Mylan Exhibit 1012, Page 1
`
`

`
`Circulation
`AN OFFICIAL JOURNAL or THE American Heart Association ®
`
`0
`
`Burton E. Sobel, Editor
`Associate Editors
`Michael E. Cain
`Peter B. Corr
`Edward M. Geltman
`Philip A. Ludbrook
`Gustav Schonfeld
`
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`
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`
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`Elizabeth Barrett-Connor
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`Edward D. Freis
`Edward D. Frohlich
`William H. Gaasch
`Stanton A. Giant:
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`
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`Mylan Exhibit 1012, Page 2
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`Mylan Exhibit 1012, Page 2
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`

`
`CHOLESTEROL AND CARDIOVASCULAR DISEASE
`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`New developments in lipid-lowering therapy:
`the role of inhibitors of hydroxymethylglutaryl-
`coenzyme A reductase
`
`J. A. TOBBRT, M.B., PH.D.
`
`ABSTRACT HMG—CoA reductase catalyzes the conversion of hydroxymethylglutarate to mevalo-
`nate, an important early rate-limiting step in the cholesterol biosynthesis pathway. Since the discovery
`of compactin, the first HMG—CoA reductase inhibitor, by Endo et al. in l9?6, several other inhibitors
`have been described. Those that have been investigated in the clinic include rnevastatin icompa‘-Tl"),
`lovastatin (mevinolin), simvastatin (synvinolin), eptastatin {CS-514, SQ-31,000), and SR1-62320.
`These compounds are competitive inhibitors, with K, values ofthe hydroxyacid forms ofaround l0'9M.
`Lovastatin irnevinolin, Mevacor*), which is in the late stages of clinical development and has been
`administered to over 1000 subjects for up to 4 years, is the inhibitor on which I116 111031 lI1f01'm3li0n
`is available. It is given in single or divided doses of 20 to S0 mgiday, and is a very effective and usually
`well-tolerated lipid-lowering agent. At 40 mg bid, lovastatin produces the following approximate mean
`changes: total plasma cholesterol. -33%; low—density lipoprotein {LDL} cholesterol, -40%; very
`low-density lipoprotein cholesterol, -35%; plasma triglycerides, -25%; high—density lipoprotein
`cholesterol, + 10%; apolipoprotein B, --20%. The substantial reduction in both LDL cholesterol and
`apolipoprotein B {the principal protein component of LDL) indicates a reduction in the number of
`circulating LDL particles. The mechanism probably involves both decreased LDL production and
`increased LDL clearance.
`Circulation 76, No. 3, 534-538, 1987.
`
`THE ROLE OF hypercholesterolemia, or more accu-
`rately hyperbetalipoproteinemia, as a risk factor for
`atherosclerosis in general and ischemic heart disease in
`particular is supported by a wealth of clinical, epide-
`tniologic, and pathologic studies. A National Institutes
`of Health Consensus Development Panel
`recently
`concluded'
`that
`the ideal blood cholesterol for all
`Americans over the age of 30 is 200 mg/dl or less, and
`that attempts should be made to lower blood cholesterol
`when it exceeds the 75th percentile, or approximately
`240 mgidl,
`in middle-aged American men. Therapy
`should always start with a lipid-lowering diet, but diets
`acceptable to most patients typically lower blood cho-
`lesterol by 10% or less. Drug therapy has been limited
`by insufficient efficacy at tolerated doses, and in some
`cases a high instance of side effects andfor significant
`safety problems?
`In individuals eating a typical Western diet, approx
`imately one~third of total body cholesterol is derived
`
`From the Department of Clinical Research, Merck Sharp Sc Dohme
`Research Laboratories, Rahway, NJ.
`Address for correspondence: J. A. Tobert, M.B., Ph.D.. Department
`of Clinical Research. Merck Sharp & Dohme Research Laboratories.
`Rahway. NJ l}'i'(l6S.
`*Rcgistcrcd trademark of Merck & Co.. Inc.
`
`534
`
`from the diet, and two-thirds is synthesized, mainly by
`the liver and intestine. The biosynthetic pathway for
`cholesterol involves more than 25 different enzymes,
`and is summarized in figure 1. An important rate-
`limiting step in this pathway is the conversion of
`hydroxymethylglutaryl—coenzyme A (HMG-COA) I0
`mevalonate, which is
`catalyzed by HMG-CoA
`reductasef‘ Early attempts to inhibit cholesterol syn-
`thesis were centered on the late stages of the pathway.
