fl2) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`:/'
`...
`.
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`· .119) World Intellectual Property
`Organization
`International Bureau
`
`1 mm 1111m1 11111~11m111111111111 rn rn 1111111111m 01111111H1111m mm m1 oia11
`
`(43) International Publication Date
`20 October 2005 (20.10.2005)
`
`PCT
`
`(10) International Publication Number
`WO 2005/097131 A2
`
`(51) InternationaJ Patent Classllicatlon7:
`
`A61K 311496
`
`(21) InternaUonaJ Application Number:
`PCT/EP2005f003636
`
`(22) lnternationaJ FWng Date:
`
`6 April 2005 (06.04.2005)
`
`(2S) FWng Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`04101470.5
`
`9 April 2004 (09.04.2004) BP
`
`TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU,
`ZA,ZM,'ZW.
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA; SD, SL, SZ. TZ, UG, ZM,
`'ZW), Eurasian (AM, AZ, BY, KO, KZ, MD, RU, TJ, TM),
`European (AT, BE, BO, CH, CY, CZ, DE, DK, EE, FS, fl,
`FR, GB, GR, HU, m. IS, IT, LT, LU, MC, NL, PL, PT, RO,
`SE, SI, SK. TR), OAPI (BP, BJ, CF, CO, CI, CM, GA, GN,
`GQ, GW, ML, MR. NE, SN, TD, TG).
`
`Dedaratlons under Rule 4.17:
`as to applicanl's entitlement to apply for and be granted
`a patent (Rule 4.17(ii)}for the following designations AE,
`AG, AL. AM, AT. AU, AZ.. BA, BB, BG, BR, BW, BY. BZ.. CA,
`CH, CN, CO, CR, CU, CZ. DE, DK, DM, DZ.. EC, EE, EG,
`ES, Fl, GB, GD, GE, GH, GM, HR, HU, ID, IL. IN, IS, JP.
`KE, KG, KM, KP. KR, KZ. LC, LK, lR, LS, LT, LU, LV. MA,
`MD, MG, MK, MN, MW. MX, MZ.. NA, NI, NO, NZ. OM,
`PG, PH, PL. PT, RO, RU, SC, SD, SE, SG, SK, SL. SM, SY,
`TJ, TM, TN, TR, IT. 7Z, UA, UG, UZ.. VC, VN, YU, ZA,
`'ZM, ZW. AR/PO patent (BW. GH, GM, KE. LS, MW. MZ..
`NA, SD, SL. SZ.. 7Z. UG, 'ZM, ZW), Eurasian patent (AM,
`A'Z. BY. KG, KZ.. MD, RU, TJ, TM), &ropean paient (AT,
`BE. BG, CH, CY. CZ. DE. DK. EE, ES, Fl, FR, GB, GR,
`HU, IE. IS, rr, LT, LU, MC, NL, PL. PT, RO, SE, SI, SK,
`TR), OAP/ pmem (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ,
`GW. ML, MR, NE, SN, TD, TG)
`as to the applicant's entillement to claim the priorily of the
`earlier applicmion (Rule 4.17(iii))for all designations
`of inventorship (Rule 4.17(iv))for US only
`
`Published:
`-
`without international seatch report and to be republished
`upon receipt of that report
`
`For two-leuer codes and other abbreviations, refer to the "Guid(cid:173)
`ance Notes on Codes and Abbrevlatlonsn appearing at the begin(cid:173)
`ning of each regular issue of the PCT Ga'IJ!rte .
`
`....-4
`~
`....-4
`t""(cid:173)
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`Q'I. =
`= N
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`...._~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~-
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`~ (54) TitJe: lNTBRM1TTENT OOSINO REGIMEN FOR OVERWEIGHT AND OBESE SUBJECTS
`
`(57) Abstract: The present invention concerns an intenninent dosing regimen for the treatment of obesity or the redaction of body
`O weight wherein a phannaceatical composition containing an apoB secretion/MTP inhibitor is administered to a subject in need thereof
`:> for a period of time, then withheld for a period of time, and agein administered for a period of time. The intennittent regimen may
`. ~ be repeated depending on the response in the subject that is being sought.
