Breast Cancer Research and Treatment 49: 859-565. 1998.
`© 1998 Kluwer Academic Publishers. Printed in the Netherlands.
`
`Report
`
`Pro-clinical and clinical review of vorOzole, a new third generation
`aromatase inhibitor
`
`Paul E. (3055
`
`The Toronto Hospital-General Division, 200 Elizabeth St, Toronto, Ontario, Canada M5 G 2C4
`
`Key words: vorozole, aromatase inhibitor, review, breast cancer
`
`Summary
`
`Vorozole (Rivizorm), is a triazole derivative and one of the new, third generation aromatase inhibitors. Voro~
`zole causes reversible inhibition of cytochrome P450 aromatase with the majority of the aromatase inhibition
`activity attributable to the dextro~isomer. In vitro the IC50 against human placental aromatase and in cultured
`rat ovarian granulosa cells is 1.38 and 0.44 nM. respectively. Vorozole is selective and does not effect other
`cytochrome P450wdependent reactions at concentrations up to at least 500 fold the aromatase inhibiting con—
`centration. In vitro vorozole. at concentrations of up to 10 uM. does not exhibit agonistic or antagonistic
`
`effects on steroid receptors including the estrogen, progestin, androgen and glucocorticoid receptors. In vivo
`vorozole produces dose-dependent inhibition of aromatase and reduces circulating estrogen levels. Vorozole
`has been shown to inhibit intratumoral aromatase activity in postmenopausal breast cancer patients pretreat-
`ed for 7 days prior to undergoing mastectomy. Tissue estrone and estradiol levels were also shown to be
`decreased by 64% and 80%, respectively. In four phase II clinical trials. vorozole produced response rates of
`18—33% corresponding to selective inhibition of estradiol. Vorozole has been examined in large. randomized
`multi—centre, controlled trials against both megestrol acetate (MA) and aminoglutethimide (AG) plus hydro—
`cortisone. Against MA, response rates were comparable (10.5% vorozole; 7.6% MA) however. a trend to—
`wards improvement: in median duration of response for vorozole (18.2 versus 12.5 months; p - 0.07) was
`shown. No differences in time to progression or survival were noted. Significant and persistent weight gain
`associated with MA administration was the most notable difference in tolerability between the two agents.
`Against AG, vorozole showed a higher response rate (23 ”/0 versus 18 %) however this did not reach statistical
`significance (p = 0.085). N o differences in duration of response, time to progression and survival were noted.
`A significantly better Functional Living lndev-(Tnncer (Fl .lC) quality of life score was associated with voro-
`zole compared to AG.
`
`Vorozole is a specific, selective and potent aromatasc inhibitor and useful for postmenopausal patients with
`advanced breast cancer.
`
`Pre-clinical pharmacology
`
`Vorozole is a potent, stereospecific inhibitor of the
`
`exclusively with the dextro [(+)-(S)]—enantiomer
`[1].];1 vitro. using granulosa cells, the dextro-isomer
`can be shown to cause a dose-dependent inhibition
`
`aromatase enzyme with its activity residing almost
`
`of aromatase with an IC50 of 0.44 nM versus 1CSOS of
`
`Address for offitrims and correspondence: RE. 6088. The Toronto Hospital—General Division. 200 Elizabeth St. Toronto, Ontario. Ca-
`nada MSG 2C4; Tel: 1—416—340‘3835; Fax: l~416-340-3220
`
`AstraZeneca Exhibit 2142 p. 1
`InnoPharma Licensing LLC v. AstraZeneca AB IPR2017-00904
`Fresenius-Kabi USA LLC v. AstraZeneca AB IPR2017-01910
`
`

