NDA 21-153/S-027
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`NEXIUM®
`(esomeprazole magnesium)
`DELAYED-RELEASE CAPSULES
`
`NEXIUM®
`(esomeprazole magnesium)
`FOR DELAYED-RELEASE ORAL SUSPENSION
`
`Rx only
`
`DESCRIPTION
`
`The active ingredient in NEXIUM® (esomeprazole magnesium) Delayed-Release Capsules and
`NEXIUM (esomeprazole magnesiumtFor Delayed-Release Oral Suspension is bis(5-methoxy-2-[(S)(cid:173)
`[ ( 4-methoxy-3,5-dimethyl-2-pyridinyl)methyl ]sulfinyl ]-lH-benzimidazole-1-yl) magnesium trihydrate,
`a compound that inhibits gastric acid secretion. Esomeprazole is the S-isomer of omeprazole, which is
`a mixture of the S- and R- isomers. Its molecular formula is (C17H1sN303S)2Mg x 3 H20 with
`molecular weight of 767.2 as a trihydrate and 713.1 on an anhydrous basis. The structural formula is:
`
`The magnesium salt is a white to slightly colored crystalline powder. It contains 3 moles of water of
`salvation and is slightly soluble in water.
`
`The stability of esomeprazole magnesium is a function of pH; it rapidly degrades in acidic media, but it
`has acceptable stability under alkaline conditions. At pH 6.8 (buffer), the half-life of the magnesium
`salt is about 19 hours at 25°C and about 8 hours at 37°C.
`
`NEXIUM is supplied in delayed-release capsules and in packets for a delayed-release oral suspension.
`Each delayed-release capsule contains 20 mg or 40 mg of esomeprazole (present as 22.3 mg or 44.5
`mg esomeprazole magnesium trihydrate) in the form of enteric-coated granules with the following
`inactive ingredients: glyceryl monostearate 40-55, hydroxypropyl cellulose, hypromellose, magnesium
`stearate, methacrylic acid copolymer type C, polysorbate 80, sugar spheres, talc, and triethyl citrate.
`The capsule shells have the following inactive ingredients: gelatin, FD&C Blue #1, FD&C Red #40,
`D&C Red #28, titanium dioxide, shellac, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, propylene
`glycol, sodium hydroxide, polyvinyl pyrrolidone, and D&C Yellow #10.
`
`Each packet of NEXIUM For Delayed-Release Oral Suspension contains 20 mg or 40 mg of
`esomeprazole, in the form of the same enteric-coated granules used in NEXIUM Delayed-Release
`Capsules, and also inactive granules. The inactive granules are composed of the following ingredients:
`dextrose, xanthan gum, crospovidone, citric acid, iron oxide, and hydroxypropyl cellulose. The
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`esomeprazole granules and inactive granules are constituted with water to form a suspension and are
`given by oral, nasogastric or gastric administration.
`
`CLINICAL PHARMACOLOGY
`Pharmacokinetics
`Absorption
`NEXIUM Delayed-Release Capsules and NEXIUM For Delayed-Release Oral Suspension contain a
`bioequivalent enteric-coated granule formulation of esomeprazole magnesium. Bioequivalency is
`based on a single dose (40 mg) study in 94 healthy male and female=volunteers under fasting condition.
`After oral administration peak plasma levels (Cmax) occur at approximately 1.5 hours (Tmax). The Cmax
`increases proportionally when the dose is increased, and there is a three-fold increase in the area under
`the plasma concentration-time curve (AUC) from 20 to 40 mg. At repeated once-daily dosing with 40
`mg, the systemic bioavailability is approximately 90% compared to 64% after a single dose of 40 mg.
`The mean exposure (AUC) to esomeprazole increases from 4.32 µmol *hr/L on day 1 to 11.2
`µmol *hr/Lon day 5 after 40 mg once daily dosing.
`
`The AUC after administration of a single 40 mg dose of esomeprazole is decreased by 43-53% after
`food intake compared to fasting conditions. Esomeprazole should be taken at least one hour before
`meals.
`
`The pharmacokinetic profile of esomeprazole was determined in 36 patients with symptomatic
`gastroesophageal reflux disease following repeated once daily administration of 20 mg and 40 mg
`capsules ofNEXIUM over a period of five days. The results are shown in the following table:
`
`Pharmacokinetic Parameters of NEXIUM on Day 5 Following Oral Dosing for 5 Days
`Parameter* (CV)
`NEXIUM
`NEXIUM
`40 mg
`20 mg
`12.6 (42%)
`4.2 (59%)
`AUC (µmol.h/L)
`4.7 (37%)
`2.1 (45%)
`Cmax (µmol/L)
`1.6
`1.6
`T max (h)
`1.5
`1.2
`1112 (h)
`*Values represent the geometric mean, except the Tma"' which is the arithmetic mean; CV= Coefficient of variation
`
`Distribution
`Esomeprazole is 97% bound to plasma proteins. Plasma protein binding is constant over the
`concentration range of 2-20 µmol/L. The apparent volume of distribution at steady state in healthy
`volunteers is approximately 16 L.
