111111111111111111111111111111111111111111111111111111111111111111111111111
`US008618135B2
`
`c12) United States Patent
`Rader
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,618,135 B2
`*Dec. 31, 2013
`
`(54) METHODS FOR TREATING DISORDERS OR
`DISEASES ASSOCIATED WITH
`HYPERLIPIDEMIA AND
`HYPERCHOLESTEROLEMIA WHILE
`MINIMIZING SIDE EFFECTS
`Inventor: Daniel J. Rader, Philadelphia, PA (US)
`(75)
`(73) Assignee: The Trustees of the University of
`Pennsylvania, Philadelphia, PA (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`This patent is subject to a terminal dis(cid:173)
`claimer.
`(21) Appl. No.: 13/046,118
`Mar. 11, 2011
`Prior Publication Data
`
`(22) Filed:
`
`(65)
`
`US 2012/0010243 Al
`
`Jan. 12,2012
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 10/591,923, filed as
`application No. PCTIUS2005/007435 on Mar. 7,
`2005, now Pat. No. 7,932,268.
`
`(60)
`
`(51)
`
`(52)
`
`(58)
`
`Provisional application No. 60/550,915, filed on Mar.
`5, 2004.
`Int. Cl.
`A61K 311445
`A61K 311501
`A61K 31152
`U.S.Cl.
`USPC . 514/321; 514/325; 514/252.03; 514/255.03;
`514/263.22
`
`(2006.01)
`(2006.01)
`(2006.01)
`
`Field of Classification Search
`USPC .......... 514/321, 325, 252.03, 255.03, 263.22,
`514/824, 210.02
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3,983,140 A
`4,231,938 A
`4,346,227 A
`4,448,784 A
`4,450,171 A
`4,499,289 A
`4,613,610 A
`4,647,576 A
`4,686,237 A
`4,716,175 A
`4,871,721 A
`4,924,024 A
`5,015,644 A
`5,026,554 A
`5,117,080 A
`5,510,379 A
`5,595,872 A
`5,684,014 A
`5,712,279 A
`5,712,396 A
`5,739,135 A
`5,760,246 A
`5,767,115 A
`
`9/1976 Endo eta!.
`1111980 Monaghan et a!.
`8/1982 T erahara et al.
`5/1984 Glamkowski et al.
`5/1984 Hoffman eta!.
`2/1985 Baran eta!.
`9/1986 Wareing
`3/1987 Hoefle eta!.
`8/1987 Anderson
`12/1987 Hoefle eta!.
`10/1989 Biller
`5/1990 Biller
`5/1991 Roth eta!.
`6/1991 Bartizal et a!.
`5/1992 Lee et al.
`4/1996 Lee et al.
`111997 Wetterau, II et a!.
`1111997 Muller eta!.
`111998 Biller et al.
`111998 Magnin eta!.
`4/1998 Biller et al.
`6/1998 Biller et al.
`6/1998 Rosenblum eta!.
`
`5,786,361 A
`5,789,197 A
`5,811,429 A
`5,827,875 A
`5,883,109 A
`5,885,983 A
`5,952,498 A
`5,990,110 A
`6,034,115 A
`6,057,339 A
`6,066,650 A
`6,066,653 A
`6,114,341 A
`6,121,283 A
`6,140,343 A
`6,194,454 B1
`6,245,775 B1
`6,265,431 B1
`6,297,233 B1
`6,344,450 B1
`6,479,503 B2
`6,492,365 B1
`
`7/1998 Muller eta!.
`8/1998 Wetterau, II et al.
`9/1998 Connell eta!.
`10/1998 Dickson, Jr. et al.
`3/1999 Gregg eta!.
`3/1999 Biller eta!.
`9/1999 Lenfers et a!.
`1111999 Firestone
`3/2000 Connell eta!.
`5/2000 Gregg
`5/2000 Biller eta!.
`5/2000 Gregg eta!.
`9/2000 Muller eta!.
`9/2000 Chang eta!.
`10/2000 DeNinno et al.
`2/2001 Dow
`6/2001 Muller eta!.
`7/2001 Muller eta!.
`10/2001 Stein eta!.
`212002 Bisacchi et a!.
`1112002 Muller eta!.
`12/2002 Wetterau, II et al.
`(Continued)
`
`FOREIGN PATENT DOCUMENTS
`
`AU
`CA
`
`7/1998
`727895
`9/1993
`2091102
`(Continued)
`
`OTHER PUBLICATIONS
`
`Visioli, "Microsomal Triglyceride Transfer Protein Inhibitors," Cur(cid:173)
`rent Opinion in Cardiovascular, Pulmonary & Renal Investigational
`Drugs (2000), vol. 2, No.3, pp. 292-293.
