Expert Opinion on Pharmacotherapy
`
`ISSN: 1465-6566 (Print) 1744-7666 (Online) Journal homepage: http://www.tandfonline.com/loi/ieop20
`
`Review of esomeprazole in the treatment of acid
`disorders
`
`David A Johnson
`
`To cite this article: David A Johnson (2003) Review of esomeprazole in the treatment of acid
`disorders, Expert Opinion on Pharmacotherapy, 4:2, 253-264, DOI: 10.1517/14656566.4.2.253
`To link to this article: https://doi.org/10.1517/14656566.4.2.253
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`Published online: 02 Mar 2005.
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`Patent Owner Ex. 2056
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`

`Drug Evaluation
`Review of esomeprazole in the
`treatment of acid disorders
`David A Johnson
`Eastern Virginia Medical School, Division of Gastroenterology, 885 Kempsville Road, Suite 114,
`Norfolk, VA 23505, USA
`
`Esomeprazole (Nexium™, AstraZeneca) is the (S)-isomer of omeprazole and
`the first proton pump inhibitor to be developed as an optical isomer. Esome-
`prazole has an improved pharmacokinetic profile, resulting in increased sys-
`temic exposure and
`less
`interindividual variability compared with
`omeprazole, and more effective suppression of gastric acid production com-
`pared with other proton pump inhibitors. In several large, double-blind, ran-
`domised trials, significantly higher rates of endoscopically-confirmed healing
`of erosive oesophagitis and resolution of heartburn have been achieved in
`patients with gastro-oesophageal reflux disease receiving 8 weeks of esome-
`prazole 40 mg o.d. compared with those receiving omeprazole 20 mg o.d. or
`lansoprazole 30 mg o.d. In the maintenance of healed erosive oesophagitis,
`esomeprazole 10, 20 or 40 mg o.d. was significantly more effective than pla-
`cebo in two 6-month, randomised, double-blind trials. Additionally, esome-
`prazole 20 mg o.d. was more effective than lansoprazole 15 mg in the
`maintenance of healed erosive oesophagitis in another 6-month, ran-
`domised, double-blind trial. Healing of oesophagitis was also effectively
`maintained by esomeprazole 40 mg o.d. in a 12-month non-comparative trial.
`Esomeprazole 20 or 40 mg o.d. effectively relieved heartburn in patients with
`gastro-oesophageal reflux disease without oesophagitis in two 4-week, pla-
`cebo-controlled trials. Clinical trials have shown that triple therapy with
`esomeprazole 40 mg o.d. in combination with amoxicillin and clarithromycin
`produced Helicobacter pylori eradication rates similar to those obtained
`using triple therapy involving twice-daily dosing with other proton pump
`inhibitors. Esomeprazole is well-tolerated, with a spectrum and incidence of
`adverse events similar to those associated with omeprazole.
`
`Keywords: esomeprazole, gastro-oesophageal reflux, Helicobacter pylori, oesophagitis, peptic ulcer,
`proton pump inhibitor
`
`Expert Opin. Pharmacother. (2003) 4(2):253-264
`
`1. Overview of proton pump inhibitors in acid-related disorders
`
`Gastro-oesophageal reflux disease (GERD) affects an estimated 19 million individuals
`in the US. In 2000, the direct and indirect costs for caring for patients with GERD
`amounted to ∼ US$10.1 billion [1]. Moreover, the actual prevalence of the disease
`tends to be underestimated; in one survey, GERD was present but not diagnosed in
`51% of patients seen in a general practice for unrelated conditions [2]. Complications
`of GERD include erosive oesophagitis, Barrett’s oesophagus and adenocarcinoma [3].
`The severity of disease and oesophageal damage does not correlate with the severity of
`GERD symptoms, resulting in difficulties in evaluating disease severity [4].
`Proton pump inhibitors (PPIs) are commonly used in the treatment of patients
`with GERD or peptic ulcers. PPIs provide rapid, consistent symptom control
`and healing of erosive oesophagitis. PPIs are also used in the treatment of other
`acid-related disorders, such as Zollinger–Ellison syndrome [5], ulcer recurrence
`following long-term low-dose aspirin use [6], for prevention and healing of ulcers
`
`2003 © Ashley Publications Ltd ISSN 1465-6566
`
`253
`
`1. Overview of proton pump
`inhibitors in acid-related
`disorders
`
`2. Introduction to esomeprazole
`
`3. Chemistry
`
`4. Mechanism of action,
`pharmacokinetics and
`metabolism
`
`5. Pharmacodynamics
`
`6. Clinical efficacy
`
`7. Safety and tolerability
`
`8. Regulatory affairs
`
`9. Expert opinion
`
`For reprint orders, please
`contact:
`reprints@ashley-pub.com
`
`Ashley Publications
`www.ashley-pub.com
`
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`Esomeprazole
`
`in patients using NSAIDs [7], and for maintenance of heal-
`ing of erosive oesophagitis [8,9]. Empiric PPI therapy is a
`practical method for diagnosing and treating patients with
`suspected GERD [10,11].