`
`Metabolism
`Esomeprazole is extensively metabolized in the liver by the cytochrome P450 (CYP) enzyme system.
`The metabolites of esomeprazole lack antisecretory activity. The major part of esomeprazole's
`metabolism is dependent upon the CYP2C 19 isoenzyme, which forms the hydroxy and desmethyl
`metabolites. The remaining amount is dependent on CYP3A4 which forms the sulphone metabolite.
`CYP2Cl9 isoenzyme exhibits polymorphism in the metabolism of esomeprazole, since some 3% of
`Caucasians and 15-20% of Asians lack CYP2C 19 and are termed Poor metabolizers. At steady state,
`the ratio of AUC in Poor metabolizers to AUC in the rest of the population (Extensive metabolizers) is
`approximately 2.
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`Following administration of equimolar doses, the S- and R-isomers are metabolized differently by the
`liver, resulting in higher plasma levels of the S- than of the R-isomer.
`
`Excretion
`The plasma elimination half-life of esomeprazole is approximately 1-1.5 hours. Less than 1 % of parent
`drug is excreted in the urine. Approximately 80% of an oral dose of esomeprazole is excreted as
`inactive metabolites in the urine, and the remainder is found as inactive metabolites in the feces.
`
`Special Populations
`Geriatric
`The AUC and Cmaxvalues were slightly higher (25% and 18%, respectively) in the elderly as compared
`to younger subjects at steady state. Dosage adjustment based on age is not necessary.
`
`Pediatric
`12 to 17 Years of Age
`The pharmacokinetics of esomeprazole were studied in 28 adolescent patients with GERD aged 12 to
`17 years inclusive, in a single center study. Patients were randomized to receive esomeprazole 20 mg
`or 40 mg once daily for 8 days. Mean Cmax and AUC values of esomeprazole were not affected by
`body weight or age; and more than dose-proportional increases in mean Cmax and AUC values were
`observed between the two dose groups in the study. Overall, esomeprazole pharmacokinetics in
`adolescent patients aged 12 to 17 years were similar to those observed in adult patients with
`symptomatic GERD.
`
`Comparison of PK Parameters in 12 to 17 Year Olds with GERD and
`Adults with Symptomatic GERD Following the Repeated Daily Oral Dose
`Administration of Esomeprazole*
`
`Adults (N=36)
`12 to 17 Year Olds (N=28)
`Parameter
`20mg
`40mg
`20mg
`40mg
`4.2
`12.6
`3.65
`13.86
`AUC (µmol*h/L)
`2.1
`4.7
`1.45
`5.13
`Cmax (µmol/L)
`1.6
`1.6
`2.00
`1.75
`1max (h)
`1.5
`1.2
`0.82
`1.22
`ty,),,z (h)
`Data presented are geometric means for AUC, Cmax and t';,A.z, and median value for tmax·
`*Duration of treatment for 12 to 17 year olds and adults were 8 days and 5 days, respectively. Data were obtained from two
`independent studies.
`
`Gender
`The AUC and Cmax values were slightly higher (13%) in females than in males at steady state. Dosage
`adjustment based on gender is not necessary.
`
`Hepatic Insufficiency
`The steady state pharmacokinetics of esomeprazole obtained after administration of 40 mg once daily
`to 4 patients each with mild (Child Pugh A), moderate (Child Pugh Class B), and severe (Child Pugh
`Class C) liver insufficiency were compared to those obtained in 36 male and female GERD patients
`with normal liver function. In patients with mild and moderate hepatic insufficiency, the AUCs were
`within the range that could be expected in patients with normal liver function. In patients with severe
`hepatic insufficiency the AUCs were 2 to 3 times higher than in the patients with normal liver function.
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`No dosage adjustment is recommended for patients with mild to moderate hepatic insufficiency (Child
`Pugh Classes A and B). However, in patients with severe hepatic insufficiency (Child Pugh Class C) a
`dose of 20 mg once daily should not be exceeded (See DOSAGE AND ADMINISTRATION).