`

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`fable 1. Effects of vorozole race-mate. enantiomers, and reter~
`once compounds on human placental aromatasc (microsomes)
`
`Compound
`
`Relative potency*
`
`1029
`Vorozole (dextro)
`5.48
`Vorozole (racemate)
`32
`Vorozole (love)
`34
`4—Hydroxyandrostene—3.l7~dione
`
`Aminoglutethimide 1
`
`>3“ The 1C“. value. (14?. 11M) obtained with aminoglntethimide is
`used as standard. From Vanden Bossche H. et a1. Biochem Phar—
`
`macol 40: 1716, 1990 (with permission)
`
`dosterone synthesis in contrast to fadrozole, a sec-
`
`ond generation inhibitor which causes substantial
`inhibition of mineralocorticoid synthesis [6] Vom-
`zole concentrations up to 10 uM did not alter the
`specific binding of estrogens, progestins, glucocor-
`ticoids and androgens to their respective receptors
`in vitro [7]. This was confirmed in vivo for the estro-
`gen receptor by measuring the ability of vorozole at
`
`doses up to 33 mg/kg to induce rat uterine ornithine
`decarboxylase activity and uterine growth in imma—
`ture rats [5]. There are no effects, either agonistic or
`antagonistic, against the uterus as measured by
`these methods.
`
`0.93 and 240 nM for vorozole racemate and the le-
`
`In PMSG-stimulated rats, vorozole causes a
`
`vo-enantiomer respectively; demonstrating a 545—
`fold difference in potency between the two man-
`tiomers [1]. In human placental microsomes the
`dextro-enantiomer is 1.9 times as potent as the race—
`rnic mixture and 32 times more potent than the levo
`form [2].
`Against human placental aromatase. the 1C50 of
`the vorozole dextro-iSOmer is 1.38 nM and the rela-
`
`tive potency of vorozole compared to aminoglu-
`tethimide is 1,029 versus 34 for 4-hydroxyandroste~
`nedione, a second generation steroidal inhibitor [2]
`(Table 1). Specificity for aromatase is demonstrated
`in Table 2 which shows that high concentrations of
`vorozole are required to inhibit other cytochrome
`P450—dependent reactions for steroid biosynthesis
`[1—5] (Table 2). In vitro vorozole does not inhibit al-
`
`dose-dependent inhibition of estradiol synthesis
`two hours after exposure to a single oral dose of the
`drug. At doses of 0.001 mg/kg and higher, plasma
`estradiol levels were significantly reduced and the
`lowest dose producing greater than 95% inhibition
`was 0.1 mg/kg [8]. The calculated EDSO-value was
`0.0034 mg/kg [1]. Specificity was confirmed in vivo
`by lack of inhibition of corticosterone and aldoste-
`rone production by doses up to 20 lug/kg of voi'o-
`zole in LHRH/ACTH-injected rats. Testosterone
`levels were significantly decreased (25 and 41% af-
`ter administration of 10 and 20 mg/kg vorozole, re—
`spectively) and was accompanied by an increase in
`progesterone and 17a-hydroxyprogesterone levels
`at the 20 mg/kg dose only. This indicated a partial
`inhibition of the 17a-hydroxylase/1720 lyase en~
`
`Table 2. Effects of vorozole on the main cytochrome P450-dependent reactions of steroid biosynthesis
`
`
`
` Enzyme Product formed Tissue 1C50 (nM)
`
`
`
`
`
`14-dcmcthylasc
`70cvhydroxylase
`cholesterol side—chain
`cleavage
`1‘7a—hydroxylase/
`17,20-lyase
`17,20—lyase
`
`cholesterol
`70t~hydroxycholesterol
`pregnenolone
`
`rat liver subccllular fractions
`rat liver microsornes
`bovine adrenal cortex mitochondria
`
`DHEA and androstenedione
`androstenedione
`androstenedione, DI IIZA,
`testosterone
`
`bovine adrenal cortex microsomes
`cultured rat and human* testicular cells
`rat testis subccllular fractions
`
`> 10,000
`> 10,000
`> 10,000
`
`> 10,000
`2 10.000
`1,800
`
`11~hydroxylase
`
`21~hydroxylase
`
`> 10,000
`bovine adrenal microsomes
`11-deoxycortisol and
`;> 10,000
`cultured rat and human" adrenal cells
`ll-dcoxycorticosteione
`> 10,000
`bovine adrenal cortex mitochondria
`cortisol and corticosterone
`2 10,000
`cultured rat and human* adrenal cells
`aldosterone
`
`cultured human adrenal cells“ 2 10,000
`
`experiments performed with the racemate. (From Vorozole Investigators Brochure 3rd edition, p. 13, May 1995, with permission).
`
`AstraZeneca Exhibit 2142 p. 2
`
`