`Teramoto et al. "Evaluating Utility[benefit] of Gradual Niceritrol
`(Perycit®) Titration to Hypercholesterolemia," in the Japan Athero(cid:173)
`sclerosis Society Journal: Atherosclerosis (1991), vol. 19, No. 2-3,
`pp. 199-208.
`Fukushima et a!. "Phase II Clinical Trial: Administration of Novel
`Antiepileptic Agent, Zonisamide (ZNA), to Epileptic Children," in
`Japanese Journal of Pediatrics (1987), vol. 40, No. 12, pp. 3389-
`3397.
`Williams et a!. "Novel Microsomal Triglyceride Transfer Protein
`Inhibitors," inExpert Opinion on Therapeutic Patents (2003), vol. 13,
`No.4, pp. 479-488.
`
`(Continued)
`
`Primary Examiner- Kevin E Weddington
`(74) Attorney, Agent, or Firm- Goodwin Procter LLP
`
`(57)
`
`ABSTRACT
`
`The present invention provides methods and compositions for
`treating hyperlipidemia and/or hypercholesterolemia com(cid:173)
`prising administering to the subject an effective amount of an
`MTP inhibitor to inhibit hyperlipidemia and/or hypercholes(cid:173)
`terolemia in said subject, wherein said administration com(cid:173)
`prises an escalating series of doses of the MTP inhibitor. In
`some embodiments the method comprises administering at
`least three step-wise, increasing dosages of the MTP inhibitor
`to the subject. In some embodiments, the method further
`comprises the administration of one or more other lipid modi(cid:173)
`:tying compounds.
`
`10 Claims, No Drawings
`
`CFAD Ex. 1007 (1 of 14)
`
`

`
`US 8,618,135 B2
`Page 2
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`12/2002 Glombik et a!.
`6,498,156 B2
`6/2003 Dedrick et a!.
`6,582,698 B1
`9/2003 Rob!
`6,620,821 B2
`9/2003 Rob!
`6,627,636 B2
`6,720,351 B2
`4/2004 Bertinato et al.
`8/2004 Lenfers et a!.
`6,774,236 B1
`1112004 Rob! eta!.
`6,812,345 B2
`112005 Hamann eta!.
`6,846,836 B2
`2/2005 Muller eta!.
`6,858,622 B2
`4/2005 Cheng et al.
`6,875,782 B2
`4/2005 Glombik et a!.
`6,884,812 B2
`6,916,809 B2
`7/2005 Chen eta!.
`7/2005 Atwal et al.
`6,916,813 B2
`9/2005 Bertinato et al.
`6,949,572 B2
`12/2005 Bertinato et al.
`6,979,692 B2
`5/2006 Davis et al.
`7,053,080 B2
`6/2006 Strony
`7,056,906 B2
`4/2008 Rob! eta!.
`7,358,254 B2
`7/2008 Iwata eta!.
`7,394,501 B2
`112010 Ye eta!.
`7,645,732 B2
`7,932,268 B2 * 4/2011 Rader ........................... 514/321
`2002/0035064 A1
`3/2002 Rob! eta!.
`2002/0045271 A1
`4/2002 Hussain et a!.
`2003/0069221 A1
`4/2003 Kosoglou et a!.
`2003/0109543 A1
`6/2003 Ogletree
`2003/0153541 A1
`8/2003 Dudley eta!.
`2003/0162788 A1
`8/2003 Thomas eta!.
`2003/0187053 A1
`10/2003 Bertinato et al.
`2004/0014748 A1
`112004 Grutzmann et a!.
`2004/0058908 A1
`3/2004 Keller eta!.
`2005/0075367 A1
`4/2005 Hagiwara et al.
`2005/0090426 A1
`4/2005 Blumberg
`2005/0101561 A1
`5/2005 Tunac
`2006/0069161 A1
`3/2006 Lee et al.
`2006/0135460 A1
`6/2006 Widder eta!.
`2006/0153913 A1
`7/2006 Yamane eta!.
`2006/0160834 A1
`7/2006 Fong et al.
`2006/0166999 A1
`7/2006 Grutzmann et a!.
`2006/0205726 A1
`9/2006 Hagiwara et al.
`2006/0211020 A1
`9/2006 Farrer et al.
`2006/0211762 A1
`9/2006 Rongen eta!.
`2006/0252733 A1
`1112006 Jansen
`2006/0270655 A1
`1112006 Swick eta!.
`2007/0027093 A1
`2/2007 Ogawaet a!.
`2007/0032404 A1
`2/2007 Sweet
`2007/0088089 A1
`4/2007 Wisler
`2007/0093468 A1
`4/2007 Wisler
`2007/0093527 A1
`4/2007 Wisler
`2007/0098778 A1
`5/2007 Borsadia
`2007/0099884 A1
`5/2007 Erondu et al.