`
`Renal Insufficiency
`The pharmacokinetics of esomeprazole in patients with renal impairment are not expected to be altered
`relative to healthy volunteers as less than 1 % of esomeprazole is excreted unchanged in urine.
`
`Pharmacokinetics: Combination Therapy with Antimicrobials
`Esomeprazole magnesium 40 mg once daily was given in combination with clarithromycin 500 mg
`twice daily and amoxicillin 1000 mg twice daily for 7 days to 17 healthy male and female subjects.
`The mean steady state AUC and Cmax of esomeprazole increased by 70% and 18%, respectively during
`triple combination therapy compared to treatment with esomeprazole alone. The observed increase in
`esomeprazole exposure during co-administration with clarithromycin and amoxicillin is not expected
`to produce significant safety concerns.
`
`The pharmacokinetic parameters for clarithromycin and amoxicillin were similar during triple
`combination therapy and administration of each drug alone. However, the mean AUC and Cmax for 14-
`hydroxyclarithromycin increased by 19% and 22%, respectively, during triple combination therapy
`compared
`to
`treatment with clarithromycin alone. This
`increase m exposure
`to 14-
`hydroxyclarithromycin is not considered to be clinically significant.
`
`Pharmacodynamics
`Mechanism of Action
`Esomeprazole is a proton pump inhibitor that suppresses gastric acid secretion by specific inhibition of
`the H+/K+-ATPase in the gastric parietal cell. The S- and R-isomers of omeprazole are protonated and
`converted in the acidic compartment of the parietal cell forming the active inhibitor, the achiral
`sulphenamide. By acting specifically on the proton pump, esomeprazole blocks the final step in acid
`production, thus reducing gastric acidity. This effect is dose-related up to a daily dose of 20 to 40 mg
`and leads to inhibition of gastric acid secretion.
`
`Antisecretory Activity
`The effect of esomeprazole on intragastric pH was determined in patients with symptomatic
`gastroesophageal reflux disease in two separate studies. In the first study of 36 patients, NEXIUM 40
`mg and 20 mg capsules were administered over 5 days. The results are shown in the following table:
`
`Effect on Intragastric pH on Day 5 (N=36)
`Parameter
`NEXIUM
`NEXIUM
`40mg
`20mg
`70%*
`53%
`(16.8 h)
`(12.7 h)
`26%
`37%
`
`% Time Gastric
`pH >4t (Hours)
`Coefficient of
`variation
`Median 24 Hour pH 4.9*
`Coefficient of
`16%
`variation
`
`4.1
`27%
`
`t GASTRIC PH WAS MEASURED OVER A 24-HOUR PERIOD
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`*p< 0. 01 NEXIUM 40 MG vs NEXIUM 20 MG
`
`In a second study, the effect on intragastric pH of NEXIUM 40 mg administered once daily over a five
`day period was similar to the first study,(% time with pH>4 was 68% or 16.3 hours).
`
`Serum Gastrin Effects
`The effect ofNEXIUM on serum gastrin concentrations was evaluated in approximately 2,700 patients
`in clinical trials up to 8 weeks and in over 1,300 patients for up to 6-12 months. The mean fasting
`gastrin level increased in a dose-related manner. This increase reached a plateau within two to three
`months of therapy and returned to baseline levels within four weeks after discontinuation of therapy.
`
`Enterochromaffin-like (EGL) Cell Effects
`In 24-month carcinogenicity studies of omeprazole in rats, a dose-related significant occurrence of
`gastric ECL cell carcinoid tumors and ECL cell hyperplasia was observed in both male and female
`animals (see PRECAUTIONS, Carcinogenesis, Mutagenesis, Impairment of Fertility). Carcinoid
`tumors have also been observed in rats subjected to fundectomy or long-term treatment with other
`proton pump inhibitors or high doses of H2-receptor antagonists.
`
`Human gastric biopsy specimens have been obtained from more than 3,000 patients treated with
`omeprazole in long-term clinical trials. The incidence of ECL cell hyperplasia in these studies
`increased with time; however, no case of ECL cell carcinoids, dysplasia, or neoplasia has been found
`in these patients.
`
`In over 1,000 patients treated with NEXIUM (10, 20 or 40 mg/day) up to 6-12 months, the prevalence
`of ECL cell hyperplasia increased with time and dose. No patient developed ECL cell carcinoids,
`dysplasia, or neoplasia in the gastric mucosa.
`
`Endocrine Effects
`NEXIUM had no effect on thyroid function when given in oral doses of 20 or 40 mg for 4 weeks.
`Other effects of NEXIUM on the endocrine system were assessed using omeprazole studies.