`

`Median tumor volume
`(ms)
`100
`
`1D
`
`1
`
`‘3
`
`W Control
`
`
`“’I— Ovaflectomy
`
`
`(«u-Verozole :
`—O- 2.5 mglkg bid
`
`”etc- 0.63 trig/kg bid
`—0— 0.18 mm bid
`
`
`
`
`
`
`D
`
`5 1015202530350045
`
`Days of treatment
`
`Figure I. Effect of ovariectolny and treatment with vorozole on
`the growth of DMBA~induced rat mammary carcinoma. (From
`Vorzole Investigators Brochure 3rd edition, p. 16. May 1995, with
`permission)
`
`zyme. In rats fed a sodium—deprived diet for 4
`weeks, then given vorozole up to 20 trig/kg daily for
`1.1 days, neither aldosterone, its precursors or plas—
`
`ma renin activity levels were affected [4, 8].
`In male cynomolgus monkeys. the effects of vo-
`rozole on peripheral aromatization were examined
`using a double-label. isotope-primed, constant—in—
`fusion technique. Conversion of androstenedione
`to estrone was measured 4—5 hours after dosing. Vo-
`rozole caused a dose-dependent inhibition of in. vi-
`
`va peripheral aromatization and at an intravenous
`dose of 130 ng/kg, 50% inhibition of peripheral aro—
`matization was observed [9].
`Vorozole was studied using the JEG-3 human
`choriocarcinoma xenograft in ovariectomi'Ied nude
`mice. The JEG—3 tumor produces estrogens via the
`aromatization of circulating androgens.
`In this
`model vorozole caused a dose—dependent inhib-
`ition of intratumoral aromatase activity and a cor-
`responding dose-dependent decrease in uterine
`weight. Half-maximal reduction in uterine weight
`and tumor aromatase activity was seen at 0.05 to
`0.1 mg/kg of vorozole [8].
`
`Anti-tumor effects
`
`The antitumoral activity of vorozole and vorozole
`racemate has been evaluated in female Sprague—
`Dawley rats treated with the carcinogen dimethyl—
`benz(a)anthracerte (DMBA) and in female Wistar
`
`rats treated with N-meth)-'lnitrosourea (NMU) [10,
`
`Pre-clirtical and clinical review of Vorozole
`
`S61
`
`11]. In the DBMA-induced rat mammary model,
`treatment. with 2.5 mg/kg vorozole twice daily for 42
`days caused tumor regression comparable to 007
`phorectomy [12] (Figure 1). Using the NMU-in-
`duced rat mammary model, treatment with 40 and
`160 mg of vorozole racemate/IOO grams of food for
`42 days reduced tumor growth to the same extent as
`ovaricctomy [5].
`
`Pharmacokinetic profile
`
`After single and multiple dosing, votozole is shown
`
`to have a pharmacological profile in man similar to
`the rat and dog and different from the rabbit Where
`
`absorption was slower and there was marked ster—
`eoselective metabolism. In dogs, after one month
`oral dosing, the vorozole tissue to plasma distribu-
`tion was found to be higher in liver and the adrenal
`gland [4]. Excretion in the rat and in man is pred0m«
`inantly in the feces and the major metabolite is a
`desmethyl form [4]. In thirteen postmenopausal
`breast cancer patients given 2.5 mg vorozole once
`
`daily, the Tmax was approximately 1.1 hours, CmX
`79.8 ng/ml and the terminal half-life 1215 hours
`
`(steady-state). Steady levels were obtained within 4
`days [4]. The AUC and terminal half—life in the post—
`menopausal breast cancer patients appeared slight-
`ly increased compared to pharmacokinetic data
`from six healthy male volunteers given 2.5 mg voro~
`
`zole for 2 weeks [Cmax 63.5 ng/ml; terminal half—life
`6.5 hours (steady state)] [4].
`
`Clinical pharmacology
`
`Inhibition ofperipheral aromalnse activity
`
`cross—over
`A randomized. placebo-controlled,
`phase I trial was performed in six healthy male vol
`unteers to study the effect of five different single
`dose of vorozole (0.25. 0.5, 1, 2.5 and 5 mg) on estra-
`diol levels to identify the lowest effective dose. All
`doses of vorozole suppressed estradiol levels, how-
`ever, the lowest dose (0.25 mg) showed a tendency
`for estradiol levels to escape at 24 hours. No statisti-
`cal differences between the doses were seen, thus a
`
`AstraZeneca Exhibit 2142 p. 3
`
`

