,. , ..
`. ,
`
`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(i9) World lnteUectual Property Organization
`International Bureau
`
`(43) International Publication Date
`26 April 2007 (26.04.2007)
`
`(51) International Patent Classification:
`A61K 311216 (2006.01)
`A61P 3110 (2006.01)
`A61K 311437 (2006.01)
`A61P 9110 (2006.01)
`A61K 3114468 (2006.0i)
`A61P 43100 (2006.01)
`A61P 3106 (2006.01)
`
`PCT
`
`(10) International Publication Number
`WO 2007/047724 A2
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): 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, FI,
`GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS,
`JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS,
`LT, LU, LV, LY, MA, MD, MG, MK, MN, MW, MX, MY,
`MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS,
`RU, SC, SD, SE, SG, SK, SL, SM, SY, SY, TJ, TM, TN,
`TR, TT, TZ, UA, UG, US, UZ, VC, VN, 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, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, Fl,
`FR, GB, GR, HU, IE, IS, IT, LT, LU, LV, MC, NL, PL, PT,
`RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA,
`GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`without international search report and to be republished
`upon receipt of tliat report
`
`For two-leuer codes and other abbreviations, refer to the "Guid(cid:173)
`ance Notes on Codes and Abbreviations" appearing at tl1e begin(cid:173)
`ning of each regular issue of the PCT Gazette.
`
`-
`
`-
`
`(21) International Application Number:
`PCT/US2006/040639
`
`(22) International Filing Date: 180ctober2006 (18.10.2006)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`6on21.664
`60n88,6t6
`
`18 October 2005 (18.10.2005) US
`3 April 2006 (03.04.2006) US
`
`(71) Appllcant (for all designated States except US): AEGE-
`
`Street, 5th Floor, New York, NY 10010 (US).
`
`(72) Inventor; and
`(75) Inventor/Applicant (for US only): WISLER, Gerald, L.
`[US/US]; 5 Forest View Drive, Gladstone, NJ 07934 (US).
`
`(74) Agents: KAVANAUGH, Theresa, C. et al.; GOODWIN
`PROCfER LLP, Exchange Place, Boston, MA 02109 (US).
`
`= RION PHARMACEUTICALS [US/US}; 31 West 21st
`-
`---
`--
`--
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`------
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`~
`M
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`~ (54) Title: METHODS FOR TREATING DISORDERS ASSOCIATED WITH HYPERLIPIDEMlA IN A MAMMAL
`...._
`t-o (57) Abstract: The invention is directed to methods for treating disorders associated with hyperlipidemia in a mammal. The meth-
`0 ods involve combination therapies using a microsomal triglyceride transfer protein (MTP) inhibitor (for example, BMS-201038 and
`M
`implitapide) and a fibrate (for example, fenofibrate). Co-administration of the MTP inhibitor with the fibrate produces a therapeu-
`0 tic benefit, for example, a reduction in the concentration of cholesterol and/or triglycerides in the blood stream, but with fewer or
`i<- ~~~c-~-~i~~:!:i;.ts !t:n,..,'~~~':,~ ~!~h:r dosages of the MTP inhibitor are used during monotherapy to provide the same or similar
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`METHODS FOR TREATING DISORDERS ASSOCIATED
`WITH BYPERLIPIDEMIA IN A MAMMAL
`
`RELATED APPLICATIONS
`
`[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No.
`
`601788,616, filed April 3, 2006, and U.S. Provisional Pate~t Application Serial No. 60/727,664,
`
`filed October 18, 2005~ the entire disclosures of which are incorporated by reference herein.
`
`FIELD OF THE INVENTION .
`
`5
`
`[0002] This invention relates generally to methods of reducing the concentration of cholesterol
`and/or triglycerides in the blood of a mammal. More ):Jarticularly, the invention relates t<;>
`
`combination therapies using a microsomal triglyceride transfer protein (MTP) inhibitor and a
`
`fibrate for reducing the concentration of cholesterol and/or triglycerides in the blood but with a
`
`reduced adverse event profile relative to MTP inhibitor monotherapy.