`2008/0016127 A1
`112008 Field
`2008/0033019 A1
`2/2008 Stamler
`2008/0051427 A1
`2/2008 Schuckler
`2008/0103122 A1
`5/2008 Veltri
`2008/0161279 A1
`7/2008 Wisler
`2008/017 5864 A1
`7/2008 Ye eta!.
`2008/0241869 A1
`10/2008 Davis
`2008/0248070 A1
`10/2008 Tunac
`2008/0253985 A1
`10/2008 Wisler
`2008/0255084 A1
`10/2008 Webb
`2008/0280992 A1
`1112008 Kunz eta!.
`2009/0042835 A1
`212009 Davis
`2009/0042941 A1
`212009 Rader
`2009/0054393 A1
`212009 Wisler
`2009/0093527 A1
`4/2009 Li eta!.
`2010/0273829 A1
`10/2010 Wisler
`
`FOREIGN PATENT DOCUMENTS
`
`CA
`CA
`DE
`EP
`EP
`
`2291471
`2325201
`19951022
`0142146
`0221025
`
`6/2000
`5/2001
`4/2001
`5/1985
`5/1987
`
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`FR
`GB
`JP
`JP
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`
`0325130
`0705831
`0779276
`0779279
`0799828
`0802198
`1099442
`1181954
`2596393
`2205837
`2002/220345
`2003-321424
`W0-86/03488
`W0-86/07054
`W0-96/26205
`W0-96/26948 A1
`W0-96/40640
`W0-97/41111
`W0-98/03069
`W0-98/03174
`W0-98/23593
`W0-98/27979
`W0-98/31225
`W0-98/31366
`W0-98/31367
`W0-98/50028
`W0-00/38725
`WO-O 1108679
`W0-2004/028544
`W0-2004/110368
`W0-2004/110375
`W0-2005/000217
`W0-2005/033100 A1
`W0-2005/051382
`W0-2005/072740
`W0-2005/085466
`W0-2005/087234
`W0-2005/087324
`W0-2005/094864
`W0-2005/097131
`W0-2006/046623
`W0-2006/062748
`W0-2006/063128
`W0-2006/ 108666
`W0-2006/111238
`W0-2007 /047724
`W0-2007 /047880
`W0-2007 /047880 A2
`W0-2008/0 12056
`W0-2008/021353
`W0-2008/030382
`W0-2008/072061
`W0-2008/075949
`W0-2008/079398 A1
`W0-2008/090 198
`W0-2008/115574
`
`7/1989
`4/1996
`6/1997
`6/1997
`10/1997
`10/1997
`5/2001
`212002
`10/1987
`12/1988
`9/1990
`1112003
`6/1986
`12/1986
`8/1996
`9/1996
`12/1996
`1111997
`111998
`111998
`6/1998
`7/1998
`7/1998
`7/1998
`7/1998
`1111998
`7/2000
`212001
`4/2004
`12/2004
`12/2004
`1/2005
`4/2005
`6/2005
`8/2005
`9/2005
`9/2005
`9/2005
`10/2005
`10/2005
`5/2006
`6/2006
`6/2006
`10/2006
`10/2006
`4/2007
`4/2007
`4/2007
`1/2008
`2/2008
`3/2008
`6/2008
`6/2008
`7/2008
`7/2008
`9/2008
`
`OTHER PUBLICATIONS
`
`Atzel, A., et a!., "Mechanism of Microsomal Triglyceride Transfer
`Protein Catalyzed Lipid Transport", Biochemistry (1993), 32,
`10444-10450.
`BakillahA. eta!., "Decreased secretion of ApoB follows inhibition of
`ApoB-MTP binding by a novel antagonist", Biochemistry (Mosc),
`(2000) 39(16):4892-4899.
`Barclay, "Hyperlipidemia", NMT Briefs, 2003.
`Bayes, M., et al., "Gateways to Clinical Trials", Methods and Find(cid:173)
`ings in Experimental and Clinical Pharmacology, 24( 1 ):2002, 37-55.
`Bays et a!., "Pharmacotherapy for Dyslipidaemia-Current Thera(cid:173)
`pies and Future Agents", Expert Opin Phamacother, Nov.
`2003;4(11): 1901-38.
`Biller et al., "Isoprenoid (phosphinylmethyl)phosphonates as inhibi(cid:173)
`tors of squalene synthetase", J. Med. Chern., 31 (10):1988, 1869-71.
`Bruckert, "New Lipid-ModifYing Therapies", Expert Opin. Investig.
`Drugs, (2003)12(3):325-35.
`Capson, (PhD dissertation, Jun. 1987, Dept. Med. Chern. U. of Utah,
`Abstract).
`
`CFAD Ex. 1007 (2 of 14)
`
`

`
`US 8,618,135 B2
`Page 3
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`Catapano, Ezetimibe: a selective inhibitor of cholesterol absorption,
`European Heart Journal Supplements 2001 (3, Supplemental E):E6-
`E10).