`

`S62
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`125
`
`100
`
`q G
`
`cn o
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`aromatization
`
`
`
`
`as
`
`plant»
`
`puma
`
`mm
`
`Figure 2. Effect of different doses of vorozolc racemare on the in viva peripheral aromatization in normal postmenopausal women. The
`percentage of conversion during the placebo experiment in the same woman was taken as 100%. After administration of the active
`compound, the conversion decreased an average of 94%. (From: Van der Wall E. ct al.. Cancer Res 53: 4565. 1993. reprinted with
`permission.)
`
`minimally effective dose could not be identified.
`However in the 2.5 and 5 mg groups more estradiol
`levels were at the assay detection limit [4]
`Inhibition of peripheral aromatization was as-
`sessed in 12 healthy postmenopausal women who
`were randomized in a double-blind fashion to re~
`
`of vorozole racemate. These two doses reduced es-
`
`tradiol levels by 45 to 55 % and estradiol levels were
`
`suppressed to the assay detection limit (10 pmol/l)
`within 2 weeks and throughout a 4—week period.
`ACTH stimulation testing was performed in all pa-
`tients at baseline and after 4 weeks on vorozole and
`
`ceive a single dose of either 1. 2.5 or 5 mg of voro—
`zole racemate. Each woman acted as her own con-
`
`no effect on circulating cortisol or aldosterone was
`seen at either dose [4].
`
`trol as an. identical experiment was performed with
`a placebo. Four hours after dosing, [”CNabeled an-
`drostenedione and [3H] labeled estrone were in-
`fused and the percentage conversion of androstene~
`dione to estrone assessed. The mean percentage in-
`hibition was 93, 93.2 and 94.4% for 1, 2.5 and 5 mg of
`vorozole racemate, respectively (Figure 2), N0 dose
`response relationship could be established [13].
`In a double—blind. placebo—controlled trial, 15
`healthy postmenopausal women received 2.5 or
`5 mg vorozole racemate once daily for seven days.
`Median estrone levels were reduced by 71% and
`67% for the 2.5 and 5 mg doses,
`respectively.
`Median estradiol levels were reduced by 42% in the
`5 mg group. No relevant changes in the circulating
`levels of cortisol, aldosterone, testosterone, proges—
`terone, FSH and LH levels were observed as com-
`
`pared to placebo [4].
`In a phase I pilot study 28 postmenopausal breast
`cancer patients were treated with either 2.5 or 5 mg
`
`Intrammoral inhibition
`
`Eleven postmenopausal breast cancer patients
`were treated with vorozole. 2.5 mg once daily, for
`seven days preceding mastectomy. Eight patients
`could be evaluated and intratumoral aromatase ac—
`
`tivity, estradiol and estrone levels were compared to
`values from nine untreated postmenopausal breast
`cancer patients. In the treated group median tissue
`aromatase activity [median 0.80 [moi/mg pro-
`tein/2 h (0.27 6.60)] was 89% lower than controls
`[median 7.19 fmol/mg/protein/2 hr
`(240-1881)]
`p < 0.00]. Additionally, median intraturnoral es-
`trone and estradiol levels were also lowered in the
`
`treated group by 64 and 80%, respectively. These
`findings were statistically significant [14].
`
`AstraZeneca Exhibit 2142 p. 4
`
`