`Most patients with GERD will require long-term manage-
`ment of their condition. There are two approaches to initial
`treatment of acid-related disorders. One approach involves
`starting treatment with the optimal dosage of the most effec-
`tive agent, a PPI and ‘stepping down’ to a lower PPI dose or a
`less efficacious agent. The speed of symptom control in
`GERD patients with moderate or severe disease treated with
`initial PPI therapy provides both a diagnostic and therapeutic
`advantage that may ultimately result in lower direct costs [12].
`Moreover, the safety, efficacy and cost-effectiveness of PPIs
`have made them the drug of choice in the long-term manage-
`ment of acid-related disorders [13,14]. Treatment with PPIs is
`associated with higher levels of patient satisfaction than treat-
`ment with H2-receptor antagonists. The other approach
`involves starting treatment with minimum intervention and
`‘stepping up’ to therapy with agents that have demonstrated
`more effectiveness. This option may result in initial treatment
`failure, resulting in additional office visits, prolongation of
`unnecessary episodes of discomforting heartburn, potential for
`disease progression and decreased quality of life (QoL) [15,16].
`Although PPIs provide rapid and effective symptom con-
`trol in patients with GERD, there is still room for improve-
`ment. In one survey published before esomeprazole was
`available, 42% of patients with heartburn treated with PPIs
`and 54% treated with H2-receptor antagonists were not
`totally satisfied with the results [17], indicating that more effec-
`tive pharmacotherapy was required. Omeprazole (Prilosec™,
`AstraZeneca),
`lansoprazole
`(Prevacid™, Takeda/TAP),
`pantoprazole
`(Protonix™, Atlanta/Wyeth),
`rabeprazole
`(AcipHex™, Eisai/Janssen), and esomeprazole (Nexium™,
`AstraZeneca) are the currently available PPIs. Esomeprazole is
`the most recent introduction into the PPI class.
`
`2. Introduction to esomeprazole
`
`The H+/K+-ATPase enzyme or ‘proton pump,’ is the final
`common pathway for gastric acid secretion in the stomach.
`Decreased secretion of hydrochloric acid by gastric parietal
`cells through inhibition of H+/K+-ATPase was first demon-
`strated for pyridylmethyl benzimidazole sulfides in the early
`1970s. Subsequent modification of these agents to sulfoxides
`led to omeprazole, the first compound of this group to be
`used clinically for the management of disease associated with
`excessive gastric acid secretion and activity [18]. A number of
`substituted benzimidazole PPIs have since been developed,
`including
`lansoprazole, pantoprazole and rabeprazole.
`Esomeprazole, the (S)-isomer of omeprazole, is the first pro-
`ton pump inhibitor to be developed as an optical isomer.
`Esomeprazole is optically stable in humans, with little
`inversion to the (R)-isomer [19], and was developed to
`improve the pharmacokinetic properties and acid-suppression
`
`characteristics of omeprazole. Systemic clearance is slower
`with the (S)-isomer (esomeprazole) than with the (R)-isomer
`or racemic omeprazole, resulting in a higher area under the
`plasma drug concentration versus time curve (AUC) with
`esomeprazole. The good correlation between AUC and acid
`suppression with esomeprazole [20] has translated into more
`effective symptom control and higher healing rates than
`with previously developed PPIs in three well-designed
`clinical trials [21-23].