`Chang et al., "Microsomal Triglyceride Transfer Protein (MTP)
`Inhibitors: Discovery of Clinically Active Inhibitors Using High(cid:173)
`Throughput Screening and Parallel Synthesis Paradigms", Current
`Opinion in Drug Discovery & Development, (2002) 5(4):562-70.
`Corey and Volante, J. Am. Chern. Soc., (1976) 98:1291-93.
`de Montellano eta!., "Inhibition of Squalene Synthetase by Farnesyl
`Pyrophosphate Analogues", J. Med. Chern., (1977) 20:243-49.
`Earl eta!., "Ezetimibe", Nature Reviews, 2003, 2:97-98.
`Evans M. eta!, "Medical Lipid-Regulating Therapy: Current Evi(cid:173)
`dence, Ongoing Trials and Future Developments", Drugs: 2004; 64
`(11): pp. 1181-1196.
`Expert Panel on Detection, Evaluation, and Treatment of High Blood
`Cholesterol in Adults. National Cholesterol Education Program:
`Adult Treatment Panel III Report. Publication No. 01-3095, I-1-IX-
`11. 2001. Bethesda, MD. National Heart, Lung, and Blood Institute.
`Farrell., "Drugs and Steatohepatitis", Semin Liver Dis, (2002)
`22(2): 185-194.
`Gagne, et a!. "Efficacy and safety of ezetimibe coadministered with
`atorvastatin or simvastatin in patients with homozygous familial
`hypercholesterolemia", Circulation, (2002) 105 (21):2469-75.
`International Search Report for Application No. PCT/US05/07435
`dated Jul. 14, 2005 (7 pages).
`International Search Report for Application No. PCT/US06/040637
`dated Jun. 12, 2007 (8 pages).
`International Search Report for Application No. PCT/US06/040639
`dated Jun. 12, 2007 (9 pages).
`International Search Report for Application No. PCT/US06/040640
`dated May 23, 2007 (9 pages).
`International Search Report for Application No. PCT/US06/040953
`dated Mar. 3, 2007 (8 pages).
`Jarnil et a!., "An inhibitor of the microsomal triglyceride transfer
`protein inhibits apoB secretion from HepG2 cells", Proc Nat! Acad
`Sci US A, (1996) 93(21):11991-11995.
`Kastelein J., "What Future for Combination Therapies", Int J. Clin
`Pract. Suppl. Mar. 2003; (134): pp. 45-50.
`Kirkpatrick eta!, "Market Indicators", Nature, 2003, 2:98.
`Knopp RH, Drug treatment of lipid disorders. New England J. Med.
`1999; 341(7): 498-511; electronic pp. 1-25.
`Liao et a!., "Blocking Microsomal Triglyceride Transfer Protein
`Interferes with apoB Secretion Without Causing Retention or Stress
`in the ER", Journal of Lipid Research, (2003) 44(5):978.
`McClard eta!., J.A.C.S., (1987) 109:5544.
`Ritter et al., "Heterocyclic Ring Scaffolds as Small-Molecule Cho(cid:173)
`lesterol Absorption Inhibitors", Org. Biomol. Chern., 2005, 3:3514-
`3523.
`Rob! eta!, "A Novel Series of Highly Potent Benzimidazole-Based
`Microsomal Triglyceride Transfer Protein Inhibitors", Journal of
`Medicinal Chemistry, 2001, 44(6):851-856.
`Shiomi eta!, "MTP Inhibitor Decreases Plasma Cholesterol Levels in
`LDL Receptor-Deficient WHHL Rabbits by Lowering the VLDL
`Secretion", Euro. Journal ofPharrna. 2001,431:127-131.
`Sorbera, L.A., eta!., "Hypolipidemic Treatment of Atherosclerosis
`MTP Inhibitor ApoB Secretion Inhibitor", Drugs of the Future,
`(2000) 25(11): 1138-1144.
`Subhop eta!., "Cholesterol absorption inhibitors for the treatment of
`hypercholesterolaemia", Drugs, 2002, 62(16):2333-2347.
`Thomas et a!., "Alleviation of MTP Inhibitor-Induced Hepatic
`Steatosis in Hyperlipidemic fa/fa Rats by Fenofibrate", Dept. of
`Metabolic Diseases and Dept. of Chemical Research, Boehringer
`Ingelheim Pharma GmbH & Co. KG, (2005).
`Wetterau et a!., "An MTP inhibitor that normalizes atherogenic
`rabbits",
`Science,
`(1998)
`lipoprotein
`levels
`in WHHL
`282(5389):7 51-754.
`Wetterau eta!., "Microsomal triglyceride transfer protein", Biochim
`BiophysActa, (1997) 1345(2):136-150.
`
`Wierzbicki A.S., "New Lipid-Lowering Agents", Expert Opinion on
`Emerging Drugs, Ashley Publications, GB, 8 (2):2003, 365-376.