`

`Table 3. Summary of key parameters from 2 phase III trials (20—21)
`
`
`
`Treatment Group
`
`VOR—lNT—3
`VOR»INT-4
`
`
`Pre—clinical and clinical review of Vorozole
`
`S63
`
`Aminoglutethimide ~+~
`Vorozole
`Megestrol Acetate
`Vorozole
`n : 225
`n : 227
`n : 277
`Hydrocortisone n : 279
`
`
`P Value
`
`P Value
`
`Overall response rate
`Clinical benefit [CR +
`PR + NC 2 6 mths)
`Median duration of
`response (mths)
`Median time to
`
`progression (mths)
`Median time to
`
`treatment failure (mths)
`Median survival (mths)
`Number AEs loading
`to withdrawal
`
`10.5% 4‘
`—
`
`7.6 % f
`
`—
`
`18.2
`
`2.7
`
`-—
`
`12.5
`
`3.6
`
`—
`
`26.0
`7 (3.1%)
`
`28.7
`14 (6.2 as
`
`0.29
`
`0.07
`
`0.46
`
`0.93
`
`23 %
`47%
`
`20.9
`
`6.7
`
`5.3
`
`18%
`37%
`
`20.4
`
`6.0
`
`4.4
`
`25.7
`s (3 9/0)
`
`21.7
`29 (10%)
`
`0.085
`0017
`
`NS
`
`NS
`
`0.040
`
`NS
`< 0.001
`
`
`
`* established by investigator assessment and confirmed by external radiological review.
`
`Choice of vorozole dose for clinical testing
`
`2.5 and 5 mg of vorozole in the proportion of pa»
`tients below detection limit values [4].
`
`The dose of 2.5 mg of vorozole used in the phase II
`and III clinical trials was selected based primarily
`on a phase II, randomized, double—blind, cross-over
`study where 24 patients received three separate
`doses of 1.0, 2.5 and 5.0 mg vorozole, each for 4
`weeks. Median serum estradiol levels were sup-
`pressed by 91, 90. and 89% for the 1, 2.5 and 5 mg
`doses, respectively. Median estrone levels and es-
`trone sulfate levels were reduced by 54, 55, and 52%
`
`and by 69. 64 and 67% for the 1.0, 2.5 and 5 mg dos-
`es, respectively. There was a trend (p = 0.02) for es-
`tradiol to be more frequently suppressed to the as—
`say detection limit [3 pmol/L] with increasing doses
`of vorozolc: 13, 31 and 40% for the 1.0, 2.5 and
`
`5.0 mg doses, respectively. The difference between
`the 2.5 and 1.0 mg doses (31 versus 13%) was signif-
`icant in favor of the 2.5 mg dose, however there was
`no difference between the 2.5 and 5.0 mg doses,
`thus supporting selection of the 2.5 mg, dose [or clin—
`ical development [15].
`Supportive data came from the previously de-
`scribed male volunteer peripheral aromatization
`study where both the 2.5 and 5 mg groups had a
`higher proportion of patients having estradiol lev-
`els below the assay detection limit than the other
`doses. However there were no differences between
`
`Clinical studies
`
`Phase II clinical trials
`
`Four phase II clinical trials have been conducted in
`
`Canada, the United Kingdom, Europe (EORTC),
`and Italy [15—19]. In total, 115 patients were enrolled
`in these studies. Eligible patients were defined as ta-
`moxifen failures — either in the metastatic (had ‘re-
`sponded’ to previous tamoxifen and subsequently
`progressed) or adjuvant (relapsed after one year or
`more of adjuvant tamoxifen) setting. Additionally
`
`patients had to have estrogen and/or progesterone
`receptor positive or unknown disease and have
`measurable lesions. Responses were evaluated us-
`ing the International Union Against Cancer
`(UICC) or European Organisation for Research
`and Treatment of Cancer (EORT’C) criteria. Re-
`sponse rates observed ranged between 18 and 33%
`[15—19]. The endocrine effects of vorozole in these
`studies demonstrated a significant reduction in es-
`trone and estradiol. An increase in gonadotrophin
`
`levels and a reduction in sex hormone binding glob-
`ulin (SHBG) were noted in patients who recently
`
`AstraZeneca Exhibit 2142 p. 5
`
`