`
`IO
`
`BACKGROUND OF THE INVENTION
`
`[0003] There are several known risk factors for·atherosclerotic cardiovascular disease (ASCVD),
`
`the major cause of mortality in the Western world. One key risk factor is hyperlipidemia, which
`
`is the. presence of elevated levels oflipids in blood plasma. Various epidemiological studies
`
`have demonstrated that ~rug mediated lowering of total cholesterol (TC) and low density
`
`ts
`
`lipoprotein (LDL) cholesterol (LDL-C) is associated with a significant reduction in ·
`
`cardiovascular events. The National Cholesterol Education Program's (NCEP's) updated
`
`guidelines recommends that the overall goal for high-risk patients is to .achieve less than I 00
`
`mg/dL ofLDL, with a therapeutic opt~on to set the goal for such patients to achieve a LDL level
`
`less than 70 mg/dL.
`
`20
`
`[0004] One form ofhyperlipide~ia is known as hypertriglyceridemia and results in the presence·
`
`of elevated amounts of triglycerides in the blood. Although triglycerides are necessary for good .
`
`health, higher-:than-Iiormal triglyceride levels, often are associated with known risk factors for
`
`heart disease.
`
`[0005] Another forn:i ofhyperlipidemia, known as hypercholesterolemia, which is the presence
`
`25
`
`of elevated amounts of cholesterol in the blood, is a polygenic disorder. Modifications in
`
`lifestyle and conventional drug treatment are usually successful in reducing cholesterol levels.
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`However, in some cases, as in familial hypercholesterolemia (FR), the cause is a monogenic
`defect. Treatment of a patient with FH can be more challenging because the levels of LDL-C
`remain elevated despite aggressive use of conventional therapy.
`
`[0006] For example, one type of FH, homozygous familial hypercholesterolemia (hoFH), is a
`
`serious life-threatening genetic disease caused by homozygosity or compound heterozygosity for
`mutations in the low density Jipoprotein (LDL) receptor. Patients with hoFH typicaUy have total
`plasma cholesterol levels over 400 mg/dL resulting in premature atherosclerotic vascular disease.
`When left untreated, most patients develop atherosclerosis before age 20 and generally do not
`survive past age 30. However, patients diagnosed with hoFH are largely unresponsive to
`conventional drug therapy and have limited treatme.nt 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 less than about 20% has been recently reported in
`patients with genotype-confirmed hoFH treated with the maximal dose ·of statins (atorvastatin or
`simvastatin administered at 80 mg/day). The addition of ezetimibe 10 mg/day to this regimen
`resulted in a total reduction ofLDL-C levels of27%, which is still far from optimal. Non(cid:173)
`
`pharmacoiogical options have also bee~ tested, including surgical interventions, such as
`portacaval shunt and ilea} bypass, and orthotopic liver transplantation, but with clear
`disadvantages and risks. Therefore, there is a tremendous unmet medical need for new medical
`therapies for hoFH.
`
`5
`
`IO
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`15
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`20
`
`[0007} Microsomal triglyceride transfer protein (MTP) inhibitors have been developed as· potent
`inhibitors.ofMTP-mediated neutral lipid transfer activity. MTP catalyzes the transport of
`triglyceride, cholesteryl ester, and phosphatidylcholine between small unilameHar vesicles. One
`exemplary MTP inhibitor is BMS-201038, developed by Bristol-Myers Squibb. See, U.S. Patent
`25 Nos. 5,739,135; and 5,712,279. Studies using an animal model for homozygous FH indicated
`that BMS-201038 effectively reduced plasma cholesterol levels in a dose dependent manner, for
`example, at 25 mg/day, suggesting that this compound might be effective for treating patients
`with hoFH. It was noticed, however, that certain patients treated with 25 mg/day of BMS-
`201038 experienced certain adverse eve~ts, for example, gastrointestinal perturbations,
`abnormalities in liver function, and hepatic steatosis. Although a promising therapeutic agent,
`large scale clinical trials ofBMS-201038 have been discontinued. Another potentMTP inhibitor.
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`known as implitapide has been developed. See, U.S. Patent Nos. 6,265,431, 6,479,503,
`
`5,952,498. During clinical studies, dosages of implitapide of 80 mg/day or greater, although
`
`therapeuticalJy effective, were found to result in certain adverse events, for example,
`
`gastrointestinal disturbances, abnormalities in liver function, and hepatic steatosis. Large scale
`
`s
`
`clinical studies using implitapide have also been discontinued.
`
`(0008] Accordingly, there is still a need for methods for aggressively treating hyperlipidemias
`
`that effectively lower, for example, circulating cholesterol and triglycerides levels but with fewer
`
`or reduced adverse effects that typically result when higher dosages of the MTP inhibitor are
`
`used alone in monotherapy.