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`INTERMITTENT DOSING REGIMEN FOR OVERWEIGHT AND OBESE SUBJECTS
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`(0001] The present Invention concerns an intermittent dosing regimen for the
`treatment of obesity or the reduction of body weight wherein a pharmaceutical
`composition containing an apoB secretlon/MTP inhibitor is administered to a subject In
`need therec>f for a period of time, then withheld for a period of time, and again
`administered for a period of time. The Intermittent regimen.may be repeated
`depending on the response in the subject that is being sought.
`
`[0002] The microsomal triglyceride transfer protein (MTP) catalyses the transfer of
`lipids such as triglycerides, cholesteryl esters and phosphatidylcholine between
`phospholipld surf aces. MTP Is found in the liver and intestine, both organs which
`produce lipoproteins. MTP is necessary for the production of apolipoproteln B (apoB)
`containing plasma Jipoproteins, in particular apoB-100 within the liver, and apoB-48
`within the intestine. ApoB-100 is the main protein component of VLDL (very low
`density lipoproteins). ApoB-48 is the main protein component of chylomfcrons.
`Compounds that Inhibit MTP reduce the secretion of apoB-containlng llpoprotelns and
`therefore have the potential to decrease VLDL and triglyceride plasmatic levels, and
`also Intestinal lipid absorption. High VLDL plasmatic levels are a major risk factor for
`atherosclerosis and coronary artery diseases. Hence an Intermittent dosing regimen
`of the present invention using apoB secretion/MT.P inhibitors may be useful in the
`prevention, management and treatment of obesity, diabetes mellitus, non-insulin
`dependent diabetes mellitos, coronary heart disease, pancreatitis, mixed dyslipidemia,
`hyperllpemia, post-prandial hyperlipemia, hypercholesterolemla, hypertriglyceridemia,
`osteoarthritis and atherosclerosis.
`
`[0003] A variety of apoB secretion/MTP inhibitors are known to one of ordinary skill
`in the art. Although any apoB secretion/MTP inhibitor may be used In the Intermittent
`dosing regimens of the present invention, generally preferred apoB secretlon/MTP
`inhibitors include those compounds that are disclosed in, for example, European
`patent applications EP-0,643,057, EP-0,719,763, EP-0,753,517, EP-0,764,-647,
`EP-0,765,878, EP-0,779,276, EP-O,n9,279, EP-0,799,8281 EP-0,799,829,
`EP-0,802, 186, EP-0,802, 188, EP-0,802, 192, and EP-0,802, 197; international patent
`applications W0-96/13499, W0-96/33193, W0-96/40640, W0-97/26240,
`W0-97/43255, W0-97/43257, W0-98/16526, W0-98/23593, W0-00/32582,
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`W0-02/081460, WQ-02/42271 and W0-02/20501; and U.S. patents US-5,595,872;
`US-5, 646,162; US-5,684,014; US-5,712,279; US-5,739,135 and US-5,789,197.
`
`[0004] A particula_r apoB secretion/MTP inhibitor is mitratapide which is the INN
`(International Non Proprietary Name) for the compound (-)-[2S-[2a,4a(S*)]J-4-[4-[4-[4-
`[2-( 4-chlorophenyl)-2-[[( 4-methyl-4H-1,2,4-trlazol-3-yl)thlo]methyl]-1,3-dioxolan-4-
`yijmethoxy]-phenyij-1-piperazinyl]phenyij-2,4-dlhydro-2-(1-methylpropyl)-3H-1,2,4-
`triazol-3-one having the following structure.
`
`
`7 \l_o-0-0-0-l~
`
`P.
`
`t)-s
`
`Cl
`
`·
`
`.