`Omeprazole given in oral doses of 30 or 40 mg for 2 to 4 weeks had no effect on carbohydrate
`metabolism, circulating levels of parathyroid hormone, cortisol, estradiol, testosterone, prolactin,
`cholecystokinin or secretin.
`
`Microbiology
`Esomeprazole magnesium, amoxicillin and clarithromycin triple therapy has been shown to be active
`against most strains of Helicobacter pylori (H. pylori) in vitro and in clinical infections as described in
`the Clinical Studies and INDICATIONS AND USAGE sections.
`
`Helicobacter
`Helicobacter pylori: Susceptibility testing of H. pylori isolates was performed for amoxicillin and
`clarithromycin using agar dilution methodology, and minimum inhibitory concentrations (MICs) were
`determined.
`
`Pretreatment Resistance: Clarithromycin pretreatment resistance rate (MIC ~ 1 µg/mL) to H. pylori
`was 15% (66/445) at baseline in all treatment groups combined. A total of> 99% (394/395) of
`patients had H. pylori isolates which were considered to be susceptible (MIC ::;; 0.25 µg/mL) to
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`amoxicillin at baseline. One patient had a baseline H. pylori isolate with an amoxicillin MIC = 0.5
`µg/mL.
`
`Clarithromycin Susceptibility Test Results and Clinical/Bacteriologic Outcomes: The baseline H.
`pylori clarithromycin susceptibility results and the H. pylori eradication results at the Day 38 visit are
`shown in the table below:
`
`H. pylori
`negative
`(Eradicated)
`
`Clarithromycin
`Pretreatment
`Results
`
`Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomes a for Triple
`Therapy - (Esomeprazole magnesium 40 mg once daily/amoxicillin
`1000 mg twice daily/clarithromycin 500 mg twice daily for
`10 days)
`H. pylori positive
`(Not Eradicated)
`Post-treatment susceptibility
`results
`Rb No MIC
`lb
`Sb
`Susceptibleb 182
`14
`2
`0
`4
`162
`Intermediateb
`1
`1
`0
`0
`0
`0
`Resistant0
`1
`2
`0
`29
`13
`13
`alncludes only patients with pretreatment and post-treatment clarithromycin susceptibility test results
`bSusceptible (S) MIC~ 0.25 µg/mL, Intermediate (I) MIC= 0.5 µg/mL, Resistant (R) MIC;:: 1.0 µg/mL
`
`Patients not eradicated of H. pylori following esomeprazole magnesium/amoxicillin/clarithromycin
`triple therapy will likely have clarithromycin resistant H. pylori isolates. Therefore, clarithromycin
`susceptibility testing should be done, when possible. Patients with clarithromycin resistant H. pylori
`should not be re-treated with a clarithromycin-containing regimen.
`
`Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes:
`In the esomeprazole magnesium/amoxicillin/clarithromycin clinical trials, 83% (176/212) of the
`patients in the esomeprazole magnesium/amoxicillin/clarithromycin treatment group who had
`pretreatment amoxicillin susceptible MICs (:=:; 0.25 µg/mL) were eradicated of H. pylori, and 17%
`(36/212) were not eradicated of H. pylori. Of the 36 patients who were not eradicated of H. pylori on
`triple therapy, 16 had no post-treatment susceptibility test results and 20 had post-treatment H. pylori
`isolates with amoxicillin susceptible MICs. Fifteen of the patients who were not eradicated of H. pylori
`on triple therapy also had post-treatment H. pylori isolates with clarithromycin resistant MICs. There
`were no patients with H. pylori isolates who developed treatment emergent resistance to amoxicillin.
`
`Susceptibility Test for Helicobacter pylori: The reference methodology for susceptibility testing of
`H. pylori is agar dilution MICs. One to three microliters of an inoculum equivalent to a No.2
`McFarland standard (1 x 107
`- 1 x 108 CFU/mL for H. pylori) are inoculated directly onto freshly
`prepared antimicrobial containing Mueller-Hinton agar plates with 5% aged defibrinated sheep blood
`(;:: 2 weeks old). The agar dilution plates are incubated at 35°C in a microaerobic environment
`produced by a gas generating system suitable for Campylobacter. After 3 days of incubation, the MICs
`are recorded as the lowest concentration of antimicrobial agent required to inhibit growth of the
`organism. The clarithromycin and amoxicillin MIC values should be interpreted according to the
`following criteria:
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`Clarithromycin MIC (µg/mL) a
`~ 0.25
`0.5
`2".1.0
`
`Interpretation
`Susceptible
`Intermediate
`Resistant
`
`(S)
`(I)
`(R)
`
`a
`
`Interpretation
`Amoxicillin MIC (µg/mL) a,b
`(S)
`Susceptible
`~ 0.25
`These are breakpoints for the agar dilution methodology and they should not be used to interpret results obtained using alternative
`methods.