`
`3. Chemistry
`
`The chemical name of esomeprazole is bis(5-methoxy-2-
`[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-
`1H-benzimidazole-1-yl) magnesium trihydrate. It has an
`empirical formula of (C17H18N3O3S)2Mg·3H2O and a
`molecular weight of 767.2 as the trihydrate or 713.1 as the
`anhydrous form [24]. The structural formula of esomeprazole
`is shown in Figure 1. The magnesium salt of esomeprazole is
`a white to slightly coloured crystalline powder that is slightly
`soluble in water. Without an enteric coating, esomeprazole
`magnesium rapidly degrades in acidic media, but has accept-
`able stability under alkaline conditions. In vitro studies have
`demonstrated that at a buffered pH of 6.8, the half-life of
`the magnesium salt is ∼ 19 h at 25°C and ∼ 8 h at 37°C. In
`the US, esomeprazole is available as delayed-release capsules
`for oral administration, each capsule containing 20 or
`40 mg of esomeprazole in enteric-coated pellets. The pellets
`also contain glyceryl monostearate 40-50, hydroxypropyl
`cellulose, hydroxypropyl methylcellulose, magnesium stear-
`ate, methacrylic acid copolymer type C, polysorbate 80,
`sugar spheres, talc and triethyl citrate, as inactive ingredi-
`ents. The capsule shells contain gelatin, FD&C Blue #1,
`FD&C Red #40, D&C Red #28, titanium oxide, shellac,
`ethyl alcohol, isopropyl alcohol, n-butyl alcohol, propylene
`glycol, sodium hydroxide, polyvinyl pyrrolidone and D&C
`Yellow #10 [24].
`Outside of the US, esomeprazole is supplied as a 20 mg or
`40 mg dispersible tablet (multiple unit pellet system [MUPS]).
`
`4. Mechanism of action, pharmacokinetics and
`metabolism
`
`4.1 Mechanism of action
`Esomeprazole is a potent inhibitor of the final common
`pathway for gastric acid secretion by gastric parietal cells. A
`weak base, esomeprazole concentrates in the acidic compart-
`ment of the secretory canaliculus of the parietal cells where
`it undergoes an acid-catalysed transformation to a tetracyclic
`achiral cationic
`sulfenamide
`[24].
`Inhibition of
`the
`H+/K+-ATPase enzyme occurs when the sulfenamide reacts
`with specific cysteines, blocking the final step in acid pro-
`duction and leading to adose-dependent reduction of gastric
`acid secretion. The binding of esomeprazole to the proton
`pump is covalent and irreversible [25,26].
`
`254
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`Johnson
`
`15 – 20% of Asians) do not express a functional form of
`CYP2C19 and are classified as ‘poor metabolisers.’ Dosage
`reductions are not considered necessary for such individuals
`because bio-equivalence data for esomeprazole indicate less
`than a twofold difference in AUC values between poor
`metabolisers and the rest of the population [18,24]. Following
`a single oral dose of rabeprazole, extensive metabolisers had
`a lower rabeprazole plasma concentration 3 – 4 h postdose,
`and less time above prespecified intragastric pH thresholds
`compared with poor metabolisers [33], indicating a possible
`need for higher doses of rabeprazole in these patients. A
`more recent study that evaluated intragastric pH following
`multiple doses of rabeprazole, omeprazole and lansoprazole
`in extensive metabolisers suggested that multiple dosing
`may ameliorate this effect [34]. With esomeprazole, there is
`less interindividual variability in AUC (versus omeprazole)
`in both extensive and poor metabolisers [28]. This property
`provided another reason for the clinical development of
`esomeprazole (P Lundberg, pers. comm., September 2002).
`Esomeprazole capsules or MUPS should be swallowed
`whole, not chewed or crushed, once-daily, at least 1 h before
`meals
`[24]. Bioequivalence has been demonstrated for
`esomeprazole when administered either as an intact capsule
`or when the enteric-coated pellets from an opened capsule
`are mixed with one tablespoon of apple sauce and swallowed
`immediately [35]. This is advantageous for patients who have
`difficulty swallowing capsules. In addition, in vitro stability
`has been demonstrated for esomeprazole pellets suspended
`for 30 min in tap water, orange juice, apple juice, cultured
`(soured) milk or yoghurt [36]. An opened capsule of
`esomeprazole 40 mg suspended in water is also suitable for
`administration via a syringe into a nasogastric tube, yielding
`a bioavailability similar to that of oral administration of the
`intact 40 mg capsule [37]. This mode of delivery can be used
`with standard or small calibre nasogastric tubes or
`gastrostomy tubes [38].
`
`4.3 Patients with GERD
`Pharmacokinetic data from a double-blind, randomised,
`three-way crossover study in 36 patients with symptoms of
`GERD indicated that the pharmacokinetic profile of esome-
`prazole in patients with GERD is similar to that in healthy
`volunteers [39]. Patients were treated with oral esomeprazole
`20 or 40 mg or omeprazole 20 mg o.d. for 5 days, with each
`treatment period separated by a washout period of at least
`2 weeks. On day 5, Cmax for both of the esomeprazole dos-
`ages was higher than that of omeprazole, although the Tmax
`was similar (a median of ∼ 1 h in each treatment group).