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`(0005) Mitrataplde has been described in W0-96/13499 as compound (40) having
`apolipoprotein B (apoB) secretion and microsomal triglyceride transfer protein (MTP)
`inhibiting properties and therefore being useful as a lipid lowering agent.
`
`(0006) Warm-blooded animals such as humans and companion animals, in particular
`dogs and cats, with an excessive accumulation of body fat to the point of being 20% or
`more over ideal body weight are considered obese. Already an overweight of 10%
`·over Ideal body weight is considered a health risk. Obesity Is known to cause liver
`disease, hypertension, constipation, heat intolerance, and increased risk under
`anaesthesia. Obese warm-blooded animals may have trouble breathing and may
`suffer from serious discomfort and body dysfunction and have life expectancies less as
`usual. Although obesity in warm-blooded animals is usually caused by too little
`exercise and Intake of too many calories, a number of wann-blooded animals become
`obese due to genetic predisposition or honnonal disorders. ·
`
`[0007) Subjects suffering from obesity or overweight can be treated by administering
`an apoB secretion/MTP inhibitor. A phannaceutical composition comprising the apoB
`secretion/MTP inhibitor is typically administered once or several times a day during a .
`period of several weeks or months until the weight of the subject is equal to or close to
`its ideal body weight.
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`It has been observed that the administration of an apoB secretion/MTP
`[0008]
`inhibitor during a continuous period of eight weeks resulted In an initial reduction of
`body weight which however levelled off after three weeks. Sustained administration of
`the apoB secretion/MTP inhibitor did not result in a further reduction of body weight.
`
`It has now been found that an Intermittent treatment schedule or dosing
`[0009]
`regimen with alternating periods of administration and non-administration of the apoB
`secretion.IMTP inhibitor can overcome the problem of body weight reduction levelling
`off. This Intermittent treatment schedule or dosing regimen comprises of a period of
`several weeks during which the subject is administered an apoB secretlon/MTP
`inhibitor followed by a period of several weeks of non-administration of the apoB
`secretion/MTP inhibitor, again followed by a period of several weeks of administration
`of the apoB secretion/MTP Inhibitor. In order to achieve a further reduction of body
`weight, It is possible to repeat this intermittent treatment schedule two, three or four
`times.
`
`[0010] For the purposes of this invention, the term "subject" includes warm-blooded
`animals, preferably mammals, including humans and companion animals such as
`dogs, cats, rabbits, ferrets, guinea pigs and the like.
`
`[0011] The term aoverweight• as used in the present invention refers to a body
`weight that is above the ideal body weight of a subject. Ideal body weight for human
`subjects can be determined using the "Body Mass Index'' (BM!). The BMI is defined as
`the body weight in kilograms divided by the square of the height in meters. A BMI
`ranging from 20 to 25 is generally considered as ideal and human subjects having a
`BMI higher than 25 are considered overweight. Another method to determine ideal
`body for human subjects is based on the Metropolitan Life tables created by the
`Metropolitan Life Insurance company. Ideal body weight for companion animals, in
`particular dogs, can be looked up in breed standards, providing breed-specific
`information on body weight and height at withers for male and female animals.
`
`[0012] The term "therapeutically effective amount of an apoB secretion/MTP
`inhibitor" as used herein, means that amount of an apoB secretion/MTP inhibitor that
`elicits the biological or medicinal response in the subject that Is being sought, which
`includes alleviation of the symptoms of the condition being treated. The
`therapeutically effective amount can be determined using routine optimization
`techniques and is dependent upon the particular condition to be treated, the condition
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`of the subject, the route of administration, the formulation, and the judgment of the
`practitioner and other factors evident to those skilled in the art. A therapeutically
`effective amount may be achieved by multiple dosing.