`One such inhibitor, triparanol (MERf29), was used
`briefly in the clinic, but was withdrawn in 1962 after
`
`reports of serious toxicity, including cataracts, ichthy—
`osis, and alopecia.4 Triparanol inhibited the conversion
`of desmosterol to cholesterol, and consequently caused
`the buildup of desmosterol in plasma and tissues.5 It is
`believed thatthe toxicity of triparanol and other late-
`stage inhibitors can be attributed, at least in part, to the
`accumulation of abnormal sterols in tissues.
`
`Inhibitors of HMG-CoA reductase inhibit the path-
`way at a much earlier stage, and therefore cannot cause
`buildup of sterol intermediates. Five inhibitors have
`been studied in the clinic: mevastatin (compactin).
`lovastatin (nievinolin, Mevacor"‘). 5iIIlV3StatiII (Synvi-
`*Registered trademark of Merck & C0,. Inc.
`
`Mylan Exhibit 1012, Page 3CIRCULATION
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`Mylan Exhibit 1012, Page 3
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`

`
`Acetyl Corn
`
`1 Several Steps
`
`HMGCoA
`
`HMGCOA Reductase
`
`I
`
`Mevaionate
`1 Several Steps --- Isopentenyl
`Adenine
`Farnesyl Pyrophosphate
`[Many Steps
`|Many S1995
`
`Many Steps
`
`Ubiquinones
`
`Cholesterol
`
`Dolichals
`
`FIGURE 1. The cholesterol biosynthesis pathway.
`
`nolin), eptastatin {CS~5l4. SQ—3l ,{}00), and SR1-
`62320 (figure 2). Mevastatin, lovastatin, and simvasta-
`tin are prodrugs; in vivo, the lactone ring is hydrolyzed
`to the corresponding ,8—hydroxyacicl, which is the prin-
`cipal active form of these drugs. These compounds are
`competitive inhibitors of HMG—CoA reductase. with K-,
`values of approximately .l0‘°M. Mevastatin, which
`was discovered by Ernie et al." in Japan,
`is the pro-
`totype of this class of compounds. However. lovafitalin
`is the agent that has been most extensively studied.
`having been given to more than I000 subjects for up
`to 4 years. Approval by the U.S. Food and Drug
`Administration is expected in 1987. Because much
`more information is available on lovastatin than on the
`
`0
`
`CHOLESTEROL AND CARDIOVASCULAR DISEASE
`
`other inhibitors, this review will summarize the clinical
`
`evaluation of this agent.
`Effect of lovastatin on lipoproteins. The first human
`studies on lovastatin were carried out in normoch0~
`
`lesterolemic volunteers eating an unrestricted diet. In
`these subjects, the hypocholesterolemic effects of the
`drug were evident after 3 days, and mean reductions in
`low~density lipoprotein (LDL) cholesterol between
`35% and 45% were obtained after 4 weeks at doses of
`6.25 to 50 mg bid.7 Similar reductions in LDL cho-
`lesterol were subsequently demonstrated in heterozy-
`gous familial hypercholesterolemia {_FH)3"2 and in
`patients with primary nonfamilial hypercholesterol—
`emia.‘°'
`'3‘ '4 In all these studies, patients were on
`lipid-lowering diets before starting treatment with
`lovastatin. Illingworth and Sextons obtained dose-re-
`lated decreases in LDL cholesterol in 13 patients with
`FH that ranged from 20% on 5 mg bid to 38% on 40
`mg bid.
`In six patients with heterozygous FH, Bil-
`heimer et al." noted a 27% decrease in LDL cholesterol
`on 20 mg bid; in another group of six patients with
`heterozygous FH. Hoeg et al. '0 reported a 34% reduc-
`tion in LDL cholesterol at the same dose. In a multi-
`center, double-blind, placebo—controlled study in 101
`patients with FH, Havel et al. " observed mean reduc-
`tions in LDL cholesterol ranging from 17% on 5 mg bid
`to 39% on 40 mg bid. The corresponding mean changes
`
`CH3
`
`H0
`
`00 N3 a
`
`
`OH
` {SFII-62320)
`
`H3C’
`
`Lmastafin
`
`Mevastatin
`{Compactin)
`H0
`
`Cozfla
`
`E
`F 0 /
`/ N,CH(CH3),
`
`H 3 0.
`
`Simvastatin
`{synvirlolinl
`
`Eptastatin
`{CS-514. S0—3‘t0O0}
`
`FIGURE 2.
