabbits that lack a functional LDL receptor: The ED5o value for lowering cholesterol was 1.9
`mg/kg and a dose of 10 mglkg essentially normalized cholesterol levels with no alteration in
`
`plasma AST or ALT. This study, conducted in the best accepted animal model for the
`
`homozygous FH, indicated that MTP inhibition by BMS-201038 might be effective in
`
`substantially reducing cholesterol levels in patients with hoFH.
`
`[0018) Clinical development ofBMS-201038 as a drug for large scale use in the treatment of
`
`hypercholesterolemia has been discontinued, because gastrointestinal side effects, elevation
`
`of serum transaminases and hepatic fat accumulation were observed, primarily at 25mg/day
`
`or higher doses.
`
`[0019] Thus, there is a need to develop methods for treating hyperlipidemia and/or
`
`hypercholesterolemia that are efficacious in lowering serum cholesterol and LDL, increasing
`
`HDL serum levels, preventing coronary heart disease, and/or treating diseases associated with
`
`hyperlipidemia and/or hypercholesterolemia, without the side-effects associated with known
`
`treatments.
`
`SUMMARY OF THE INVENTION
`
`[0020] The present invention relates to methods of treating a subject suffering from a
`
`disorder associated with hyperlipidemia. The methods comprise administering to the subject
`
`an effective amount of an MTP inhibitor to ameliorate hyperlipidemia in the subject. The
`
`administration comprises at least three step-wise, increasing dosages of the MTP inhibitor.
`
`[0021] The present invention also relates to methods for inhibiting MTP in a subject. The
`
`method comprises administering to the subject an effective amount of an MTP inhibitor to
`
`. inhibit MTP in the subject. Administration comprises at least three step-wise, increasing
`
`dosages of the MTP inhibitor.
`
`[0022] The present invention relates to kits for treating a disorder related to hyperlipidemia in
`
`a subject. The kits comprise a) a pharmaceutical composition comprising at least three sets of
`
`dosage units. The first set of dosage units provides 0.03mg/kg/day for a first interval. The
`
`second set of dosage units provides 0.1 mg/kg/day for a second interval. The third set of
`
`dosage units provides 0.3 mg/kg/day for a third interval. The kit also comprises instructions
`
`for use.
`
`-7-
`
`

`
`UPN0026-001 (Q3474)
`
`PROVISIONAL
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`[0023] The present invention is based on the surprising discovery that one may treat an
`
`individual who has hyperlipidemia and/or hyperlcholesterolemia with an MTP inhibitor in a
`
`manner that results in the individual not experiencing side-effects normally associated with
`
`the inhibitor, or experiencing side-effects to a lesser degree. Accordingly, the present
`
`invention provides a method of treating a subject suffering from a disorder associated with
`
`hyperlipidemia while reducing side-effects, the method comprising the step of administering
`
`to the subject an effective amount of the inhibitor to ameliorate hyperlipidemia in the subject
`
`according to a treatment regimen that reduces and/or eliminates side-effects associated with
`
`the use of the inhibitors.
`
`[0024] Microsomal triglyceride transfer protein (hereinafter referred as MTP) is known to
`
`catalyze the transport of triglyceride and cholesteryl ester by preference to phospholipids
`
`such as phosphatidylcholine. It was demonstrated by D. Sharp et al., Nature (1993) 365:65
`
`that the defect causing abetalipoproteinemia is in the MTP gene. This indicates that MTP is
`
`required for the synthesis of Apo B-containing lipoproteins such as VLDL, the precursor to
`
`LDL. It therefore follows that an MTP inhibitor would inhibit the synthesis of VLDL and
`
`LDL, thereby lowering levels of VLDL, LDL, cholesterol and triglyceride in humans. MTP
`
`inhibitors have been reported in Canadian patent application No. 2,091,102 and in WO
`
`96/26205. Inhibitors have also been reported in U.S. Pat. No. 5,760,246 as well as in W0-
`
`96/40640 and W0-98/27979.