`b
`There were not enough organisms with MICs > 0.25 µg/mL to determine a resistance breakpoint.
`
`Standardized susceptibility test procedures require the use of laboratory control microorganisms to
`control the technical aspects of the laboratory procedures. Standard clarithromycin and amoxicillin
`powders should provide the following MIC values:
`
`Microorganism
`
`MIC (µg/mL)
`
`a
`
`Antimicrobial
`Agent
`Clarithromycin
`
`H. pylori ATCC
`0.016- 0.12
`43504
`(µg/mL)
`H. pylori ATCC
`0.016- 0.12
`43504
`(µg/mL)
`a These are quality control ranges for the agar dilution methodology and they
`should not be used to control test results obtained using alternative methods.
`
`Amoxicillin
`
`Clinical Studies
`Healing of Erosive Esophagitis
`The healing rates ofNEXIUM 40 mg, NEXIUM 20 mg, and omeprazole 20 mg (the approved dose for
`this indication) were evaluated in patients with endoscopically diagnosed erosive esophagitis in four
`multicenter, double-blind, randomized studies. The healing rates at weeks 4 and 8 were evaluated and
`are shown in the table below:
`
`Erosive Esopha2itis Healin2 Rate (Life-Table Analysis)
`No. of
`Significance
`Level*
`Study Patients Treatment Groups
`1
`588
`NEXIUM20mg
`N.S.
`Omeprazole 20 mg
`588
`654
`NEXIUM40mg
`NEXIUM20mg
`656
`Omeprazole 20 mg
`650
`NEXIUM40mg
`576
`Omeprazole 20 mg
`572
`1216 NEXIUM40mg
`1209
`Omeprazole 20 mg
`
`Week4 Week8
`68.7%
`90.6%
`69.5%
`88.3%
`75.9%
`94.1%
`70.5%
`89.9%
`64.7%
`86.9%
`71.5%
`92.2%
`68.6%
`89.8%
`81.7%
`93.7%
`68.7%
`84.2%
`
`p < 0.001
`p < 0.05
`
`N.S.
`
`p < 0.001
`
`2
`
`3
`
`4
`
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`*log-rank test vs omeprazole 20 mg
`N.S. =not significant (p > 0.05).
`
`In these same studies of patients with erosive esophagitis, sustained heartburn resolution and time to
`sustained heartburn resolution were evaluated and are shown in the table below:
`
`Sustained Resolutioni of Heartburn (Erosive Esophagitis Patients)
`
`Cumulative Percent11
`with Sustained
`Resolution
`
`Significance
`Level*
`N.S.
`
`No. of
`Day 14
`Study Patients Treatment Groups
`Day 28
`72.7%
`64.3%
`1
`573
`NEXIUM20mg
`70.9%
`64.1%
`555
`Omeprazole 20 mg
`74.2%
`64.8%
`621
`NEXIUM40mg
`70.1%
`62.9%
`NEXIUM20mg
`620
`66.6%
`56.5%
`626
`Omeprazole 20 mg
`73.9%
`65.4%
`NEXIUM40mg
`568
`73.1%
`65.5%
`551
`Omeprazole 20 mg
`75.1%
`67.6%
`1187 NEXIUM40mg
`70.8%
`62.5%
`1188 Omeprazole 20 mg
`+ Defined as 7 consecutive days with no heartburn reported m dally patient diary.
`#Defined as the cumulative proportion of patients who have reached the start of sustained resolution
`*log-rank test vs omeprazole 20 mg
`N.S. =not significant (p > 0.05).
`
`2
`
`3
`
`4
`
`p <0.001
`N.S.
`
`N.S.
`
`p <0.001
`
`In these four studies, the range of median days to the start of sustained resolution (defined as 7
`consecutive days with no heartburn) was 5 days for NEXIUM 40 mg, 7-8 days for NEXIUM 20 mg
`and 7-9 days for omeprazole 20 mg.
`
`There are no comparisons of 40 mg of NEXIUM with 40 mg of omeprazole in clinical trials assessing
`either healing or symptomatic relief of erosive esophagi tis.
`
`Long-Term Maintenance of Healing of Erosive Esophagitis
`Two multicenter, randomized, double-blind placebo-controlled 4-arm trials were conducted in patients
`with endoscopically confirmed, healed erosive esophagitis to evaluate NEXIUM 40 mg (n=l 74), 20
`mg (n=l80), 10 mg (n= 168) or placebo (n=l 71) once daily over six months of treatment.
