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`US007932268B2
`
`112; United States Patent
`Rader
`
`(10) Patent No.:
`(45) Date of Patent:
`
`Us 7,932,268 B2
`Apr. 26, 2011
`
`l)ISEASl4IS ASS()(fIA'[‘lC[) W['l‘[I
`IIYWJRLIPIDEMIAAND
`IIYPERCII()I.llIS'l‘ER()I.-EMIAWIIILIC
`MINIMIZING SIDE El“FlC(f'l‘S
`
`(75)
`
`Inventor: Daniel J. Rader, Plliladelphia. PA (US)
`,
`_
`_
`(73) Assignee: The Trustees of the University of
`Pennsylvania. Plliladelpllia, PA (US)
`
`( ’* ) Notice:
`
`Subject to any disclaimer. the term ofthjs
`putelit is cxtclidcd or zlciillslcd under 35
`
`(21) Appl. NCL:
`
`l0:"591..923
`
`5357.1 15 A 3‘
`Q
`5.811.429 A
`51321375 A
`5.333.109 A "‘
`5.835.983 A
`
`E.-':.l993 Roscnblum Cl a1.
`‘fl-cl al_
`9.-"1993 Conncllctal.
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`m_.-‘mos
`3-"1999 Gregg ela|-
`3.-‘"1999 Billcr ct al.
`
`514-‘-210.02
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`514321
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`L:
`6:ll34.i IS A
`61]51339 A
`6.066.650 A
`6.ll66.653 A
`54 '43“ A
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`6.265.431 Bl
`6.29’.-‘.233 Bl
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`5.-"2000 Billcr ct a1.
`5.-'2(iUU Gregg el al.
`93000 Mull” 6‘ “'-
`
`all
`
`6.-"2001 Muller er al.
`'?.u"20Ul Muller et al.
`lC|.u"20U1 Sleinet al.
`
`Mar. 7, 2005
`PCT»'US2005»'007435
`
`J""- 21° 2007
`
`(22) PCI‘ Filed:
`(861 PCT No:
`<c><w-
`(23: (431339:
`v ‘
`P(. 1 Pub. No.: W()2ll05f087234
`PCT Pub. Dale: Sep. 22., 2005
`
`(87)
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`451104 Bgrtinato ct al_
`S.-"2004 Lenfers el :11.
`(cominucd)
`FOREIGN PATENT DOCUMENTS
`
`(65)
`
`Prior Publication Data
`US 2()()91’0()4294lA1
`1-‘ch. 12. 2009
`
`AU
`
`737395
`
`-,v_.-1993
`(Continued)
`
`Related U.S. Application Data
`
`OTHER PUBLICATIONS
`
`(60)
`
`PI-ovisiunal application No‘ (,Ul/550.315‘ mcd on Mar_
`5, 2004‘
`
`(51 )
`
`]nt_ (:1_
`,
`,
`514432]: 5l4'(-325
`“I-5 ('l-
`(52)
`51416252-03-
`(58) F19” of ('l3951fi'33t'0n Search
`5l4i"255.03, 263.22. 321, 325, 824. 210.02
`See application file for complete Search history.
`
`(56)
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`.l"ri'riiari-‘ Emiitiiirer — Kevin Weddiligtoli
`.
`'
`,
`x‘IHUF'H'(.’_|r‘, Agent. 0!’ Fir!!! — GOOCIVVIII PFOCIBI‘
`
`(57)
`.
`
`ABSTRACT
`..
`.
`.
`.
`lheprcsclillnw-:n-lion provides methods andcornposltlons for
`treating hyperilplderma andfor llypercllolesterolelnla com-
`prisiligadministcriligtolhesuhiectanclicclivcamotllitofan
`M'l‘Pi11llibi10r10 inhibit liypcrlipidcrrua andfor l1ypc1t:ho1cs-
`lerolcmia in said stllfecl wherein said admiliistration corn-
`.
`‘
`.‘
`-‘
`.-'
`‘
`. .
`.
`prises an escalating series of doses of the Ml P inhibitor. in
`some embodimellts the method comprises administering, at
`least three step—wise_. illcreasingdosages ofthe MTP inhibitor
`to the subicct. in some cmboclimcllts. the lnctllod tilrtlicr
`.
`‘h
`dl
`.
`._
`.
`f
`1
`1.
`.d
`d.