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`(0013] The regimen which is the basis of the present invention is an intermittent
`dosing regimen ·wherein a pharmaceutical composition containing an apoB secretion/
`MTP inhibitor is administered for a period of time, then withheld for a period of time,
`. and again administered for a period of time. These three periods of time may be of the
`same or of cflfferent length. The length of each period can be expressed in days or in
`weeks and - dependent upon the specific apoB secretion/MTP inhibitor that is being
`used and the response of the subject - may range from 1 to 56 days or from 1 to 8
`weeks. Said intermittent regimen may be repeated two, three, four or more times
`depending on the response in the subject that is being sought. The period of time
`between two intermittent dosing regimens is varlabl~ and In practice ranges from 2 to
`6 months.
`
`(0014] The intermittent dosing regimen consists of three terms which can be all of
`different length. Hence an infinite number of intermittent dosing regimens is possible
`by varying the length of each of the three terms. From a practical viewpoint it is
`pref arable to express each term as a number of weeks so that one intermittent dosing
`regimen is defined as Aw-Bw-CW wherein A represents the number of weeks during
`which an apoB secretion/MTP inhibitor Is administered, B represents the number of
`weeks during which administration Is withheld, and C represents the number of weeks
`during which an apoB secretion/MTP Inhibitor is again administered. In practice, the
`first administration period ranges from 2 to 4 weeks, the period during which
`administration is withheld ranges from 2 to 4 weeks, and the second administration
`period ranges from 2 to 4 weeks. For instance, in a 4w-3w-4w dosing regimen, the
`pharmaceutical composition comprising the apoB secretion/MTP inhibitor Is
`administered for 4 weeks, withheld for 3 weeks, and again administered for 4 weeks.
`Practical dosing regimens are 4w-4w-4w, 4w-3w-4w, 4w-2w-4w, 3w-3w-3w,
`3w-2w-3w, and 2w-2w-2w. The three terms of the intermittent dosing regimen may
`also be expressed in number of days.
`
`(0015] The three terms of the intermittent dosing regimen may also be defined
`alternatively with a starting date and a final date. Accordingly a 4w-3w-4w dosing
`regimen can be expressed as 1-28/29-49/50-77 which refers to administration of an
`apoB secretion/MTP inhibitor from day 1 to day 28, no administration from day 29 to
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`day 49, and again administration from day 50 to day 7.7. The following table lists the
`above described practical dosing regimens expressed in weeks recalculated with a
`starting and final date.
`
`Intermittent dosing regimen with starting and final dates
`181 administration
`2nd administration
`no administration
`-
`- -
`-
`-period
`period
`period
`Start date Final date· Start date Anal date Start date Final date
`29
`84
`1
`.28
`56
`57
`50
`77
`28
`49
`29
`1
`43
`42
`29
`28
`70
`1
`22
`42
`43
`63
`21
`1
`22
`21
`36
`1
`56
`15
`14
`29
`1
`42
`
`35
`28
`
`I
`
`I
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`4w-4w-4w
`4w-3w-4w
`4w-2w-4w
`- 3w-3w-3w
`3w-2w-3w
`2w-2w-2w
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`[0016] The present invention provides an Intermittent dosing regimen for the
`treatment of obesity which is defined as Aweeks-Bweeks-Cweeks wherein A
`represents the number of weeks during which a pharmaceutical composition
`containing an apoB secretion/MTP inhibitor as the active ingredient in a therapeutically
`effective amount ls administered to a subject in need thereof, B represents the number
`of weeks during which administration Is withheld, and C represents the number of
`weeks during which said pharmaceutical composition containing the apoB
`secretion/MTP inhibitor is again administered. In practice, A ranges from 2 to 4
`weeks, B ranges from 2 to 4 weeks and C ranges from 2 to 4 weeks. Practical dosing
`regimens are 4w-4w-4w; 4w-3w-4w, 4w;.2w-4w, 3W-3w-3w, 3w-2w-3w, and 2w-2w-2w.