`Aggarwal, et al; BMC Cardiovasc. Disord. 27;5(1):30 (2005).
`Chandler, et al., J. Lipid. Res. 44(10):1887-901 (2003).
`Cuche! et al., "Inhibition of Microsomal Triglyceride Transfer Pro(cid:173)
`tein in Familial Hypercholesterolemia," N Eng! J Med., (2007);
`356:148-156.
`Funatsu eta!. "Atorvastatin Increases Hepatic Fatty Acid Beta-Oxi(cid:173)
`dation in Sucrose-Fed Rats: Comparison with an MTP Inhibitor."
`Eur. J. Pharm. 2002 455:161-167.
`Li, eta!., "Discovery of Potent and Orally Active MTP Inhibitors as
`Potential Anti -Obesity Agents," Bioorganic & Medicinal Chemistry
`Letters, Oxford, GB, vol. 16, No. 11, Jun. 1, 2006, pp. 3039-3042.
`Looije, Norbert A., et a!., "Disodiwn Ascorbyl Phytostanyl Phos(cid:173)
`phates (FM-VP4) Reduces Plasma Cholesterol Concentration, Body
`Weight and Abdominal Fat Gain Within a Dietary-Induced Obese
`Mouse Model," Journal of Pharmacy & Pharmaceutical Sciences: A
`Publication of the Canadian Society for Pharmaceutical Sciences,
`vol. 8, No. 3, 2005, pp. 400-408.
`Samaha, eta!., "Inhibition of Microsomal Triglyceride Transfer Pro(cid:173)
`tein Alone or With Ezetimibe
`in Patients With Moderate
`Hypercholesterolemia," Nature Clinical Practice, (2008), pp. 1-9.
`Aguilar-Salinas eta!. (2000) "Efficacy and Safety of Atorvastatin in
`Hyperlipidemic, Type 2 Diabetic Patients. A 34-Week, Multicenter,
`Open-Label Study," Atherosclerosis, 152:489-496.
`Capuzzi et al. (2000) "Niacin Dosing: Relationship to Benefits and
`Adverse Effects," Current Atherosclerosis Reports, 2:64-71.
`Orgogozo eta!. (2002) "Efficacy and Safety ofMemantine in Patients
`with Mild to Moderate Vascular Dementia: A Randomized, Placebo(cid:173)
`Controlled Trial (MMM 300)," Stroke, 33:1834-839.
`Parsons et a!. (1999) "Memantine is a Clinically Well Tolerated
`N-Methyl-DAspartate (NMDA) Receptor Antagonist-A Review of
`Preclinical Data," Neuropharmacology, 38:735-767.
`Hussain, M.M., et a!., "Multiple Functions of Microsomal
`Triglyceride Transfer Protein," Nutrition & Metabolism, 2012, 9:14,
`pp. 1-16.
`http:/ /en.wikipedia.org/wiki/, Microsomal Triglyceride Transer Pro(cid:173)
`tein (Updated Mar. 17, 2013.).
`van Darn, M.J., et al., "Efficacy and Safety of Implitapide (Bay 13
`9952), A Microsomal Triglyceride Transfer Protein Inhibitor, in
`Patients with Primary Hypercholesterolemia," Chapter 2, Disserta(cid:173)
`tion, (200 1 ).
`Excerpt from Clinical Trials.gov, "Implitapide in Patients with
`Hypertriglyceridemia (HTG) on Maximal, Concurrent Triglyceride(cid:173)
`Lowering Therapy," received Mar. 23, 2004.
`Excerpt from Clinica!Trial.gov, "Implitapide in Patients with
`Homozygous Familial Hypercholesterolemia (HoFH) on Maximal
`Concurrent Lipid-Lowering Therapy," received Mar. 17,2004.
`News Release: PPD presenting business; Jan. 15, 2004.
`Inventor Presentation, Feb., 2004, available electronically Apr. 15,
`2004.
`Title: Pink Sheet, Feb. 16, 2004.
`Gruetsmann, et al., "Implitapide (BAY 13/9952) Inhibits Secretion of
`apoB Associated Lipoproteins by Inhibition of the Microsomal
`Triglyceride Transfer Protein (MTP)", Eur Heart J. 2000, 21 (Suppl),
`Abst 3271.
`Bischoff, et a!., "BAY 13/9952 (Implitapide): Pharmacodynamic
`Effects of a New Microsomal Triglyceride Transfer Protein (MTP)
`Inhibitor on Plasma Lipids and Adipose Tissue in Animals," Eur
`Heart J 2000, 21 (Suppl), Abst P3501.
`Zaiss, et a!., "BAY 13/9952 (implitapide), An Inhibitor of the
`Microsomal Triglyceride Transfer Protein (MTP), Inhibits Athero(cid:173)
`sclerosis and Prolongs Lifetime in Apo-E Knockout Mice," Eur Heart
`J. 2000, 21 (Suppl), Abst 194.