`
`No additional clinical benefit was seen with NEXIUM 40 mg over NEXIUM 20 mg.
`
`The percentage of patients that maintained healing of erosive esophagi tis at the various time points are
`shown in the figures below:
`
`MYL-EN000523789
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`Maintenance of Healing Rates by Month (Study 177)
`':: \.< -·: -- ---··- --
`
`........ -·- -·- - - .. - - - - -·- .......
`
`. ...
`
`....
`
`·-..
`
`.. •
`
`... ...
`
`·•·· ·········· ... •······ ······· ...•. ....
`... - ... .. __ _ ·-- .. ......... .. ........ .. ........... .. .. .... .. ........ ..
`
`-
`
`NEXIUM 40 mg (N~92)
`NEXIUM 20 mg (N=9B)
`NEXIUM 10 mg (N=9 1)
`- .. • - • Placebo (n=94)
`
`80
`-g 70
`c
`$ 60
`c
`"iii
`~50
`c
`~40
`<J)
`a. 30
`
`20
`
`10
`
`0 0
`
`s= scheduled visit
`
`2
`
`3S
`M onth
`
`4
`
`5
`
`Maintenance of Healing Rates by Month (Study 178)
`
`100 •\:--'" ___ ,___,==::-"t:::=::::::-_ -------· .. ---__ -_-_-_-_ -4_ ...... _-_-_-_ -_ -__ ~.,._..__ -
`\ "·
`\ ""
`'"
`\
`"·
`\ .................... ..
`\
`"·
`\
`
`90
`
`80
`
`-
`
`-
`
`-
`
`-
`
`. ..................................... .
`.................
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`\
`\
`\
`\
`\
`\
`\
`\
`
`\ ..__ ----......... _
`--
`
`-+- NEXIUM 40 mg (n~82)
`·-·•-·· NEXIUM 20 mg (n~82)
`..... NEXIUM 10 mg (n~77)
`-+-- Placebo (n~77)
`
`-----....------+------+------+
`
`o'------'-----'-----'------'-----'----"---
`o
`1 s
`3 s
`6 s
`Month
`
`s= scheduled visit
`
`MYL-EN000523790
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`Patent Owners' Ex. 2057
`IPR2018-00272
`Page 9 of 37
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`

`

`NDA 21-153/S-027
`NDA 21-689/S-008
`Page 12
`
`Patients remained in rem1ss1on significantly longer and the number of recurrences of erosive
`esophagitis was significantly less in patients treated with NEXIUM compared to placebo.
`
`In both studies, the proportion of patients on NEXIUM who remained in remission and were free of
`heartburn and other GERD symptoms was well differentiated from placebo.
`
`In a third multicenter open label study of 808 patients treated for 12 months with NEXIUM 40 mg, the
`percentage of patients that maintained healing of erosive esophagi tis was 93. 7% for six months and
`89.4% for one year.
`
`Symptomatic Gastroesophageal Reflux Disease (GERO)
`Two multicenter, randomized, double-blind, placebo-controlled studies were conducted in a total of
`717 patients comparing four weeks of treatment with NEXIUM 20 mg or 40 mg once daily versus
`placebo for resolution of GERD symptoms. Patients had ~ 6-month history of heartburn episodes, no
`erosive esophagitis by endoscopy, and heartburn on at least four of the seven days immediately
`preceding randomization.
`
`The percentage of patients that were symptom-free of heartburn was significantly higher in the
`NEXIUM groups compared to placebo at all follow-up visits (Weeks 1, 2, and 4).
`
`No additional clinical benefit was seen with NEXIUM 40 mg over NEXIUM 20 mg.
`
`The percent of patients symptom-free of heartburn by day are shown in the figures below:
`
`Percent of Patients Symptom-Free of Heartburn by Day
`(Study 225)
`
`100
`
`75
`
`50
`
`25
`
`-
`·-·...tr..- -
`---•--
`
`NEXIUM 40 mg
`NEXIUM 20 mg
`Placebo
`
`.. ____ '
`
`.• .
`
`/" ,•--·-----·
`
`...
`
`- ..
`
`" \
`.....
`
`o'--~~~~--'-~~~~~-'-~~~~~-----~~~~~..._
`0
`14
`28
`21
`Diary Day
`
`MYL-EN000523791
`
`Patent Owners' Ex. 2057
`IPR2018-00272
`Page 10 of 37
`
`

`

`NDA 21-153/S-027
`NDA 21-689/S-008
`Page 13
`
`Percent of Patients Symptom-Free of Heartburn by Day
`(Study 226)
`
`100
`
`-
`
`-·...,-·-
`---•--
`
`NEXIUlv140mg
`NEXIUJ:v120mg
`Placebo
`
`_..,_ __ .... _
`
`. /·--·--· •. -• -----.