`
`[0025] Pharmacologic inhibition ofMTP with Bristol-Myers Squibb's BMS-201 038, a potent
`
`inhibitor of MTP, has been shown to reduce low density lipoprotein cholesterol (LDL-C) by
`
`up to 65% in healthy volunteers with hypercholesterolemia. Despite these impressive LDL-C
`
`reductions, steatorrhea, elevation of serum transaminases and hepatic fat accumulation were
`
`observed, primarily at 25mg/day or higher doses. Thus, Bristol-Myers Squibb decided that
`
`these side effects made it unlikely that BMS-201038 could be developed as a drug for large
`
`scale use in the treatment of hypercholesterolemia.
`
`[0026] MTP inhibitors belong to the class of polyarylcarboxamides. MTP inhibitors,
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`methods of use and preparation thereof are known to the art skilled and are described, inter
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`alia, in Canadian Patent Application Ser. No. 2,091,102, U.S. application Ser. No. 117,362,
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`WO 92/26205 published Aug. 29, 1996, U.S. application Ser. No. 472,067, filed Jun. 6, 1995,
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`U.S. application Ser. No. 548,811, filed Jan. 11, 1996, U.S. provisional application Ser. No.
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`60/017,224, filed May 9, 1996, U.S. provisional application Ser. No. 60/017,253, filed May
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`10, 1996, U.S. provisional application Ser. No. 60/017,254, filed May 10, 1996, U.S.
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`provisional application Ser. No. 60/028,216, filed Oct. 1, 1996, U.S Patent 5,595,872, U.S.
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`Patent 5,789,197, U.S. Patent 5,883,109, and U.S. Patent 6,066,653. All of the above,
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`including structures, are incorporated herein by reference.
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`[0027] In some embodiments the MTP inhibitors are piperidine, pyrrolidine or azetidine
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`compounds. In some embodiments the inhibitor is 9-[ 4-[ 4-[[2-(2,2,2-trifluoromethyl)(cid:173)
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`benzoyl]amino ]-1-piperidinyl]butyl]-N-( 2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide.
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`[0028] Other cholesterol lowering drugs or delipidating drugs which may be used in the
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`method of the invention include HMG CoA reductase inhibitors, squalene synthetase
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`inhibitors, fibric acid derivatives, bile acid sequestrants, probucol, niacin, niacin derivatives
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`and the like.
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`[0029] The HMG CoA reductase inhibitors suitable for use herein include, but are not limited
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`to, mevastatin and related compounds as disclosed in U.S. Pat. No. 3,983,140, lovastatin
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`(mevinolin) and related compounds as disclosed in U.S. Pat. No. 4,231,938, pravastatin and
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`related compounds such as disclosed in U.S. Pat. No. 4,346,227, simvastatin and related
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`compounds as disclosed in U.S. Pat. Nos. 4,448,784 and 4,450,171, with pravastatin,
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`lovastatin or simvastatin being preferred. Other HMG CoA reductase inhibitors which may
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`be employed herein include, but are not limited to, fluvastatin, cerivastatin, atorvastatin,
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`pyrazole analogs of mevalonolactone derivatives as disclosed in U.S. Pat. No. 4,613,61 0,
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`indene analogs of mevalonolactone derivatives as disclosed in PCT application WO
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`86/03488, 6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-ones and derivatives
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`thereof as
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`disclosed in U.S. Pat. No. 4,647,576, Searle's SC-45355 (a 3-substituted pentanedioic acid
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`derivative) dichloroacetate, imidazole analogs of mevalonolactone as disclosed in PCT
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`application WO 86/07054, 3-carboxy-2-hydroxy-propane-phosphonic acid derivatives as
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`disclosed in French Patent No. 2,596,393, 2,3-di-substituted pyrrole, furan and thiophene
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`derivatives as disclosed in European Patent Application No. 0221025, naphthyl analogs of
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`mevalonolactone as disclosed in U.S. Pat. No. 4,686,237, octahydronaphthalenes such as
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`disclosed in U.S. Pat. No. 4,499,289, keto analogs of mevinolin (lovastatin) as disclosed in
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`European Patent Application No. 0,142,146 A2, as well as other known HMG CoA reductase
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`inhibitors.