`
`10
`
`1~
`
`SUMMARY OF THE INVENTION
`
`[0009] The invention provides methods for lowering the concentration of cholesterol and/or
`
`triglycerides in the blood, and/or reducing the amount of one or more markers of atherosclerosis.
`
`The method includes administering an MfP inhibitor, such as, BMS-201038 or implitapide, in
`
`combination with. a fibrate, such as fenofibrate. The MTP inhibitors can be administered at
`certain lower dosages that are still therapeutically effective when combined with a fibrate but yet
`create fewer or reduced adverse effects when compared to ·therapies using therapeutically
`
`effective dosages of the MTP inhibitors during monotherapy.
`
`· [0010) In one aspect, the invention provides a method of reducing the concentration of
`
`cholesterol and/or triglycerides in the blood of a mammal, and/or the amount of a marker of
`
`20
`
`atherosclerosis in a mammal. 'The method comprises a combination therapy whereby a
`
`combination of a fibrate and BMS-201038 are administered each day to the mammal. ·In this
`
`protocol,,BMS~201038 initjally is administered at a first dosage in the range of 1 to 5 mg/day for
`
`at least 4 weeks, is then administered at a second dosage in the range of 3 to 7 mg/day for at least
`
`4 weeks, and is then administered at a third dosage in the range of 6 to 9 mg/day for at least 4
`
`25 weeks. Optionally, the method further comprises administering a fourth dosage ofBMS-~01038
`
`in the range of 9 to 12 mg/day for at least 4 weeks. Optionally, the method further comprises
`ad~inistering a fifth dosage of BMS-20 I 03 8 in the range of 12 to 17 mg/day for at least 4
`
`weeks.
`
`[0011} In one embodiment, the first dosage ofBMS-201,038 is 2.5 mg/day. In another
`
`30
`
`embodiment, the second dosage is 5 mg/day. In another embodiment, the third dosage is 7.5
`
`.. mg/day. In another embodiment, the optional fourth dosage is 10 mg/day. In another
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`embodiment, the optional fifth dosage is 15 mg/day. Furthermore, the fibrate is administered at
`
`a dosage of25 to 500 mg/day, optionally at a dosage of25 to 250 mg/day, and optionally at a
`
`dosage of I 00 to 200 mg/day. In certain embodiments, the fibrate is administered at a dosage of
`
`160 mg/day.
`
`5
`
`(0012] The fibrate and BMS-201038 can be administered together in the same dosage form, or in
`
`different dosage forms. In the case of the separate dosage forms, the fibrate can be administered
`
`before, after, or simultaneously with BMS-201038.
`
`[0013) The foregoing method may reduce the concentration of at least one of cholesterol and
`
`triglycerides in the blood but with a reduced incidence of an adverse event as compared to
`
`10
`
`administration of a dosage of25 mg/day ofBMS-201038 in ~onotherapy. In addition, the
`
`method may reduce the number or amount of plaques on a wall of a blood vessel of the mammal
`
`but with a reduced incidence of an adverse event as compared to administration of a dosage of25
`
`mg/day ofBMS-201038 in monotherapy. Contemplated adverse events include, for example,
`
`gastrointestinal disturbances, abnormalities in liver function, and hepatic steatosis.
`
`15
`
`(0014) In another aspect, the invention provides a method of reducing the concentration of
`
`cholesterol and/or triglycerides in the blood of a mammal, and/or the amount of a marker of
`
`atherosclerosis in a mammal. The method comprises administering each day to the mammal a
`
`combination of a fibrate and implitapide.
`
`(0015) The implitapide can be administered at a dosage in the range of 0.01to60 mg/day. It is
`.
`.
`understood that the implitapide preferably is administered ata dosage·in the range of20-60
`
`20
`
`mg/day, for example, 20 mg/day, 25 mg/day, 30 mg/day, 35 mg/day, 40 mg/day, 45 m'g/day, 50
`
`mg/day, 55 mg/day or even 60 mg/day. The fibrate can be administered at a dosage of25 to 250
`mg/day, and optionally in the range of I 00 to 200 mg/day. In one embodiment, the fibrate is
`
`administered at a dosage of 160 mg/day. The implitapide and fibrate can be administered
`
`25
`
`together in the same dosage form or in different dosage forms. In the case of separate dosage
`
`forms, the fibrate can be administered before, after, or simultaneously with implitapide.