`---· .
`
`25
`
`---
`
`&
`;
`
`-..
`·--•,
`. ,..·-------. . '\·---------(cid:173)
`
`.•
`
`·--
`
`·-.
`
`o
`
`o.__~~~~-'-~~~~--"-~~~~~,__~~~~-'--
`14
`21
`28
`Diary Day
`
`In three European symptomatic GERD trials, NEXIUM 20 mg and 40 mg and omeprazole 20 mg were
`evaluated. No significant treatment related differences were seen.
`
`Risk Reduction of NSAID-Associated Gastric Ulcer
`Two multicenter, double-blind, placebo-controlled studies were conducted in patients at risk of
`developing gastric and/or duodenal ulcers associated with continuous use of non-selective and COX-2
`selective NSAIDs. A total of 1429 patients were randomized across the 2 studies. Patients ranged in
`age from 19 to 89 (median age 66.0 years) with 70.7% female, 29.3% male, 82.9% Caucasian, 5.5%
`Black, 3.7% Asian, and 8.0% Others. At baseline, the patients in these studies were endoscopically
`confirmed not to have ulcers but were determined to be at risk for ulcer occurrence due to their age
`(2:_60 years) and/or history of a documented gastric or duodenal ulcer within the past 5 years. Patients
`receiving NSAIDs and treated with NEXIUM 20 mg or 40 mg once-a-day experienced significant
`reduction in gastric ulcer occurrences relative to placebo treatment at 26 weeks. No additional benefit
`was seen with NEXIUM 40 mg over NEXIUM 20 mg. These studies did not demonstrate significant
`reduction in the development ofNSAID-associated duodenal ulcer due to the low incidence.
`
`Cumulative percentage of patients without gastric ulcers at 26 weeks:
`
`Study
`
`No. of Patients Treatment Group
`
`% of Patients
`Remaining Gastric
`Ulcer Free 1
`
`1
`
`2
`
`191
`194
`184
`
`267
`271
`257
`
`NEXIUM20mg
`NEXIUM40mg
`Placebo
`
`NEXIUM20mg
`NEXIUM40mg
`Placebo
`
`95.4
`96.7
`88.2
`
`94.7
`95.3
`83.3
`
`1 %=Life Table Estimate. Significant difference from placebo (p<0.01).
`
`MYL-EN000523792
`
`Patent Owners' Ex. 2057
`IPR2018-00272
`Page 11 of 37
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`

`

`NDA 21-153/S-027
`NDA 21-689/S-008
`Page 14
`
`Helicobacter pylori (H. pylori) Eradication in Patients with Duodenal Ulcer Disease
`Triple Therapy (NEXIUM/amoxicillin/clarithromycin): Two multicenter, randomized, double-blind
`studies were conducted using a 10 day treatment regimen. The first study (191) compared NEXIUM 40
`mg once daily in combination with amoxicillin 1000 mg twice daily and clarithromycin 500 mg twice
`daily to NEXIUM 40 mg once daily plus clarithromycin 500 mg twice daily. The second study (193)
`compared NEXIUM 40 mg once daily in combination with amoxicillin 1000 mg twice daily and
`clarithromycin 500 mg twice daily to NEXIUM 40 mg once daily. H. pylori eradication rates, defined
`as at least two negative tests and no positive tests from CLOtest®, histology and/or culture, at 4 weeks
`post-therapy were significantly higher in the NEXIUM plus amoxicillin and clarithromycin group than
`in the NEXIUM plus clarithromycin or NEXIUM alone group. The results are shown in the following
`table:
`
`Study
`191
`
`193
`
`Treatment Group
`NEXIUMplus
`amoxicillin and
`clarithromycin
`NEXIUMplus
`clarithromycin
`
`NEXIUMplus
`amoxicillin and
`clarithromycin
`NEXIUM
`
`H. pylori Eradication Rates at 4 Weeks after 10 Day Treatment Regimen
`% of Patients Cured
`[95% Confidence Interval]
`(Number of patients)
`Intent-to-Treat t
`Per-Protocolt
`77%*
`84%*
`[71, 82]
`[78, 89]
`(n=233)
`(n=l96)
`52%
`55%
`[ 45, 59]
`[48, 62]
`(n=215)
`(n=l87)
`78%**
`85%**
`[67, 87]
`[74, 93]
`(n=74)
`(n=67)
`4%
`5%
`[O, 23]
`[O, 21]
`(n=22)
`(n=24)
`f Patients were included in the analysis if they had H. pylori infection documented at baseline, had at least one endoscopically verified
`duodenal ulcer;:: 0.5 cm in diameter at baseline or had a documented history of duodenal ulcer disease within the past 5 years, and were
`not protocol violators. Patients who dropped out of the study due to an adverse event related to the study drug were included in the
`analysis as not H. pylori eradicated.