`Notice of Opposition to European Patent, Aug. 21,2013.
`* cited by examiner
`
`CFAD Ex. 1007 (3 of 14)
`
`

`
`US 8,618,135 B2
`
`1
`METHODS FOR TREATING DISORDERS OR
`DISEASES ASSOCIATED WITH
`HYPERLIPIDEMIA AND
`HYPERCHOLESTEROLEMIA WHILE
`MINIMIZING SIDE EFFECTS
`
`5
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`FIELD OF THE INVENTION
`
`The present invention generally relates to therapy for
`hypercholesterolemia and hyperlipidemia.
`
`BACKGROUND OF THE INVENTION
`
`This application is a continuation of U.S. Ser. No. 10/591,
`923, which is a national phase application under 35 U.S.C.
`§371 ofPCTIUS05/007435 filed Mar. 7, 2005 which in turn
`claims priority benefitofU.S. Ser. No. 60/550,915, filed Mar.
`5, 2004, all of which are hereby incorporated by reference in
`their entireties.
`
`2
`lesterolemia, familial combined hyperlipidemia, familial
`hypercholesterolemia, remnant hyperlipidemia, chylomi(cid:173)
`cronemia syndrome and familial hypertriglyceridemia.
`A number of treatments are currently available for lower-
`ing serum cholesterol and triglycerides. However, each has its
`own drawbacks and limitations in terms of efficacy, side(cid:173)
`effects and qualifying patient population.
`Bile-acid-binding resins are a class of drugs that interrupt
`the recycling of bile acids from the intestine to the liver; e.g.,
`10 cholestyramine (Questran Light®, Bristol-Myers Squibb),
`and colestipol hydrochloride (Colestid®, The Upjohn Com(cid:173)
`pany). When taken orally, these positively-charged resins
`bind to the negatively charged bile acids in the intestine.
`Because the resins cam10t be absorbed from the intestine, they
`15 arc excreted carrying the bile acids with them. The usc of such
`resins, however, at best only lowers serum cholesterol levels
`by about 20%, and is associated with gastrointestinal side(cid:173)
`effects, including constipation and certain vitamin deficien(cid:173)
`cies. Moreover, since the resins bind other drugs, other oral
`20 medications must be taken at least one hour before or four to
`six hours subsequent to ingestion of the resin; thus, compli(cid:173)
`cating heart patient's drug regimens.
`The statins are cholesterol-lowering agents that block cho-
`!estero! synthesis by inhibiting HMGCoA reductase-the
`Hypercholesterolemia is a well-known risk factor for
`ASCVD, the major cause of mortality in the Western world. 25 key enzyme involved in the cholesterol biosynthetic pathway.
`Numerous epidemiological studies have clearly demon-
`The statins, e.g., lovastatin (Mevacor®, Merck & Co., Inc.),
`strated that pharmacological lowering of total cholesterol
`simvastatin (Zocor®, Merck & Co., Inc.), atorvastatin (Lipi-
`(TC) and Low-density Lipoprotein (LDL) Cholesterol (LDL-
`tor®, Pfizer), rosuva (Crestor®, Astra Zeneca) and pravasta-
`C) is associated with a significant reduction in clinical car-
`tin (Pravachol®, Bristol-Myers Squibb Co.), and combina-
`diovascular events. Hypercholesterolemia is often caused by 30 tions thereof are sometimes used in combination with bile-
`a polygenic disorder in the majority of cases and modifica-
`acid-binding resins. Statins significantly reduce serum
`tions in lifestyle and conventional drug treatment are usually
`cholesterol and LDL-serum levels, and slow progression of
`successful in reducing cholesterol levels. However, in few
`coronary atherosclerosis. However, serum HDL cholesterol
`cases, as in familial hypercholesterolemia (FH), the cause is a
`levels are only moderately increased. The mechanism of the
`monogenicdefectandtheavailabletreatmentinhomozygous 35 LDL lowering effect may involve both reduction ofVLDL
`patients can be much more challenging and far from optimal
`concentration and induction of cellular expression of LDL-
`because LDL-C levels remain extremely elevated despite
`receptor, leading to reduced production and/or increased
`aggressive use of combination therapy. Therefore, for this
`catabolism of LDLs. 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.
`40 sicians Desk Reference, Medical Economics Co., Inc.,
`Triglycerides are common types of fats (lipids) that are
`Montvale, N.J., 2004; hereinafter "PDR"). The FDA has
`essential for good health when present in normal amounts.
`approved atorvastatin to treat rare but urgent cases of familial
`They account for about 95 percent of the body's fatty tissue.
`hypercholesterolemia.
`Abnormally high triglyceride levels may be an indication of
`Ezetimibe is a cholesterol absorption inhibitor which
`such conditions as cirrhosis of the liver, underactive thyroid 45 reduces the amount of cholesterol absorbed by the body.