`

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`
`LH
`
`GHBB ANBD EHEA Hut 1?. OHP
`
`Figure 3. Change in endocrine levels after 1 month. Values are
`mean percentage of pretreatment level (i SE). Sample size va-
`ries from 21—24 women from whom both basal and month 1 sam-
`
`ples were available. P values from Wilcoxon signed rank test on
`paired replicates. i. P < 0.05 versus pretreatment: “5"”. P < 0.001
`versus pretreatment. (From Goss PE ct al.. Clin Cancer Res. 1:
`291, 1995. with permission)
`
`discontinued tamoxifen [16] (Figure 3). This phe-
`nomenon was considered related to the washout of
`
`tamoxifen rather than attributable to vorozole. No
`
`blunting of the ACTH stimulation test was detected
`at one month after treatment for either cortisol or
`
`aldosterone production.
`
`Phase [I] Clinical trials
`
`Two large. multicentre. phase III comparative trials
`have been performed: vorozole 2.5 mg daily versus i)
`megestrol acetate (MA) 40 mg qid (North America)
`and ii) aminoglutethimide (AG) 250 mg bid plus hy-
`drocortisone ('10 mg tid) supplementation (Europe).
`These data are summarized in Table 3. Patients en—
`rolled in those studies were tamoxifen failures
`
`either in the metastatic (had ‘responded’ to previous
`tamoxifen and subsequently progressed) or adjuvant
`(relapsed after one year or more of adjuvant tamoxi-
`fen) setting. Patients were treated until progression
`and standard criteria of response were used.
`
`VOR-IN‘T»3 - vorozole 2.5 mgpo daily versus
`MA 40 172ng qid
`
`452 postmenopausal women with advanced breast
`cancer were enrolled in the vorozole (n = 225) ver-
`
`sus MA (11 : 227) trial. Patients were stratified by
`disease: measurable, evaluable, and non-measura-
`
`ble, non-evaluable and 190 and 185 patients were
`evaluable for response in the vorozole and MA treat"
`ment groups, respectively. Responses were deter—
`mined by investigator assessment and confirmed by
`an external blinded radiological review. The primary
`endpoint of the study was response rate. Secondary
`endpoints included: duration of response. time to
`progression and survival. Response rates (CR, PR)
`
`were comparable between the two treatment arms
`(10.5 %. vorozole and 7.6%, MA). There was a trend
`for vorozole for improvement in median duration of
`
`response: 18.2 versus 12.5 months (p = 0.07). The
`median time to disease progression was 2.7 versus 3.6
`months and the median survival time was 26 versus
`
`28.7 months for vorozole and MA. respectively. Both
`treatments were well—tolerated. The most frequent
`treatment—related adverse events were hot flushes
`
`(vorozole) and inappropriate weight gain (MA).
`Adverse events leading to treatment withdrawal oc-
`curred in 3.1% (n z 7) and 6.2% (n - 14) of vorozole
`
`and MA-treated patients. respectively [20].
`
`l/UR-1N1L4 — vorozole 2.5 mg po daily versus
`AG 250 mg bid
`556 postmenopausal women with advanced breast
`
`cancer were enrolled in the vorozole (n z 277) versus
`AG (11 z 279) trial. Study endpoints included: re—
`sponse rate, duration of response, time to progres—
`sion, time to treatment failure, survival. performance
`status. tolerability score (0 = excellent. 4 2: unbear-
`
`able) and quality of life as assessed by the Functional
`Living Index — Cancer (FLIC) questionnaire. Re—
`sponse rates (CR, PR) were 23% (vorozole) and
`17% (AG), however. the difference did not reach
`statistical significance (p = 0.085). The median dura-
`
`tion of response was 20.9 versus 20.4 months for the
`vorozole and AG treatment arms, respectively. The
`median time to disease progression was 6.7 versus 6
`months and the median survival time was 25.7 versus
`
`21.7 months for vorozole and AG, respectively and
`were not statistically significantly different. Overall
`clinical benefit rate, defined as response or disease
`stabilization for B 6 months. was significantly higher
`with vorozole (47%) than with AG (37%) p : 0.017
`as was the median time to treatment failure 5.3 ver-
`
`sus 4.4 months (p <: 0.040). Quality of Life ("/0 AUG)
`was improved to a greater extent in patients treated
`
`AstraZeneca Exhibit 2142 p. 6
`
`

`

`with vorozole (104.0) than AG (101.8) (p = 0.014).
`The mean tolerabilitv score at endpoint was signif—
`icantly better in the vorozole arm (0.4) than the AG
`arm (0.7) p 1‘3 0.001. Vorozole was better tolerated
`
`than AG with the incidence of drug-related adverse
`events 31 versus 53% (p < 0.001) and the withdrawal
`rates due to adverse events were 3 versus 10% in vo-
`
`rozole and Athreated patients. respectively (p <
`0.001) [2.1].
`
`Summary
`
`Vorozole is a potentspecific reversible inhibitor of
`aromatase, as seen using both in vitro and in ViVO
`models. In clinical trials this drug has been shown to
`be well-tolerated and effective after tamoxifen in a
`
`proportion of postmenopausal women with ad-
`vanced breast cancer. The side effects are compat-
`ible with its well-established mechanism of action.
`
`Vorozole has been shown to be equivalent to MA.
`and appears superior to AG. in terms of quality of
`life, clinical benefit and time to treatment failure. Vo~
`
`rozole is a useful new alternative therapy for the
`treatment of postmenopausal breast cancer patients.
`
`References
`
`1. Wouters W. De Coster R, Van Dun J et al.: Comparative
`effects of the aromatase inhibitor R76713 and of its enan-
`
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`AstraZeneca Exhibit 2142 p. 7
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