`
`[0017] The present invention also provides an Intermittent dosing regimen for the
`reduction of body weight which is defined as Aweeks-Bweeks-Cweeks wherein A
`represents the number of weeks during which a pharmaceutical composition
`containing an apoB secretion/MTP inhibitor as the active ingredient in a therapeutically
`effective amount is administered to a subject in need thereof, B represents the number
`of weeks during '!'hich administration is withheld; and C represents the number of
`weeks during which said pharmaceutical composition containing the apoB
`secretion/MTP inhibitor is again administered. In practice, A ranges from 2 to 4
`weeks, B ranges from 2 to 4 weeks and C ranges from 2 to 4 weeks. Practical dosing
`regimens are 4w-4w-4w, 4w-3w-4w, 4w-2w-4w, 3W-3w-3w, 3W-2w-3w, and 2w-2w-2w.
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`[0018) Consequently there is provided the use of a pharmaceutical composition
`containing an apoB secretion/MTP inhibitor as the active ingredient in a therapeutically
`effective amount for the manufacture of a medicament for the treatment of obesity or
`the reduction of body weight wherein said pharmaceutical composition is administered
`according to an intermittent Aweeks-Bweeks-CWeeks regimen wherein A represents
`the number of weeks during which said pharmaceutical composition is administered to
`_a subject In need thereof, B represents the number of weeks during which
`administration is withheld, and C represents the number of weeks during which said
`· pharmaceutical composition is again administered. In practice, A ranges from 2 to 4
`weeks, B ranges from 2 to 4 weeks and C ranges from 2 to 4.weeks. Practical
`regimens are 4w-4w-4w, 4w-3w--4w, 4w-2w-4w, 3w-3w-3w, 3w-2w-3w, and 2w-2w-2w.
`
`[0019] Alternatively, an intermittent dosing regimen is provided for the treatment of
`obesity or the reduction of body weight comprising administering a pharmaceutical
`composition containing an apoB secretion/MTP inhibitor as the active ingredient in a
`therapeutically effective amount to a subject in need thereof on days 1 to 28, and on
`days 57 to 84. Other intermittent dosing regimens ar~ administration on
`a) days 1 to 28, and on days 50 to 77; or on
`b) days 1to28, and on days 43 to 70; or on
`c) days 1 to 21, and on days 43 to 63; or on
`d) days 1 to 21 , and on days 36 to 56; or on
`e) days 1to14, and on days 29 to 42.
`
`(0020] Consequently there is provided the use of a pharmaceutical composition
`. ~ontalni~g _a_n _apoB secretion/MTP inhibitor as the active ingredient in a therapeutically
`effective amount for the manufacture of a medicament for the treatment of obesity or
`the reduction of body weight wherein said pharmaceutical composition is administered
`Intermittently to a subject In need thereof on days 1 to 28, and on days 57 to 84. Other
`intermittent regimens are administration on
`a) days 1 to 28, and on days SO to 77; or on
`b) days 1 to 28, and on days 43 to 70; or on
`c) days 1 to 21, and on days 43 to 63; or on
`d) days 1 to 21, and on days 36 to 56; or on
`e) days 1to14, and on days 29 to 42.
`
`[0021] According to a further aspect of the present invention there is also provided a
`pharmaceutical kit comprising dosage forms for administration to a subject in need
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`thereof on days 1 to 28 and on days 57 to 84, which kit comprises dosage forms
`containing an apoB secretlon/MTP Inhibitor as the active ingredient In a therapeutically
`effective amount and a memory aid in the form of numbers or a calendar indicating on
`which days of the regimen the dosage forms should be ingested. The pharmaceutical
`kit may further comprise a patient information leaflet comprising the memory aid and
`further Instructions concerning the intermittent dosing regimen. The memory aid may
`also be in the form of an electronic timing device with an LCD readout displaying the
`date that the last dosage forms has been taken and/or the date when the next dosage
`form is to be taken. Also provided ls the same pharmaceutical kit suitable for
`administration to a subject in need thereof on
`a} days 1 to 28, and on days 50 to 77; or on
`· b} days 1to28, and on days 43 to 70; or on
`c} days 1 to 21, and on days 43 to 63; or on
`d) days 1 to 21, and on days 36 to 56; or on
`e) days 1 to 14, and on days 29 to 42.