`eonlpnsest ea 11ll‘l:lbTl‘aI10I10 oneornloreotler lpl mo 1-
`iylns °0f11P0“11d5-
`
`8 Claims, No Drawings
`
`1 of 13
`
`PENN EX. 2297
`
`CFAD V. UPENN
`IPR20l5-01836
`
`

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`US 7,932,268 B2
`Page 2
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`US 7,932,268 B2
`Page 3
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`Wellemii el al..
`"‘l\«"1icrosomal Triglyceride Transfer Protein".
`Biochimica Biophysica Aeta. (1997) 1345{2):136-150.
`Wierzbicki A.S.. “New Lipid-Lowering Agents”. Expert Opinion on
`Emerging Dnigs. Ashley Publications. GB. 8 (2)1003. 355-375.
`
`* cited by examiner
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`30113
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`CFAD V. UPENN
`IPR20l5—0l836
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`1
`Ml4I'I'IIOl)S FOR 'l"REA'I‘IN(} l)IS()RI)lCRS OR
`DISEASES ASSOCIATED WITH
`IIYPERLIPIDENIIA AND
`IIYPERCIIOLES'l"EROLI£}'IIA WIIILE
`M[_\'[y[[z[NG SIDE EFFECTS
`
`(_‘R()Sg_R};1.‘};R};N(j] .; 10 RM ‘,\']‘| 5])
`AppL1CAT10Ng
`
`I-‘11«;1,]) 01-‘ '1‘11]-', 1NV1«;N'1‘1(]N
`
`invention generally relates to therapy for
`The present
`]]ypc1'(;]]()]c5T_t:1't)lcrt'1ia and ltypet-1ipidemin_
`
`BACKGROUND OF THE INV"l3.l'\'TION
`
`remnant hyperlipidemia. chylomi-
`hypercholesterolemia,
`croncmia syndrome and familial hypertriglyceridemia.
`A mtinber of treatments are currently available for lower-
`ing serum cholesterol and triglycerides. I Iowever, each has its
`5 own drawbacks and limitations in terms of efficacy. side-
`efiects 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 l.ightCK‘-, Bristol-Myers Squibb).
`This application is a national phase application under 35 10 and colestipol llydrocllloride (C-01estid®', The Upjohn Com-
`U.S.(.‘. §371 orPc:'1'nJs()5t()07435 filed Mar. 7, 2005 which
`pimyl When taken orally. lhcsc positively-cllarscd rt-‘Sins
`in turn clai111s priority benefit of U.S. Ser. No. 60f550.9l5,
`hind 1"’ ll“: “I-‘gatiwly Cllargcd bu” ?“3id5 in ll“: intestine-
`mcd Man 5__ 2004, at] of which are hereby im-m-p0m1,_.d by
`Because the resins cannotbe absorbed fromtheintestine, they
`rcfcrcncc in their cm 11.31 1cs_
`are excreted carrying the bile acids with them, The use of such
`IS resins. however, at best only lowers seru111 cholesterol levels
`by about 20%, and is associated with gastrointestinal side-
`eflects, including constipation and certain vitamin deficien-
`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; th11s, compli-
`eating heart patient’s drug regimens.
`The statins are cholesterol-lowering agents that block cho-
`lesterol synthesis by inhibiting IIM(i(.'oA reductase
`the
`[hr
`llypercholesterolemia is a well-known risk factor
`key enzyme involved in the cholesterol biosynthetic pathway.
`ASCVD, the major cause of mortality in the Western world.
`Numerous epidemiological studies have clearly den1on— 25 The statins, e.g., lovastatin (Mevaco1’«E‘-_. Merck & C 0., Inc.).
`strated that phamiacological lowering of total cliolcsteml
`simvastati11(Zoco1‘-ii‘. Merck &Co._. Inc.}, atorvastatin (Lipi-
`(TC) and Low—density Lipoprotein (LDL) Cholesterol [LDL—
`tor®_. Pfizer], rosuva (Crestor<R‘-_. Astra Zeneca) and pravasta—
`(I) is associated with a significant reduction in clinical car-
`tin (Pravachtil-iii), Bristol-Myers Squibb Co.). and co1nbina-
`diovascular events. Ilypertcholesterolemia is often caused by
`tions thereof, are sometimes used i11 combination with bile-
`a polygenic disorder iii the majority of cases and n1odifica— 30 acid—binding resins. Statins
`significantly reduce serum
`tions in lifestyle a11d conventional drug treatment are usually
`cholesterol and I.l')l.-scrum levels, and slow progression of
`successful i11 reducing cholesterol levels. However.