`
`Inhibitors of HMG—CoA reductase studied in the clinic.
`
`Vol. 76, No. 3, September 1987
`
`Mylan Exhibit 1012, Page 4
`
`535
`
`Mylan Exhibit 1012, Page 4
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`

`
`TOBERT
`
`in total cholesterol ranged from 14% to 34%. In two
`patients with homozygous Fl-I undergoing treatment by
`plasma exchange,” lovastatin was relatively ineffec-
`tive, producing reductions in serum cholesterol of only
`7% and 12%. The effects of lovastatin in patients with
`nonfamilial primary hypercholesterolemia are similar
`to those in patients with FH. I-Ioeg et al. '0 obtained a
`34% reduction in LDL cholesterol at 20 mg bid in 18
`patients with nonfatnilial hypercholesteroiemia, and
`Grundy and Vega” reported a 31% reduction in 12
`patients at the same dose. In another muiticenter study
`using the
`same double-blind, placebo-controlled
`design as that of Havel et al. in their study of patients
`with FH, I-Iunninghake et al.” reported very similar
`results in 100 patients with nonfarnilial hypercholes-
`terolemia. At 40 mg bid, total and LDL cholesterol fell
`by 32% and 39%, respectively.
`In addition to reducing LDL cholesterol, lovastatin
`increases high—density lipoprotein (HDL) cholesterol
`by 5% to 10%, '°- "- '4 although this effect is too small
`and variable to be reliably detected in small studies. As
`a result of the large decreases in LDL cholesterol cou-
`pled with the small increases in HDL cholesterol, the
`ratio of LDL cholesterol to HDL cholesterol, which
`some consider to be the best predictor of atherogenic
`risk,"
`is
`almost halved
`during therapy with
`Iovastatin."'
`'4 Very low—density lipoprotein (VLDL)
`cholesterol is also reduced almost as much as LDL
`°h01e5t€I‘0i.'0'
`'4 and plasma triglycerides have been
`reported to fall about 25% in most studies.‘‘'
`'0‘ "' '4
`AP'31iP0PF0tein B also fails substantially?‘ '°' "' '3'
`'4
`Since each LDL particle contains one molecule of
`aP°1iP0P1"0t3il1 1.3P0) B '6 and since little apo B is found
`if‘ the Other iipoproteins, '7 the indication is that lovasta-
`ttn reduces the concentration of circulating LDL par-
`ticles. Consistent with the effects on HDL cholesterol,
`the concentrations of apo AI and apo All (which are
`carried in HDL) also tend to rise slightly."‘ *4
`The time course of the therapeutic response is shown
`in figure 3. The maximum therapeutic response is
`obtained in 4 to 6 weeks, after which the response is
`quite stable. The effects of progressive increases in
`dose on plasma cholesterol are shown in figure 4.
`Lovastatin is given with meals,
`in single or divided
`doses. Divided doses are slightly more effective, '4'
`'3
`but single daily doses are more convenient and
`may be adequate for patients with milder forms of
`hypercholesterolemia. If the drug is given once a day,
`a dose given in the evening is more effective than the
`same dose given in the moming,” probably because
`human cholesterol synthesis reaches a peak around
`midnight. '9
`
`536
`
`
`
`4
`
`3
`6
`Weeks
`
`10
`
`12
`
`14
`
`16
`
`13
`
`
`
`TotalCholesterolmgtdl
`
`-4
`
`-2
`
`D
`
`2
`
`FIGURE 3. Effect of a fixed dose of Iovastatin (20 mg bid) on plasma
`cholesterol. (Reproduced. with permission. from Hunninghake et al.")
`
`Mechanism of action. Lovastatin is a potent compet-
`itive inhibitor of HMG-CoA reductasc,2° and this
`action can be demonstrated in human subjects by mea-
`suring plasma and urinary mevalonate. In norrnocho-
`lesterolemic volunteers. plasma and urinary mevalo-
`nate clearly fall after administration of Iovastatin. 2" 22
`In a limited number of patients with FH, however,
`Illingwotth et al.” observed increases in plasma meva-
`lonate. This paradoxical effect is not understood at the
`present time.