`
`[0022] During the administration periods of the intermittent dosing regimen the dally
`dosage of the apoB secretion/MTP Inhibitor mitratapide may range between 0.1 mg
`per kg body weight and 5 mg per kg body weight, particular between 0.31 mg/kg and
`1 .25 mg/kg. In practice a dally dosage of 0.63 mg per kg body weight is used. It may
`be appropriate to administer the dally dose In the form of two or more sub-doses at
`appropriate intervals throughout the day.
`
`[0023] The daily dosage of the apoB secretion/MTP inhibitor may be calculated daily
`c;turing the administration periods on the basis of the body weight or it may be .
`calculated once weekly at the start of each week during the administration periods. In
`practice, the daily dosage of the apoB secretion/MTP inhibitor is calculated once at the
`beginning of each administration period. Alternatively the dally dosage of the apoB
`secretion/MTP inhibitor may also be calculated once at the start on one intermittent
`dosing regimen and remain unchanged during the two administration periods.
`
`(0024] The effect on body weight reduction of the intermittent dosing regimens of the ·
`present invention can be improved If the subject under treatment Is altering Its eating
`habits. For instance, a reduction of the caloric intake wlll llkely have a beneficial effect
`on body weight reduction when a subject is undergoing treatment for obesity. The
`effect of the intermittent dosing regimen can be Improved when a subject Is following a
`maintenance diet whereby the caloric content of said diet equals the caloric
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`expenditure of the subject during any or all of the three periods of the intermittent
`dosing regimen. In practice, a subject may follow the first period of the intermittent
`dosing regimen without altering its eating habits and then switch to a maintenance diet
`at the beginning of the second period during which administration of the apoB
`secretion/MTP inhibitor is withheld, and continue with the same maintenance diet
`during the third period wherein the apoB secretion/MTP inhibitor is adininistered again.
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`The caloric content of the maintenance diet Is determined at the beginning of the
`second period and may be maintained or adapted during the remaining time of the
`Intermittent dosing regimen. At the end of the second administration period a
`10 maintenance diet may be determined based on the weight of the subject in order to
`presel'Ve the weight loss resulting from the intermittent dosing regimen.
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`In a further aspect of the present Invention, a method for the reduction of body
`[0025]
`weight or the treatment of obesity of a subject in need thereof is provided wherein the
`Intermittent dosing regimen is combined with a maintenance diet having a caloric
`content equal to the caloric expenditure of said subject. The maintenance diet may be
`followed concomitant with the beginning of the first, second or third period of the
`intermittent dosing regimen.
`
`In another aspect, the intermittent dosing regimens of the present invention
`[0026)
`may be used In the cosmetic treatment of the human or animal body wherein the
`appearance of the human or animal body is improved by the loss of body weight. It
`may be desirable to obtain such a cosmetic improvement of bodily appearance by
`following an intermittent dosing regimen of the present invention.
`
`[0027] The pharmaceutical compositions comprising an apoB secretion/MTP Inhibitor
`can be administered to a subject either orally, parenterally (for example intravenously,
`intramuscularly or subcutaneously), percutaneously, or rectally.
`
`[0028) Solid dosage forms for oral administration include capsules, dragees, tablets,
`powders and granules. These solid dosage forms are preferably formulated in dosage
`unit form for ease of administration and uniformity of dosage. aoosage unit form" as
`used herein refers to physically discrete units suitable as unitary dosages, each unit
`containing a predetermined amount of active ingredient calculated to produce the
`desired therapeutic effect in association with the required pharmaceutical carrier.
`Examples of such dosage unit forms are tablets (including scored or coated tablets),
`capsules, pills, powder. packets, wafers, injectable solutions or suspensions,
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`teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
`
`[0029] Liquid dosage forms for oral administration include pharmaceutically
`acceptable emulsions, solutions, suspensions, suspo-emulsions, syrups and elixirs.