`in few
`coronary atherosclerosis. llowever, seru111 lll)l. cholesterol
`cases, as in familial hypercholesterolemia {Fl-I). the cause isa
`levels are only moderately increased. The mechanism of the
`Inonogenic defectandthe available treatment inhomozygous
`[.l)[. lowering effect may involve both reduction ofV[.l)[.
`patients can be much 111ore challenging and far from optimal 35 concentration and induction of cellular expression of I.DI.-
`because LDL—C levels remain extremely elevated despite
`receptor.
`leading to reduced production andfor increased
`aggressive use of combination therapy. Therefore. for this
`catabolisrn ofLDLs. Side effects, including liver and kidney
`group of high-risk patients. effective medical
`therapy is
`dysfunction are associated with the use of these drugs (Phy-
`urgently needed.
`sicians Desk Reference, Medical Economics Co..
`Inc..
`Triglycerides are common types of fats (lipids) that are 40 Montvale. N..l., 2004; hereinafter “l-’l)R"). The l-‘l).r\ has
`essential for good health when present in normal amounts.
`approved atorvastatin to treat rare but urgent cases of familial
`They account for about 95 percent of the body’s fatty tissue.
`hypercholesterolernia.
`Abnormal ly high triglyceride levels may be an indication of
`Ezetimibe is a cholesterol absorption inhibitor which
`such conditions as cirrhosis of the liver. underactive thyroid
`reduces the amount of cholesterol absorbed by the body.
`(hypothyroidism), poorly controlled diabetes. or pancreatitis 45 Ezetimibe is used to reduce the amount of total cholesterol.
`[inflammation of the pancreas). Researchers have identified
`LDL cholesterol (by about 18%), and apolipoprotein B.
`triglycerides as an independent risk factor for heart disease.
`Iimetimibe is often used with a low cholesterol diet and.
`in
`lligher-than-normal triglyceride levels are often associ-
`some cases, other cholesterol lowering medications.
`ated with known risk factors for heart disease. such as low
`Niacin, or nicotinjc acid, is a water soluble vitamin B—com—
`levels of l-lDl. (“good“) cholesterol. high levels of IDI. 50 plex used as a dietary supplement and antihyperlipidemic
`(“bad") cholesterol and obesity. Triglycerides may also con-
`agent. Niacin diminishes production o fV’I .l)I . and is effective
`tribute to thickening of artery walls—a physical change
`at lowering LDL. In some cases, it is used in combination
`believed to be a predictor of atherosclerosis.
`with bile-acid binding resins. Nl.1\Sl-’_/\_NIiD has been approved
`Therefore, high triglyceride levels are at least a warning
`to prevent recurrent heart attacks in patients with high cho-
`sig11 that a patient‘s heart health maybe at risk. In response,
`53 lesterol. Niacin can increase IIDL when used at adequate
`physicians may be more likely to stress the importance of
`doses. however,
`its usefulness is limited by serious side
`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.
`lowering drugs used to treat various for111s of hyperlipidetnia
`A large number of genetic and acquired diseases can result 60 (ie, elevated serum triglycerides) which may also be associ-
`in hyperlipidernia. They can be classified into primary and
`ated with hypercholesterolemia. Fibrates appearto reduce the
`secondary hyperlipidemic states. The most common causes
`VLDL fraction and modestly increase I-IDL. However, the
`ofthe secondary hyperlipidemias are diabetes mellitus. alco—
`effects of these drugs on serum cholesterol
`is variable.
`l1ol abuse_. dntgs. hypothyroidism. chronic renal
`failure.
`Fibrates are mainly used to lower high triglyceride levels.