`(hypothyroidism), poorly controlled diabetes, or pancreatitis
`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.
`Ezetimibe is often used with a low cholesterol diet and, in
`Higher-than-normal triglyceride levels are often associ-
`some cases, other cholesterol lowering medications.
`ated with known risk factors for heart disease, such as low 50
`Niacin, or nicotinic acid, is a water soluble vitamin B-com-
`levels of HDL ("good") cholesterol, high levels of LDL
`plex used as a dietary supplement and antihyperlipidemic
`("bad") cholesterol and obesity. Triglycerides may also con-
`agent. Niacin diminishes production ofVLDL 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. NIASPAN® has been approved
`Therefore, high triglyceride levels are at least a warning 55 to prevent recurrent heart attacks in patients with high cho-
`sign that a patient's heart health may be at risk. In response,
`!estero!. Niacin can increase HDL 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.
`60 lowering drugs used to treat various forms of hyperlipidemia
`A large number of genetic and acquired diseases can result
`(i.e., elevated serum triglycerides) which may also be associ-
`in hyperlipidemia. They can be classified into primary and
`a ted with hypercholesterolemia. Fibrates appear to reduce the
`secondary hyperlipidemic states. The most common causes
`VLDL fraction and modestly increase HDL. However, the
`of the secondary hyperlipidemias are diabetes mellitus, alco-
`effects of these drugs on serum cholesterol is variable.
`hoi abuse, drugs, hypothyroidism, chronic renal failure, 65 Fibrates are mainly used to lower high triglyceride levels.
`nephrotic syndrome, cholestasis and bulimia. Primary hyper-
`Although fibrates typically do not appear as effective as
`lipidemias have also been classified into common hypercho-
`statins in lowering total cholesterol and LDL cholesterol lev-
`
`CFAD Ex. 1007 (4 of 14)
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`

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`US 8,618,135 B2
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`3
`els, they are sometimes used in combination with statins or
`other medications to lower very high cholesterol levels. For
`example, fibrates are also sometimes added to statins to raise
`HDL cholesterol levels. In the United States, fibrates have
`been approved for use as antilipidemic drugs, but have not
`received approval as hypercholesterolemia agents. For
`example, clofibrate (Atromid-S®, Wyeth-Ayerst Laborato(cid:173)
`ries) is an antilipidemic agent which acts to lower serum
`triglycerides by reducing the VLDL fraction. Although serum
`cholesterol may be reduced in certain patient subpopulations, 10
`the biochemical response to the drug is variable, and is not
`always possible to predict which patients will obtain favor(cid:173)
`able results. Atromid-S® has not been shown to be effective
`for prevention of coronary heart disease. The chemically and
`pharmacologically related drug, gcmfibrozil (Lopid®, Parke(cid:173)
`Davis) is a lipid regulating agent which moderately decreases
`serum triglycerides and VLDL cholesterol, and moderately
`increases HDL cholesterol-the HDL2 and HDL3 subfrac(cid:173)
`tions as well as both ApoA-I and A-II (i.e., the AIIAII-HDL
`fraction). However, the lipid response is heterogeneous, espe(cid:173)
`cially among different patient populations. Moreover, while
`prevention of coronary heart disease was observed in male
`patients between 40-55 without history or symptoms of exist(cid:173)
`ing coronary heart disease, it is not clear to what extent these
`findings can be extrapolated to other patient populations (e.g.,
`women, older and younger males). Indeed, no efficacy was
`observed in patients with established coronary heart disease.
`Fenofibrate (Tricor, Secalip) is also used to reduce levels of
`cholesterol and triglycerides. Serious side-effects have been
`associated with the use of several fibrates including toxicity 30
`such as malignancy, (especially gastrointestinal cancer), gall(cid:173)
`bladder disease and an increased incidence in non-coronary
`mortality. Fibrates are often not indicated for the treatment of
`patients with high LDL or low HDL as their only lipid abnor(cid:173)
`mality (Physician's Desk Reference, 2004, Medical Econom(cid:173)
`ics Co., Inc. Montvale, N.J.).
`Oral estrogen replacement therapy may be considered for
`moderate hypercholesterolemia in post-menopausal women.
`However, increases in HDL may be accompanied with an
`increase in triglycerides. Estrogen treatment is, of course,
`limited to a specific patient population (postmenopausal
`women) and is associated with serious side effects including
`induction of malignant neoplasms, gall bladder disease,
`thromboembolic disease, hepatic adenoma, elevated blood
`pressure, glucose intolerance, and hypercalcemia.
`Homozygous familial hypercholesterolemia (hoFH) is a
`serious life-threatening genetic disease caused by homozy(cid:173)
`gosity or compound heterozygosity for mutations in the low
`density lipoprotein (LDL) receptor. Total plasma cholesterol
`levels are generally over 500 mg/dl and markedly premature
`atherosclerotic vascular disease is the major consequence.