`Pharmaceutical compositions for parenteral injection may comprise physiologically
`acceptable sterile aqueous or nonaqueous solutions, dispersions, suspension, or
`emulsions, or may comprise sterile powders for reconstitution Into sterile Injectable
`solutions or dispersions.
`
`[0030) Pharmaceutical compositions comprising an apoB secretion/MTP inhibitor for
`administration to non-human animals can be administered In the drinking water so that
`a therapeutically effective amount Is ingested with the dally water supply. The
`pharmaceutical compositions can also be added directly to the feed, as such, or in the
`form of an animal feed supplement, also referred to as a premix or concentrate.
`
`[0031] The apoB secretion/MTP inhibitor may be used In conjunction with other
`pharmaceutical agents, in particular a lipid-lowering agent, thus leading to a so-called
`combination lipid-lowering therapy. The said additional lipid-lowering agent may be, for
`instance, a known drug conventionally used for the management of hyperlipidaemia
`such as e.g. a bile acid sequestrant resin, a fibrlc acid deriv~tive or nicotinic acid.
`Suitable additional lipid-lowering agents also include other cholesterol biosynthesis
`inhibitors and cholesterol absorption Inhibitors, especially HMG-CoA reductase
`inhibitors and HMG-CoA synthase inhibitors, HMG-CoA reductase gene expression
`inhibitors, CETP inhibitors, ACAT inhibitors, squalene synthetase inhibitors, CB-1
`antagonists, cholesterol absorption inhibitors such as ezetimibe, and the like. The
`apoB secretion/MTP inhibitor and the 0th.er pharmaceutical agent for use In
`combination lipid-lowering therapy may be administered as separate dosage units or
`combined In one dosage unit.
`
`(0032) Any HMG-CoA reductase Inhibitor may be used as the second compound in
`the combination therapy aspect of this invention. The term aHMG-CoA reductase
`inhibitor" as used herein, unless otherwise stated, refers to a compound which inhibits
`the blotransformation of hydroxymethylglutaryl-coenzyme A to mevalonlc acid as
`catalyzed by the enzyme HMG-CoA reductase. Such "HMG-CoA reductase inhlbitorsa
`are, for example, lovastatin, simvastatin, fluvastatin, pravastatln, rivastatln, and
`atorvastatin.
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`[0033] Any HMG-CoA synthase Inhibitor may be used as the second compound in
`the combination therapy aspect of this invention. The term "HMG-CoA synthase
`inhibitor'' as used herein, unless otherwise stated, refers to a compound whlt:h inhibits
`the biosynthesis of hydroxymethylglutaryl-coenzyme A from acetyl-coenzyme A and
`acetoacetyl-coenzyme A, catalyzed by the enzyme HMG-CoA synthase.
`
`[0034) .Any -HMG-CoAreductase gene expression Inhibitor may be used as the
`second compound in the combination therapy aspect of this invention. These agents
`may be HMG-CoA reductase transcription inhibitors that block the transcription of DNA
`or translation inhibitors that prevent translation of mRNA coding for HMG-CoA
`reductase into protein. Such inhibitors may-either affect transcription_ or translation
`directly or may be biotransformed into compounds having the above-mentioned
`attributes by one or more enzymes in the cholesterol blosynthetic cascade or may lead
`to accumulation of a metabolite having the above-mentioned activities.
`
`(0035] Any CETP inhibitor may be used as the second compound in the combination
`therapy aspect of this invention. The term acETP inhlbltor0 as used herein, unless
`otherwise stated, refers to a compound which inhibits the cholesteryl ester transfer
`protein (CETP) mediated transport of various cholesteryl esters and triglycerides from
`HDL to LDL and VLDL.
`
`(0036) Any ACAT inhibitor may be used as the second compound in the combination
`therapy aspect of this invention. The term _nACAT inhibitor" as used herein, unless
`otherwise stated, refers to a compound which inhibits the intracellular esterification of
`dietary cholesterol by the enzyme acyl CoA:cholesterol acyltransferase.