`nephrotic syndrome, cholestasis and bulimia. Primary liyper- 65 Although [ibrates typically do 11ot appear as effective as
`lipidemias have also been classilied into common hyperclio-
`statins in lowering total cholesterol and I.f)I. cholesterol lev-
`lesterolemia,
`familial combined hyperlipidemia,
`familial
`els, they are sometimes used in combination with statins or
`PENN EX. 2297
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`patients, btit obvious disadvantages and risks are associated
`with this approach. Although hof-‘ll 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
`
`5
`
`US ?,932,268 B2
`
`4
`
`3
`other medications to lower very high cholesterol levels. For
`example, fibrates are also sometimes added to statins to raise
`lll)l. cholesterol levels. In the United States. fibrates have
`been approved for use as antilipidemic drugs. but have not
`availability of safe vectors that provide long—terni expression
`1*‘-’°eiVed
`5'PP1'W31
`as
`h)’Pei‘°1101e5le1'01eI11la
`3Psem5~ For
`ofLDL receptor gene. Thus, the current standard of care in
`e_Xaml_’le= °1°fil?§al}°-‘ (A_lmmld'S®~ WYeth'AYer5‘ L3b°mt°'
`hol"ll is ID], apheresis, a physical method of filtering the
`nés) 15 5}“ allllllpldefnlc a-gel“ whhjsh ajcts to lower Serum
`plasma of LDL—C which as moiiotlierapy can transiently
`mglycendes by reducmglh§VLDf1fractlon‘Although S"°f‘mm
`reduce ”—)I’_C by abm“ 50%_ Aphcmsis uses am-nity COL
`I
`cholesterol may be reduced in certain peltICI'lT.'Slll)p0pl]lal]()]'lS,
`the biochemical "“"51°°“?“" to file drug. 13 Variable‘ arid 15 not 1” umns to selectively remove apoB—containin0 lipoproteins.
`always possible to predict which patients will obtain favor-
`_
`W
`‘ _
`.
`_ I
`_ _
`I
`.
`°
`.
`.
`able results. _/\_troi11id-SIR) has not been shown to be effective
`Ilowwu’ hocdllff of rdpld rf-duiumfilduon of LDL"-(J In
`P
`dry
`Y
`-
`-
`-
`.-
`for
`reventioii of coron'
`heart disease. The cheinicall and
`plasma’ apheresls has to be repeaied frequently (every 1-2
`pharmacologically related drug, gemfibmzil (L0pid®, Parke_
`weeks) and retiuires 2 separate sites for IV access. Although
`Davis) is a lipid regulating agent which moderately decreases I S
`"’““’_°d‘?“3,“Y this 1?‘°°ed“’em‘"{Y delay the Onset (‘id ather,0SCle'
`serum triglycerides and VLDL cholesterol. and moderately
`10515! ll '5 ]ab0“°“5= e_xPe“51"'e-‘ and not "‘°_-‘adlly aVa11ab1e-
`increases HDL cliolesterol—tl1e HDL2 and HDL; subfrac—
`F““h31'1“0W.- 319100811 1l_ 15 3 P1'0°3d111'3 111?“ ‘-5 Béllerdlly We“
`‘ions as wen as both ApoA_1 and A41 (i_e_, theA],.rA]1_HDL
`tolerated, the fact that it needs frequent repetition and IV
`fraction). I lowever, the lipid response is heterogeneous, espe-
`390955 03“ hc Chan‘-'“ElT1l% f01' many ‘if 111959 YUUUE Fallen“-
`cially among different patient poptilalions. Moreover. while 20 'll1L‘rcf0rL‘, there is a tremendous unmet medical need for new
`prevention of coronary heart disease was observed in male
`medical therapies for hoFl-l.
`patients between 40-55 without history or symptoms ofexisl-
`Patients with heterozygous l-‘I I can usually be successfully
`ing coronary heart disease, it is not clear to what extent these
`treated with combination drug therapy to lower the I.l)l ..-(.' to
`findings can be extrapolated to other patient populations (e.g.,
`acceptable levels. In contrast, hoFl-I is unresponsive to con-
`women, older and younger males). Indeed, no efficacy was 25 ventional drug therapy and thus there are limited treatment
`observed in patients with established coronary heart disease.
`options. Specifically, treatment with statins, which reduce
`Fenofibrate (Tricor, Secalip) is also used to reduce levels of
`LDL—C by inhibiting cholesterol synthesis and upregulating
`cholesterol and triglycerides. Serious side-effects have been
`the hepatic l.l)l . receptor, have negligible effect in patients
`associated with the use of several librates including toxicity
`whose l,l')l. receptors are non-existent or defective.