`
`[0016] This method may reduce the concentration of at least one of cholesterol and triglycerides
`
`in the blood but with a reduced incidence of an adverse event as compared to administration of a
`
`dosage of 80 mg/day or greater of implitapide, for example, 80 mg/day and 160 mg/day, during
`
`30 monotherapy. Furthermore, this method may reduce the number and/or amount of plaques on a
`
`wall of a blood vessel of the mammal but with a reduced incidence of an adverse event as
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`compared to administration of a dosage of 80 mg/day or greater of implitapide, for example, 80
`
`mg/day or 160 mg/day, during monotherapy.
`
`(0017J The foregoing methods can be used to treat (i) patients with hyperlipidemia, for example,
`
`hypercholesterolemia (for example, homozygous or heterozygous familial hypercholesterolemia)
`
`5
`
`or hypertriglyceridemia, (ii) patients resistant to statin monotherapy, (iii) statin-intolerant
`patients, and/or (iv) patients having a combination of (i) and (ii), (i) and (iii), (ii) and (iii), and
`(i), (ii) and (iii).
`
`DETAILED DESCRIPTION
`
`[0018) This invention relates, in part, to methods of reducing at least one of (i) the concentration
`
`10
`
`of cholesterol and/or triglycerides in the blood of a mammal, and (ii) ~he amount of a marker of
`
`atherosclerosis 'in a mammal. The methods are based on combination therapies where an MfP
`
`inhibitor, for example, BMS-201038 or implitapide, is administered with a fibrate, for example,
`
`fenofibrate. The disclosed methods use lower dosages of the MTP inhibitor but, which in
`
`15
`
`combination with the fibrate, can 'be effective at reducing the concentration of cholesterol and/or
`triglycerides in the blood but with fewer adverse ev~nts, less severe· adverse events and/or
`reduced frequency of adverse events resulting from the use of higher dosages of the MfP
`
`inhibitor during monotherapy.
`
`1. Definitions ;
`
`[0019) For convenience, certairi terms used in the specirication, examples, and appended claims
`
`20
`
`are collected in this section.
`
`[0020) The phrase "combination therapy," as used herein, refers to co-administering an MfP
`
`inhibitor, for example, BMS-201038 and implitapide, or a combination thereof, and a fibrate, for
`
`example, fenofibrate, as part of a specific treatment regimen intended to provide the beneficial
`
`effect from the co-action of these therapeutic agents. The beneficial effect of the co.mbination
`
`25 ·
`
`includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the
`
`combination of therapeutic agents. Administration of these therapeutic agents in combination
`
`typically is carried out over a defined time period (usually weeks, months or years myasthenia
`
`depending upon the combination selected). Combination therapy is intended to embrace
`
`administration of multiple therapeutic agents in a sequential manner, that is, wherein each
`
`30
`
`therapeutic agent is administered at a different time, as well as administration of these
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`therapeutic agents, or at least two of the therapeutic agents, in a substantialJy simultaneous
`
`manner. Substantially simultaneous administration can he accomplished, for example, by
`
`administering to the subject a single tablet or capsule having a fixed ratio of each therapeutic
`
`agent or in multiple, single capsules for each of the therapeutic agents. Sequential or
`substantially simultaneous administration of each therapeutic agent can 1;>e effected by any
`
`5
`
`appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular
`
`routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be
`
`administered by the same route or by different routes. For example, a first therapeutic agent of
`
`the combination seleeted may be administered by intravenous injection while the other
`
`10
`
`therapeutic agents of the combination may be administered orally. Alternatively, for example,
`
`alJ therapeutic agents may be administered orally or all therapeutic agents may be administered
`
`by intravenous injection.
`
`[0021] Combination therapy also can embrace the administration of the therapeutic agents as
`
`described above in further combination with other biologically active ingredients and non-drug
`
`15
`
`therapies. Where the combination therapy further comp~ises a non-drug treatment, the non-drug
`
`treatment may be conduct~d at any suitable time so long as a beneficial effect from the co-action
`
`of the combination of the therapeutic agents and non-drug treatment is achieved. For example,
`
`in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is
`
`temporally removed from the administratio.n of the therapeutic agents, perhaps by days or even
`
`·20 weeks.