`
`[0037) Any squalene synthetase Inhibitor may be used as the second compound in
`the combination therapy aspect of this invention. The term "squalene synthetase
`inhibitor" as used herein, unless otherwise stated, refers to a compound which inhibits
`the condensation of two molecules of famesylpyrophosphate to form squalene,
`catalyzed by the enzyme squalene synthetase.
`
`(0038) The following examples describe the invention In greater detail and are
`intended to Illustrate the invention.
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`Description of the drawings
`(0039] Figure 1 is a graph displaying the results of an efficacy study wherein the
`. apoB secretion/MTP inhibitor mitratapide was administered during 8 weeks to a group
`of obese Beagle dogs. The four curves illustrate the effect on body weight by plotting
`the '(%) body weight relative to the weight at the start' when mitratapide was
`administered with a dosage of O mg per kg body weight (A curve), 0.16 mg per kg
`body weight (B curve), 0.31 _mg per kg body weight (C curve) and 0.63 mg per kg body
`weight in function of the duration of the study.
`
`[0040] Figure 2 shows a graph displaying the results of a 4w-4w-4w intermittent
`dosing regimen study using the apoB secretion/MTP inhibitor mltratapide. Mltratapide
`was administered for a first period of four weeks at a dosage of 0.63 mg/kg body
`weight, withheld for four weeks and again administered for four weeks at a dosage of
`0.63 mg/kg body weight At day 29, the feeding was restricted from ad lib/tum access
`to food, to a maintenance diet having a caloric content equal to the caloric expenditure
`.of the test subject.
`
`[0041] Figure 3 shows a graph displaying the results of two intermittent dosing
`regimens : 3w-2w-3w and 4w-4w-4w including two placebo groups.
`
`Experimental part
`Experiment 1 : efficacy study with continuous administration of mltrataplde
`during 8 weeks
`(0042] The efficacy of the apoB secretion/MTP inhibitor mitrataplde for the reduction
`of body weight was studied in a blind, randomised study with 4 parallel groups of 6
`dogs each. Three groups were treated orally with three different doses of mitratapide
`and one group was treated orally with the vehicle and served as a placebo group. The
`vehicle solution contained the same ingredients as the test formulations with omission
`of the test substance mltrataplde.
`The treatment groups were :
`- placebo group A treated orally with vehicle
`- group B treated orally with 0.16 mg mltratapide per kg body weight
`- group C treated orally with 0.31 mg mltratapide per kg body weight
`- group D treated orally with 0.63 mg mitratapide per kg body weight
`The test subjects were healthy, male Beagle dogs with a body weight of 13.6 to 22.6
`kg at the start of the experiment and between 1 and 8 years old. All dogs were treated
`orally using a 5 ml syringe, once daily, in the morning for a period of 8 weeks (56 days)
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`depending on their body weight. Body weight was measured once weekly on days o,
`7, 14, 21, •.. up to day 56. The volurrie of test formulation was 1 ml per 4 kg body
`weight. The test formulation was an aqueous 10% hydroxypropyl-13-cyclodextrin
`solution containing no mitratapide, 0.63 mg mltratapide per ml, 1.25 mg mltratapide
`per ml or 2.5 mg mitratapide per ml. Each test subject had free access (in volume and
`time) to commercial dog feed (Bento Kronen Professional Power) and water during the
`8-week study. -
`The effect on body weight for each of the four treatment groups is plotted In Figure 1.
`As can be seen from Figure 1, a daily dosage of at least 0.31 mg/kg was necessary to
`decrease body weight. A daily dosage of 0.63 mg/kg was more effective in reducing
`body weight. As illustrated in curve D, the reduction of body weight started to level off
`after three weeks and a further administration of mltratapide for the remaining five
`weeks did not result In a further reduction of body weight.