`such as malignancy, (especially gastrointestinal cancer), gall— 30
`In Jilly 2004, the NCEP published a paper entitled “Impli-
`bladder disease and an increased incidence in non-coronary
`cations of Recent Clinical Trials for the National Cholesterol
`mortality. l-‘ibrates are often not indicated for the treatment of
`Iiducation Program Adult Treatment Panel III Guidelines”,
`patients with high LDL or low HDL as their only lipid abnor—
`updating certain elements of the “Adult Treatment Panel Ill
`Inality (I-’hysician‘s Desk Reference, 2004, Medical liconom-
`(ATP lll)” cholesterol guidelines released in 2()0 1. For high-
`ics Co, Inc. Montvale, N..l.).
`35 risk patients, individuals who have coronary heart disease
`Oral estrogen replacement therapy may be considered for
`(C HD) or disease of the blood vessels to the brain or extremi-
`iiioderate hypercholesterolemia in post—menopausal women.
`ties, or diabetes, or multiple (2 or more) risk factors that give
`llowever, increases in lll)I. may be accompanied with an
`them a greaterthan 20 percent chance of havingalieart attack
`increase in triglycerides. Estrogen treatment is, of course,
`within 10 years, the ATP III update recommends that the
`limited to a specific patient population (postmenopausal 40 overall goal for high-risk patients is still an I .l)I. less than l0()
`women) and is associated with serious side effects including
`mg/dl ,with a therapeutic option to set the goal at an l.l)l .. less
`induction of malignant neoplasms, gall bladder disease,
`than 70 inydL for very high—risk patients, those who have had
`tliroiiiboeiiibolic disease, hepatic adenoina. elevated blood
`a recent heart attack, or those who have cardiovascular dis-
`pressure, glucose intolerance. and hypercalceinia.
`ease combined with either diabetes, or severe or poorly con-
`Homozygous familial hypercholesterolemia (lioFH) is a 45 trolled risk factors (such as continued smoking), or metabolic
`serious lile—threatening genetic disease caused by homozy—
`syndrome (a cluster of risk factors associated with obesity
`gosity or compound hetero;r.ygosity for mutations in the low
`that includes high triglycerides and low lll)l. cholesterol).
`density lipoprotein (l.l)l.) receptor. Total plasma cholesterol
`The ATP lll update also recommends consideration of drug
`levels are generally over 500 mgfdl and markedly premature
`treatment in addition to lifestyle therapy for LDL levels 100
`atherosclerotic vascular disease is the major consequence. 50 mg/'dl. or higherin high-risk patients, and characteri7es drug
`Untreated, most patients develop atherosclerosis before age
`treatment as optional for l .l)I. less than l()0 mgfdl
`For
`20 and generally do not survive past age 30. The primary goal
`moderately high—risk patients, individuals who have multiple
`o ftherapy consists of controlling the hypercholesterolemia to
`(2 or more] (‘I ll) risk factors together with a l()-2() percent
`delay the development of atherosclerotic cardiovascular dis-
`risk for a heart attack within 10 years. the ATI-’ Ill update
`ease [ASC\»"l_)]. Ilowever, patients diagnosed with holill are 53 recommends the overall goal
`for moderately high—risk
`largely unresponsive to conventional drtig therapy and have
`patients to be an l D] , less than 130 mg;"dI .. There is a thera-
`limited treatment options. A mean l.| )l .-C reduction of only
`petitic option to set the t.reatmei1t goal at an l.l)l . less than l0(l
`about 5.5% has been recently reported in patients with geiio—
`mgi’dL, and to use drug treatment if LDL is 100- 129 mgfdls.
`type-confirmed hol-‘ll
`treated with the maximal dose of
`For high-risk and moderately high-risk patients. the .r\'l'l-’ lll
`statins (atorvastatin or simvastatin 80 mg/day). The addition 60 update advises that the intensity ofI.DI.-lowering drug treat-
`of ezetiiiiibe I0 mgfday to this regimen resulted in a total
`iiieiit in high—risk and moderately high—risk patients be sutl'l—
`reduction of LDL—C levels of 27%. which is still far from
`cieiit to achieve at Ieasta 30 percent reduction in LDL levels.
`optimal. Severalnon—pharinacologicaloptions have also been
`Patients sufl'ering from severe hypercholesterolemia may
`tested. Surgical interventions, such as portacaval shunt and
`also be unable to reach the new goals for LDL and HDL
`ileal bypass have resulted only in partial and transient l.l')l.-C 65 described above. Ftirexample, a large ntunber ofpatients may
`lowering. Orthotopic liver transplantation has been deinon-
`be unable to attain l.T)l. levels less than 70 using maximally
`strated to substantially reduce l.l)l .-C levels
`in hol"l l
`tolerated current methodologies.