`Untreated, most patients develop atherosclerosis before age
`20 and generally do not survive past age 30. The primary goal
`of therapy consists of controlling the hypercholesterolemia to
`delay the development of atherosclerotic cardiovascular dis(cid:173)
`ease (ASCVD). However, patients diagnosed with hoFH are
`largely unresponsive to conventional drug therapy and have
`limited treatment options. A mean LDL-C reduction of only
`about 5.5% has been recently reported in patients with geno(cid:173)
`type-confirmed hoFH treated with the maximal dose of
`statins (atorvastatin or simvastatin 80 mg/day). The addition
`of ezetimibe 10 mg/day to this regimen resulted in a total
`reduction of LDL-C levels of 27%, which is still far from
`optimal. Several non-pharmacological options have also been
`tested. Surgical interventions, such as portacaval shunt and
`ileal bypass have resulted only in partial and transient LDL-C
`lowering. Orthotopic liver transplantation has been demon-
`
`4
`strated to substantially reduce LDL-C levels in hoFH
`patients, but obvious disadvantages and risks are associated
`with this approach. Although hoFH could be an excellent
`model for gene therapy, this modality of treatment is not
`foreseeable in the near future due to the limitations on the
`availability of safe vectors that provide long-term expression
`of LDL receptor gene. Thus, the current standard of care in
`hoFH is LDL apheresis, a physical method of filtering the
`plasma of LDL-C which as monotherapy can transiently
`reduce LDL-C by about 50%. Apheresis uses affinity col(cid:173)
`unms to selectively remove apoB-containing lipoproteins.
`However, because of rapid re-accumulation of LDL-C in
`plasma, apheresis has to be repeated frequently (every 1-2
`weeks) and requires 2 separate sites for IV access. Although
`15 anecdotally this procedure may delay the onset of atheroscle(cid:173)
`rosis, it is laborious, expensive, and not readily available.
`Furthermore, although it is a procedure that is generally well
`tolerated, the fact that it needs frequent repetition and IV
`access can be challenging for many of these young patients.
`20 Therefore, there is a tremendous unmet medical need for new
`medical therapies for hoFH.
`Patients with heterozygous FH can usually be successfully
`treated with combination drug therapy to lower the LDL-C to
`acceptable levels. In contrast, hoFH is unresponsive to con-
`25 ventional drug therapy and thus there are limited treatment
`options. Specifically, treatment with statins, which reduce
`LDL-C by inhibiting cholesterol synthesis and upregulating
`the hepatic LDL receptor, have negligible effect in patients
`whose LDL receptors are non-existent or defective.
`In July 2004, the NCEP published a paper entitled "Impli-
`cations of Recent Clinical Trials for the National Cholesterol
`Education Program Adult Treatment Panel III Guidelines",
`updating certain elements of the "Adult Treatment Panel III
`(ATP III)" cholesterol guidelines released in 2001. For high-
`35 risk patients, individuals who have coronary heart disease
`(CHD) or disease of the blood vessels to the brain or extremi(cid:173)
`ties, or diabetes, or multiple (2 or more) risk factors that give
`them a greater than 20 percent chance of having a heart attack
`within 10 years, the ATP III update recommends that the
`40 overall goal for high-risk patients is still an LDL less than 100
`mg/dL with a therapeutic option to set the goal at an LDL less
`than 70 mg/dL for very high-risk patients, those who have had
`a recent heart attack, or those who have cardiovascular dis(cid:173)
`ease combined with either diabetes, or severe or poorly con-
`45 trolled risk factors (such as continued smoking), or metabolic
`syndrome (a cluster of risk factors associated with obesity
`that includes high triglycerides and low HDL cholesterol).
`The ATP III update also recommends consideration of drug
`treatment in addition to lifestyle therapy for LDL levels 100
`50 mg/dL or higher in high-risk patients, and characterizes drug
`treatment as optional for LDL less than 100 mg/dL. For
`moderately high-risk patients, individuals who have multiple
`(2 or more) CHD risk factors together with a 10-20 percent
`risk for a heart attack within 10 years, the ATP III update
`55 recommends the overall goal for moderately high-risk
`patients to be an LDL less than 130 mg/dL. There is a thera(cid:173)
`peutic option to set the treatment goal at anLDL less than 100
`mg/dL, and to use drug treatment ifLDL is 100-129 mg/dL.
`For high-risk and moderately high-risk patients, the ATP III
`60 update advises that the intensity ofLDL-lowering drug treat(cid:173)
`ment in high-risk and moderately high-risk patients be suffi(cid:173)
`cient to achieve at least a 30 percent reduction in LDL levels.
`Patients suffering from severe hypercholesterolemia may
`also be unable to reach the new goals for L