`
`[0022] The components of the combination may be administered to a patient simultaneously
`
`or sequentially. It will be appreciated that the components may be present in the same
`
`pharmac.eutically acceptable carrier and, therefore, are administered simultaneously.
`
`Altematively,'the active ingredients may be present in separate pharmaceutical carriers, such
`
`25
`
`as, conventional oral dosage forms, that can be administered either simultaneously or
`
`sequentially.
`
`[0023] The terms, "individual," "patient," or "subje~t" are used interchangeably herein and
`
`include any mammal, including animals, for example, primates, for example, humans, and other
`
`animals, for example, dogs, cats, swine, cattle, sheep, and horses. The compounds of the
`
`30
`
`invention can be administered to a mammal, such as a human, but can also be other mammals,
`
`for example, an animal in need of veterinary treatment, for example, domestic animals (for
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`example, dogs, cats, and the like), farm animals (for examplet cowst sheep, pigs, horses, and the
`
`like) and laboratory animals (for example, rats, mice, guinea pigs, and the like).
`
`[0024] The term, "patient resistant to statin monotherapy," as used herein includes those patients
`
`for whom conventional statin monotherapy has been found ineffective or less effective than
`
`5
`
`desired. A physician designing lipid reduction therapy for a patient will be able to determine via
`
`diagnosis ar:id observation of periodic blood cholesterol and/or triglyceride levels whether such a
`
`patient is or has been resistant to statin monotherapy.
`
`(0025] The term,'"statin-intolerant patient," as used herein includes those patients for whom
`
`conventional statin therapy, for example, for serum lipid redu~tion, has been found to be
`
`. 10
`
`ineffective and/or for whom an effective lipid-reducing dose of statins is too high to be tolerated
`
`or that there is an unacceptable adverse event associated with a particular dose. For example,
`statin therapy may be discontinued by the physician/patient due to concern over an adverse event
`such as Liver Function Test abnormality, muscle aches and pains or'inflammation - myalgia or
`
`rnyostitis, elevation in enzymes (CK) showing muscle adverse event. A physician designing
`
`15
`
`·lipid reduction therapy for a patient will be able to determine via diagnosis and.observation of_
`
`periodic blood cholesterol and/or triglyceride levels whether such a patient is statin-intolerant.
`
`[0026] The phrase "minimizing adverse effects," "reducing adverse events," or "reduced adverse
`
`events," as used herein refer to an amelioration or elimination of one or more undesired side
`
`effects associated with the use ofMTP inhibitors of the present invention.· Side effects of
`
`20 .
`
`traditional use of the MTP inhibitors include, without limitation, nausea, gastrointestinal
`
`disorders, steatorrhea, abdominal cramping, distentic>D, elevated liver function tests, fatty liver
`
`(hepatic steatosis); hepatic fat build up, polyne~ropathy, peripheral neuropathy, rhabdomyolysis,
`
`arthralgia, myalgia, chest pain, rhinitis, dizziness, arthritis, peripheral edema,· gastroenteritis,
`
`liver function tests abnormal, colitis, rectal hemorrhage, esophagitis, eructation, stornatitis,
`
`25 · biliary pain, cheilitis, duodenal ulcer, dysphagia, enteritis, melena, gu~ hemorrhage, stomach
`
`ulcer, tenesmus, ulcerative stomatitis, hepatitis, pancreatitis, cholestatic jaundice, paresthesia, . ·
`
`amnesia, libido decreased, emotional !ability, incoordination, torticollis, facial paralysis,
`
`hyperkinesia, depression, hypesthesia, hypertonia, leg cramps, bursitis, tenosynovitis,
`
`myasthenia, tendinous contracture, myositis, hyperglycemia, creatine phosphokinase increased,
`
`30
`
`gout, weight gain, hypoglycemia, anaphylaxis, angioneurotic edema, and bullous rashes
`
`(including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis). ·
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`Accordingly, the methods described herein provide an effective therapy while at the same time
`
`causing fewer or less significant adverse events.