`
`5 of 13
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`6
`and small intestine correlated with decrease in serum TC} and
`
`SUMMARY Oi; -iiiin; INWH,-Nvi-ION
`
`5
`Abetalipoproteinemia is a rare genetic disease character-
`ized by extremely low cholesterol and TG levels. absent apo-
`cholesterol levels. These changes are a consequence o l'the
`lipoprotein (apo) l3-containing lipoproteins in plasma,
`[at
`phannacologic elTects oi‘ l3lVlS-201038. In rats, but not
`in
`malabsorption, scvcre vitamin E deficiency. and progressive
`dogs. doses of 0.2 rrigfkg and higher were associated with
`subacme jnfiainmmjgn and Single_ce1l necrosis of 113mm.
`spinocerebellar and retinal degeneration. lt has been deter— 5
`cytes and liistiocytosis (phospholipidosisj in the lungs. The
`111111ed_1115'1 111111311011‘-5 111 1113 MTP We1'e_l11e 2-e11el1° Cause of
`hepatic accumulation ollipids was reversed in rats at the end
`ebelellpeprolelllelllle Mill] 15 respellslble for lransfemng
`of a l—i1iontli washout period. Studies in animals indicated
`llplde-' Pa“1‘_=“1“1¥TG= emo llle asselllellllgz Cllylellllelell and
`tliatBMS-201038 effectively reduced plasma cholesterol lev-
`Vl ’l)l' pamclcs lll llll: llllesllllc end llle llvce’ rcS1ll"ll”:llw"‘ly'
`Although the inechanisms by which hpoproteins are iormed in eis in a dose dependem manner BMs_20i0.is was found to
`arenot completely understood. it is currently believed that the
`h _ _n.
`_1.
`_.
`_d
`_.
`_i
`int:
`ii, _i‘ .
`‘ I bbs ‘ n I I i, is
`assembly ofapol3 containing lipoproteins requires two steps.
`{IL Ci’ we m R Hung L 1_0 L5 U0 Wt’ 5 H1.”
`l_b .l‘l
`‘ll’
`The first step occurs within the endoplasmic reticulum that
`a 1-UHCUOHTLDL receptor’ The ED5e value 10110“ emle ebo-
`involves the synthesis of particles that contain only a small
`le5leml_ was l9 lllglllg and 5' dojse of lo lllglllg efssellllally
`fraction of the lipid core found in the secreted lipoprotein. A IS llorlllellzed clloleelelol levels wllll llo ‘llllelalloll lll plasma
`larger core oflipid is added to the nascent particle ina second
`AST or ALT- T1115 5me3l= eenduelee “l_ the best accepted
`step. MTP is thought to be essential for the transfer of lipid to
`f11"1_11*_'1_ 11101131 101' 11113 1101110Z)'E01'5 FH= 11}(11‘3_111311 111311 MTP
`the apeg during the first step efthe process‘ in the absence of
`inhibition by |3MS-201038 might be effective in substantially
`functional MTP. chylomicrons and VI _.l)[. are not effectively
`1'1-‘dlll-31113 C11011-‘1*1C1‘111 10/013 111 P31191113 W1111 110111 1-
`asseinbled or secreted in the circulation and apoli is likely 20
`Clinical dt-‘Vt-‘lfirllmtlll 01‘l3MS-201038 HS El drug T01’ large
`targeted for degradation. V’I.T)l_. serves as the metabolic pre—
`scale use in the treatment of hypercholesterolemia has been
`cursorto l.l)l.andtheinabilityto secrete V[.l)l , from theliver
`discontinued, because of significant and serious hepatotox-
`results in the absence of l .l)l . in the blood. The concept that
`icities, For example__ gastrointestinal side effects, elevation of
`MTP Ina)’ reglllate 2113013 1ip0pl'0IeiI1 assembly is Sllppflffed
`serum transaininases and hepatic fat accumulation were
`by observations in mice models. in heterozygous knockout 25 observed__ primarily at 2 5 mg,tday0;-}11g11e1-dose-5,”[11u5‘i11e1-e
`11111313 M11’ 111RNA= P10113111 and a‘311‘’11Y 1131“: 11131311 1'13P01'1‘-‘11
`is a need to develop methods for