`+ Patients were included in the analysis if they had documented H. pylori infection at baseline, had at least one documented duodenal
`ulcer at baseline, or had a documented history of duodenal ulcer disease, and took at least one dose of study medication. All dropouts
`were included as not H. pylori eradicated.
`*p < 0.05 compared to NEXIUM plus clarithromycin
`**p < 0.05 compared to NEXIUM alone
`
`The percentage of patients with a healed baseline duodenal ulcer by 4 weeks after the 10 day treatment
`regimen in the NEXIUM plus amoxicillin and clarithromycin group was 75% (n=l56) and 57% (n=60)
`respectively, in the 191 and 193 studies (per-protocol analysis).
`
`Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome
`In a multicenter, open-label dose escalation study of 21 patients (15 males and 6 females, 18 Caucasian
`and 3 Black, mean age of 55.5 years) with pathological hypersecretory conditions, such as Zollinger(cid:173)
`Ellison Syndrome, NEXIUM significantly inhibited gastric acid secretion.
`Initial dose was 40 mg
`twice daily in 19/21 patients and 80 mg twice daily in 2/21 patients. Total daily doses ranging from 80
`mg to 240 mg for 12 months maintained gastric acid output below the target levels of 10 mEq/h in
`
`MYL-EN000523793
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`Patent Owners' Ex. 2057
`IPR2018-00272
`Page 12 of 37
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`NDA 21-153/S-027
`NDA 21-689/S-008
`Page 15
`
`patients without prior gastric acid-reducing surgery and below 5 mEq/hr in patients with prior gastric
`acid-reducing surgery. At the Month 12 final visit, 18/20 (90%) patients had Basal Acid Output
`(BAO) under satisfactory control (median BAO= 0.17 mmol/hr). Of the 18 patients evaluated with a
`starting dose of 40 mg twice daily, 13 (72%) had their BAO controlled with the original dosing
`regimen at the final visit.
`
`Adequate Acid Suppression at final visit by Dose Regimen
`
`NEXIUM dose at the Month 12
`visit
`40 mg twice daily
`80 mg twice daily
`80 mg three times daily
`*One patient was not evaluated.
`
`BAO under adequate control at
`the Month 12 visit (N=20)*
`13/15
`4/4
`1/1
`
`INDICATIONS AND USAGE
`Treatment of Gastroesophageal Reflux Disease (GERO)
`Healing of Erosive Esophagitis
`NEXIUM is indicated for the short-term treatment (4 to 8 weeks) in the healing and symptomatic
`resolution of diagnostically confirmed erosive esophagitis. For those patients who have not healed after
`4-8 weeks of treatment, an additional 4-8-week course of NEXIUM may be considered.
`
`Maintenance of Healing of Erosive Esophagitis
`NEXIUM is indicated to maintain symptom resolution and healing of erosive esophagitis. Controlled
`studies do not extend beyond 6 months.
`
`Symptomatic Gastroesophageal Reflux Disease
`NEXIUM is indicated for treatment of heartburn and other symptoms associated with GERD.
`
`Risk Reduction of NSAID-Associated Gastric Ulcer
`NEXIUM is indicated for the reduction in the occurrence of gastric ulcers associated with continuous
`NSAID therapy in patients at risk for developing gastric ulcers. Patients are considered to be at risk
`due to their age (::::_ 60) and/or documented history of gastric ulcers. Controlled studies do not extend
`beyond 6 months.
`
`H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
`Triple Therapy (NEXIUM plus amoxicillin and clarithromycin): NEXIUM, in combination with
`amoxicillin and clarithromycin, is indicated for the treatment of patients with H. pylori infection and
`duodenal ulcer disease (active or history of within the past 5 years) to eradicate H. pylori. Eradication
`of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence. (See Clinical Studies and
`DOSAGE AND ADMINISTRATION.)
`
`In patients who fail therapy, susceptibility testing should be done. If resistance to clarithromycin is
`demonstrated or susceptibility testing is not possible, alternative antimicrobial therapy should be
`i