`It is clear that the mechanism of action of lovastatin
`
`is not simply and solely due to inhibition of cholesterol
`
`synthesis. In five patients studied by sterol balance
`techniques, Grundy and Biii'16il'1'!Bl23 showed a modest
`decline in fecal output of neutral and acidic sterols in
`three patients but no changes in another two. Changes
`in the fecal output of sterols did not correlate with the
`degree of lowering of LDL cholesterol. Bilheimer et
`al.9 had earlier shown that lovastatin could increase the
`
`fractional catabolic rate of LDL in patients with FH,
`which may indicate an increase in the number of LDL
`
`receptors. The importance of the LDL receptor is sup-
`ported by limited data in patients with homozygous FH,
`who have very few or no functioning LDL receptors,
`
`Cholesterolmgtldt
`Total
`
`-Ii
`
`-2
`
`O
`
`2
`
`4
`
`B
`6
`Weeks
`
`10
`
`12
`
`14
`
`16
`
`18
`
`FIGURE 4. Effect of progressive increases in dosage of lovastatin on
`plasma cholesterol. (Reproduced. with permission. from Hunninghake
`et al. ")
`
`Mylan Exhibit 1012, Page 5 CIRCULATION
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`Mylan Exhibit 1012, Page 5
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`

`
`and in whom iovastatin is relatively ineffective.” In
`one patient with homozygous Fl-I in whom functioning
`LDL receptors were restored by means of liver trans-
`plantation,
`lovastatin reduced LDL cholesterol by
`41%.“ Grundy and Vega” studied a group of patients
`with nonfamilial hypercholesteroiemia in whom they
`were unable to establish a convincing effect on LDL
`catabolism, but did find decreases in LDL production
`rate. They interpreted these data to indicate that induc-
`tion of the LDL receptor also occurred in these patients,
`but was manifested primarily by increased catabolism
`of VLDL remnants, rather than of LDL. Since LDL is
`formed from VLDL remnants, LDL production rate
`could be lowered by this mechanism. It is clear that
`lovastatin causes
`substantial
`reductions
`in VLDL
`cholesterol,‘°‘ 1“ whose measurement by ultracentri-
`fugation includes VLDL remnants, but whether this is
`due to an increase in remnant catabolism or a decrease
`in VLDL secretion, or both, has not been established.
`In summary, the mechanism of action of lovastatin is
`Complex and not yet fully understood. It seems prob-
`able that different mechanisms may predominate in
`different patients, and there may well be differences
`between patients with and without FH. The technical
`difficulties of performing these studies are formidable.
`Therefore, an early resolution of the problem is not
`expected.
`Tolerability and safety. Lovastatin has been given to
`more than 1000 patients for up to 4 years. As of Sep-
`tember l986, about 500 patients had taken the drug for
`more than 1 year. I have reviewed all available data on
`all patients who have been treated with lovastatin. In
`controlled clinical
`studies,
`involving about 750
`patients, the frequency of patient withdrawal from ther-
`apy due to adverse events attributable to lovastatin was
`less than 1%, indicating that lovastatin is a very well-
`tolerated drug. Various gastrointestinal symptoms are
`the most commonly reported adverse events in patients
`treated with lovastatin, but these have generally been
`mild and transient and have rarely required discontin-
`uation of treatment. Headache, rash, and myositis have
`
`also been reported occasionally.
`Small increases in transaminases, particularly SGI-‘T
`(ALT), are sometimes seen, often within 6 weeks of the
`onset of therapy. '4 These may be transient and have
`not required withdrawal of therapy. The same phe-
`nomenon has been reported with most lipid-lowering
`drugs,
`including cholestyramine.2' 25 Since bile-acid
`sequestrants are not absorbed, small increases in trans-
`aminases may be a general response to changes in lipid
`metabolism, rather than a direct effect of lipid-lowering
`drugs on the liver. A more important finding is that
`
`V01. 76. No. 3. September 1987
`
`CHOLESTEROL AND CARDIOVASCULAR DISEASE
`
`1.9% of patients have had larger and persistent asymp-
`tomatic increases of transaminases, particularly SGPT,
`which has been observed to rise above three times the
`
`upper limit of normal. When the drug was discontin-
`ued, the transaminases returned to pretreatment levels,
`usually within a few weeks. In contrast to the small
`increases in transaminases that appear early in therapy,
`the larger increases have usuaily occurred after at least
`3 months on drug. Alkaline phosphatase remained
`essentially normal, indicating that the effect is most
`probably hepatocellular rather than cholestatic. It
`is
`clear that these idiosyncratic increases in transaminases
`are not the result of hypersensitivity, but otherwise the
`mechanism of the effect is unknown.