`
`[0027] In certain embodiments, side effects are partially eliminated. As used herein, the phrase
`
`"partially eliminated" refers to a reduction in the severity, extent, or duration of the particular
`
`s
`
`side effect by at least 30%, 40%, 50%, 60%, 70%, 80%,.90%, 95% and 99% relative to that
`
`found by administering 25 mg/day ofBMS-201038 during monotherapy or either 80 mg/day or
`160 mg/day of implitapide during monotherapy. In certain embodiments, side effects are
`
`completely eliminated. Those skilled in the art are credited with the ability to detect and grade
`
`the severity, extent, or duration of side effects as well as the degree of amelioration of a side
`
`IO
`
`effect. In some embodiments, tWo or more side effects are ameliorated.
`
`[0028] The term, "therapeutically effective" refers to the ability of an active ingredient, for
`
`e:rample, BMS-20103 8 and implitapide, to elicit the biological or medical response ·that is being
`
`sought by a researcher, veterinarian, medical doctor or otlier clinician. Non-limiting examples
`
`include reduction of cholesterol (for example, LDL-C) and/or triglyceride levels in a patient,
`
`15
`
`reduction .of the amount of plaques, for example, arterial plaques, on the wall of a blood vessel,
`
`and the like.
`
`[0029] The term, "therapeutically effective amount'' includes the amount of an active ingredient,
`
`for example, BMS-201038 and implitapide, that will elicit the biological or medical response
`
`that is being sought by the researcher, veterinarian, medical doctor or other clinician. The
`
`20
`
`compounds of the invention are administered in amounts effective at lowering the cholesterol
`
`concentration in the blood, and/or the triglyceride concentration in the blood and/or reducing the
`
`amount of plaques, for example, arterial plaques disposed upon the blood contacting _wall of one
`
`or more blood vessels~ Alternatively, a therapeutically effective amount of an active ingredient
`
`is the quantity of the compound required to achieve a desired therapeutic and/or prophylactic
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`effect, such as the amount of the active ingredient that results in the prevention of or a decrease
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`in the symptoms associated with the condition (for example, to meet an end-point) ....
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`[0030] The terms, "pharmaceutically acceptable" or "pharmacologically acceptable" refer to
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`molecular entfries and compositions that do not produce an adverse, allergic or other untoward
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`reaction when administered to an animal, or to a human, as appropriate. The term,
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`"pharmaceutically acceptable carrier'' includes any and all solvents, dispersion media, coatings,
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`antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use
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`. of such media and agents for phannaceuticaJ active substances is well known in the art. Except
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`insofar as any conventional media or agent is incompatible with the active ingredient, its use in
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`the therapeutic compositions is contemplated. Supplementary active ingredients can also be
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`incorporated into the compositions.
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`5
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`[0031] As used herein, the phrase, "BMS-201038" refers to a compound known as N-(2,2,2-
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`Trifluorethyl)-9-f 4-[ 4-[[[ 4'-(trifluoromethyl)[l, l 'biphenyl]-2-Yl]carbonyl]amino ]-l(cid:173)
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`pipei'idinyl]butyl]9H-fluorene-9-carboxamide, having ·the formula:
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`stereoisomers thereof, and/or pharmaceutically acceptable salts or esters thereof.
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`[0032] As used herein, the phrase "implitapide,, refers to a compound known as (28)-2- ·
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`cyclopentyl-2-[4-[(2,4-dimethyl-9H-pyrido[2,3-b]indol-9-yl)methyl]phenyl]-N-[(1S)-2-hydroxy-
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`1-pheny1ethyl]ethanamide and having the structure shown below:
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`to
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`OH
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`stereoisomers thereof, and/or pharmaceutically acceptable salts or esters thereof.
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`[0033] Pharmaceutically acceptable salts of the foregoing compounds can be synthesized, for
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`example, from the parent compound, which contains a basic or acidic moiety, by conventional
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`chemical methods. Generally, such salts can-be prepared by reacting the free !tCid or base forms
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`of these compounds with a stochiometric amount of the appropriate base or acid in water or in an
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`organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl
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`acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in
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`Remington's Pharmaceutical Sciences, 20th ed., Lippincott Williams & Wilkins, Baltimore, MD,
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`2000, p. 704.
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`[0034] As used herein, the term "stereoisomers" refers to compounds made up of the same atoms
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`bonded by the same bonds but having different spatial structures which are not interchangeable.
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`The three-dimensional structures are called configurations. As used herein, the term
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`"enantiomers" refers to two stereoisomers whose molecules are nonsuperimposable mirror
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`10
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`images of one another. The terms "racemate," "racemic mixture" or "racemic modification"
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`refer to a mixture of equal parts of enantiomers.