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`[0030] In addition, phosphinic acid compounds useful in inhibiting HMG CoA reductase
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`suitable for use herein are disclosed in GB 2205837.
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`[0031] The squalene synthetase inhibitors suitable for use herein include, but are not limited
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`to, a.-phosphonosulfonates disclosed in U.S. application Ser. No. 08/266,888, filed Jul. 5,
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`1994 (HX59b ), those disclosed by Biller et al, J. Med. Chern. 1988, Vol. 31, No. 10, pp 1869-
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`1871, including isoprenoid (phosphinylmethyl)phosphonates including the triacids thereof,
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`triesters thereof and tripotassium and trisodium salts thereof as well as other squalene
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`synthetase inhibitors disclosed in U.S. Pat. Nos. 4,871,721 and 4,924,024 and in Biller et al,
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`J. Med. Chern., 1988, Vol. 31, No. 10, pp 1869 to 1871.
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`[0032] In addition, other squalene synthetase inhibitors suitable for use herein include the
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`terpenoid pyrophosphates disclosed by P. Ortiz de Montellano et al, J. Med. Chern.; 1977,20,
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`243-249, the famesyl diphosphate analog A and presqualene pyrophosphate (PSQ-PP)
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`analogs as disclosed by Corey and Volante, (J. Am. Chern. Soc. 1976, 98, 1291-1293),
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`phosphinylphosphonates reported by McClard, R. W. et al, (J.A.C.S., 1987, 109, 5544) and
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`cyclopropanes reported by Capson, T. L., (PhD dissertation, June, 1987, Dept. Med. Chern.
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`U. of Utah, Abstract, Table of Contents, pp. 16, 17,40-43,48-51, Summary).
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`In some
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`embodiments the inhibitor is pravastatin, lovastatin or simvastatin.
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`[0033] The present invention provides methods for treating diseases or disorders associated
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`with hyperlipidemia and/or hypercholesterolemina while minimizing side-effects ordinarily
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`associated with the use of such inhibitors. In some embodiments, the inhibitor is an MTP
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`inhibitor.
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`[0034] As used herein, the phrase "diseases or disorders associated with hyperlipidemia
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`and/or hypercholesterolemina" refers to diseases related to or caused by elevated lipid or
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`cholesterol levels.
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`[0035] In
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`some
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`embodiments,
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`the disease
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`associated with hyperlipidemia
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`is
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`hypercholesterolemia.
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`In some embodiments, the disease is homozygous/heterozygous
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`familial hypercholesterolemia. In some embodiments the disease is hypertriglyceridemia.
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`[0036] In some embodiments, cholesterol levels in the subject are reduced by at least 25%.
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`In some embodiments, triglyceride levels in the subject are reduced by at least 25%. In some
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`embodiments, apolipoprotein B levels in said subject are reduced by at least 25%.
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`[0037] In some embodiments, triglyceride levels achieved are less than 500 mg/dl. In some
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`embodiments, triglyceride levels achieved are less than 300 mg/dl. In some embodiments,
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`triglyceride levels achieved are less than 200 mg/dl. In some embodiments, triglyceride levels
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`achieved are less than 150 mg/dl.
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`[0038] In some embodiments, the ApoB/ApoAl ratio achieved by treatment according to the
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`present invention is from 0.25 to 1.25.
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`In some embodiments the ApoB/ApoA1 ratio
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`achieved is from 0.1 to 2.0. In some embodiments the apoB level achieved is from 48-130.
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`In some embodiments the apoB level achieved is from 20-180.
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`[0039] In some embodiments the inhibitor lowers plasma LDL-cholesterol to at least 50% of
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`normal LDL blood levels, and lowers triglycerides to at least 50% of normal triglyceride
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`blood levels.
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`[0040] In some embodiments total cholesterol is reduced by at least 30%. In some
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`embodiments, non-HDL cholesterol is reduced by at least 30%. In some embodiments, apoB
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`is reduced by at least 15%. In some embodiments, LDL-Cholesterol is reduced by at least
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`30%.
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`In some embodiments one or more of Total Chol