`In dogs, lovastatin produces posterior and anterior
`subcapsular cataracts in about 10% of treated animals,
`albeit at doses at least 50 times the maximum thera-
`peutic dose. This phenomenon was not noted in rats or
`mice. * Because of this finding and the recorded effects
`of triparanolf‘ the ophthalmologic data on patients
`treated with lovastatin have been scrutinized very care-
`fully. More than 600 patients have had full ophthal-
`mologic examinations, including slit-lamp biomicros—
`copy of the lens, at baseline and once or more during
`treatment.
`
`Lens opacities were reported at baseline in approx-
`imately 30% of patients, which was not unexpected in
`view of the fact that lens opacities are very common in
`middle age.“ In controlled studies, the prevalence of
`lens opacities remained essentially unchanged during
`treatment with lovastatin. In one early study in 101
`patients, '4 an increase in the prevalence of lens opac-
`ities was reported; however, this experience is atypical
`and is probably the result of bias induced by the finding
`of cataracts in dogs, which were discovered after
`almost all patients in this study had had their baseline
`examinations, but before the majority had had their
`posttreatment examination. (It is well known that the
`detection of small
`lens opacities is subjective and
`depends, for example, on the time the examiner spends
`and the degree of pupillary dilatation achieved.) Thus
`it is likely that many, if not all, of the so-called new
`opacities reported in this study were merely small pre-
`existing opacities missed at baseline. In later studies,
`begun after the report of cataracts in dogs and involving
`about 500 patients,
`there was littie difference from
`baseline in the prevalence of lens opacities during treat-
`ment. The data thus indicate no detectable effect of
`lovastatin on the human lens within the period of time
`studied to date, i.e., up to 18 months.
`
`*MacDo11ald .lS: Personal communication.
`
`Mylan Exhibit 1012, Page 6
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`537
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`Mylan Exhibit 1012, Page 6
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`

`
`l3.
`
`l4.
`
`l8.
`
`I9.
`
`20.
`
`TOBERT
`
`Although cholesterol is the precursor of all steroid
`hormones,
`lovastatin has no detectable effect on
`adrenal” '2' 14‘ 27 or gonadal” '4 stcroidogcnesis.
`Benefit-to-risk analysis. The utility of any drug is a
`function of the relationship between benefit and risk.
`In terms of benefit, lovastatin clearly produces large
`lipid-lowering effects of a nature and magnitude that
`cannot be achieved with any existing approved agents.
`The drug is well
`tolerated and well accepted by
`patients. Based on the results of the Lipid Research
`Clinics Coronary Primary Prevention Trial,” as well
`as much other clinical, epidemiologic, and pathologic
`evidence, these effects on lipids would be expected to
`result in a substantial reduction in coronary event rates.
`Set against the benefit, there is a small risk of myositis
`and of adverse effects on the liver. However, symp-
`tomatic liver injury has not been observed thus far, and
`its risk should be minimal if liver function is monitored
`appropriately. Therefore, a reasonable overall assess-
`meiit of the data is that the risk is substantially out-
`weighed by the benefit.
`_ In conclusion, based on the experience with lovasta-
`U11. Inhibitors of HMG-CoA reductase are likely to
`P1"0Ve a major advance in the treatment of hypercho—
`lesterolemia. They may well usher in a new era in the
`management of this disorder, playing a role comparable
`to that of the tliiazides in hypertension a quarter of a
`century ago.
`
`References
`
`et al. lNIH Consensus Conference): Lowering blood
`l. Ellgilnberg
`2 Br
`°5‘eh':l’S'° Pffllefll hcan disease. JAMA 253: 2080, 1985
`-
`_ Own
`'
`, Goldstein_JL: Drugs used in the treatment of hyper.
`gfiloprotelnemlfls. In Clilman AG. Goodman LS Ran Tw Mumd
`editors): The l1
`1
`‘
`'lba '-
`'
`e
`'
`1935. Maclvlillalrji iaostigirm 5“ of thmpems‘ New Ymk‘
`3. godwell VW, Nordstroni JL, Mitschell Jl: Regulation of WW6-
`c-A reductase. Adv Lipid Res 14,
`1
`1976
`4. Kirby TJ: Cataracts prod
`d b
`'
`‘
`|
`.
`Opmha] Soc 65: 493’ I9’-$9
`Y “'|Parano tIvlERi'29). Trans Am
`5‘ Slcmbcrg 13- A‘''lS3l] 1. Feigelson EB: Effects of triparanol (MER-
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