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`2. Methods of the Invention
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`{0035] In general the invention provides methods for treating hyperlipidemia using one or mor~
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`MTP inhibitors, for example, BMS-201038 or implitapide. The MTP inhibitors can be used at
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`dosages lower.than those already found to result in one or more adverse events, for example,
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`gastrointestinal disorders, abnormalities in liver functional and/or hepatic steatosis (for example,
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`25 mg/day ofBMS-201038, 80 mg/day ofimplitapide and 160 mg/day of implitapide have been
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`found to cause gastrointestinal disorders, abnormalities in liver function and/or hepatic steatosis)
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`but are still are therapeutically effective when combined with a fibrate, for example, fenofibrate.
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`(a) Combination Therapies Using BMS-201038 and Fibrate
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`[0036] In certain aspects, the invention provides a method of reducing at leas~ one of (i) the
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`concentration of cholesterol and/or triglycerides in the blood of a mammal, and (ii) the amount
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`of a marker of atherosclerosis in the blood stream of a mammal. The method comprises a
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`combination therapy, which can be achieved by co-administering to the mammal, each day, a
`fibrate and BMS-201038. In one protocol, BMS-201038 initially is administered at a first
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`dosage in the range of 1 to 5 mg/day for at least 4 weeks, is then administered at a second dosage
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`in the range of 3 to 7 mg/day for at least 4 weeks, and is then administered at a third dosage in
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`the range of 6 to 9 mg/day for at least 4 weeks. The protocol may optionally include a fourth
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`dosage in the range of 9 to 12 mg/kg for at least 4 weeks. The protocol may optionally include a
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`fifth dosage in the range of 12 to 17 mg/kg for at least 4 weeks.
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`(0037] The first dosage ofBMS-201038 can be for example 2.5 mg/day. The second dosage of
`BMS-201038 can be 5 mg/day. The third dosage ofBMS-201038 can be 7.5 mg/day. The
`optional fourth dosage can be IO mg/day. The optional fifth dosage can be 15 mg/day. In
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`certain embodiments, the second dosage is administered immediately following the firs~ dosage,
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`5
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`i.e., the second dosage is administered starting at five weeks from the initial first dosage.
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`Similarly, in certain other embodiments, the third dosage ofBMS-201038 is admi~istered
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`immediately following the second dosage, e.g., the second dosage is administered at nine weeks
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`from the initial first dosage. Similarly, in certain other embodiments the fourth dosage is
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`administered immediately following the third dosage, e.g., the fourth dosage is administered at
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`thirteen weeks from the .initial first dosage. Similarly~ in certain other embodiments the fifth
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`dosage is administered immediately following the fourth dosage, e.g., the fifth dosage is
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`administered at seventeen weeks from the initial first dosage.
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`[0038] In this approach, BMS-201,038 is administered with a fibrate. Exemplary fibrates
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`include fenofibrate (also known as Tricor), bezafibrate, ciprofibrate, clofibrate and gemfibrozil
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`15
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`(also known as Lopid). The fibrate is administered at a dosage of25 to 500 mg/day, optionally
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`at a dosage of25 to 250 mg/day, and optionally at a dosage of 100 to 200 mg/day. In certain
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`embodiments, the fibrate is administered at a dosage of 160 mg/day. The fibrate and BMS-
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`20 I 038 ca~ be administered together in the same dosage fomi, or .in different dosage forms. In
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`the case of the separate dosage forms, the fibrate can be administered before, after, or
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`. simultaneously with BMS-201038.
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`·
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`[0039] The foregoing method may reduce the concentration of at least one of cholesterol and
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`triglycerides in the blood but with a reduced incidence of an adverse event as compared to
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`administration of a dosage of 25 mg/day ofBMS-201038 in monotherapy. In additjon, the
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`method may reduce the number or amount of plaques on a wall of a blood vessel of the mR;IJlmal
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`25
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`but with a reduced inc_idence of an adver~e event as compared to administration of a dosage of25
`
`m'g/day ofBMS-201038 in monotherapy. The amount of arterial plaques and the reduction
`thereof, can be measured using conventional non-invasive techniques known in the art, for:
`example, magnetic resonance imaging, computerized tomography, and nuclear scintigraphic
`
`techniques. Contemplated adverse events include, for example, gastrointestinal disturbances,
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`30
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`abnormalities in liver function, and hep