`Although the Cmax appeared to increase proportionally with
`the dose of esomeprazole, there was a disproportionate
`increase in AUC. Notably, the geometric mean AUC for
`esomeprazole 20 and 40 mg was approximately twofold and
`over fivefold higher, respectively, compared with that for
`omeprazole 20 mg o.d. (Table 1). Interpatient variability in
`AUC was lower with esomeprazole than with omeprazole [39].
`
`O
`
`O
`
`S
`
`NH
`
`N
`
`O
`
`Figure 1. Chemical structure of esomeprazole.
`
`4.2 Data in healthy volunteers
`Esomeprazole is rapidly absorbed after oral administration.
`Peak concentration in plasma (Cmax) is reached within
`1 – 3.5 h after ingestion of 40 mg as enteric-coated pellets
`encapsulated in a hard gelatin capsule [27]. Dose-related
`increases in systemic exposure to esomeprazole occur after sin-
`gle doses, as demonstrated by AUC values. Of interest,
`repeated administration results in increased systemic exposure
`to esomeprazole. In two analyses involving a total of
`32 healthy volunteers treated with a solution of esomeprazole
`20 mg o.d., the mean AUC∞ on day 5 of dosing increased by
`90% and Cmax by 43% relative to day 1. Mean systemic bioa-
`vailability also increased, from 50 to 68% [27]. In the same
`study, systemic bioavailability of the esomeprazole capsule
`40 mg o.d. increased with repeated once-daily dosing from
`64% on day 1 to 89% on day 5, while C max increased by 95%
`and AUC∞ by 159% over the same period [27].
`Decreased first-pass metabolism and reductions in sys-
`temic clearance appear to be responsible for the increase in
`systemic exposure with esomeprazole. The mean AUC for
`the once-daily esomeprazole 20 mg capsule was 67% higher
`than that for omeprazole 20 mg at steady-state [20]. Esome-
`prazole is 97% bound to plasma proteins, which is similar
`to omeprazole and other PPIs [13,24,28-31]. Esomeprazole is
`extensively metabolised in the liver by the cytochrome
`P450 (CYP450) enzyme system to metabolites lacking
`antisecretory activity [32]. Of an oral dose administered as
`an aqueous solution ∼ 80% is excreted as inactive metabo-
`lites and < 1% as active drug in the urine, with the balance
`eliminated as metabolites in the faeces [24,28]. Both optical
`isomers of omeprazole are converted primarily to hydroxy
`and 5-O-desmethyl metabolites by the CYP2C19 isoen-
`zyme and to the sulfone metabolite by CYP3A4 [32]. How-
`in vitro
`ever,
`studies
`indicate
`that
`the affinity of
`esomeprazole for the CYP2C19 isoenzyme is approximately
`tenfold that for CYP3A4. The rate of formation of the
`hydroxy metabolite is lower with esomeprazole and that of
`the sulfone and 5-O-desmethyl metabolites is higher, com-
`pared with (R)-omeprazole. The sum of the intrinsic clear-
`ance values for in vitro formation of the three major
`metabolites of (R)-omeprazole is three times that of the
`(S)-isomer, which predicts that esomeprazole would be
`cleared more slowly and would result in higher plasma con-
`centrations – and greater systemic exposure – than racemic
`omeprazole [32]. Indeed, clinical studies confirmed this pos-
`tulate. A proportion of the population (∼ 3% of whites and
`
`Expert Opin. Pharmacother. (2003) 4(2)
`
`255
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`IPR2017-01995
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`Esomeprazole
`
`Table 1. Pharmacokinetic variables on day 5 of once-daily esomeprazole or omeprazole in patients with symptoms of
`GERD (adapted with permission from [39]).
`
`Variable
`
`Treatment group
`
`Esomeprazole 20 mg
`
`Esomeprazole 40 mg
`
`Omeprazole 20 mg
`
`Geometric mean AUC (µmol/h/l)
`2.34
`12.64*
`4.18*
`Median Cmax (µmol/l)
`1.41
`5.13
`2.42
`Median T½λz (h)
`1.0
`1.6
`1.3
`1.0
`1.2
`1.0
`Median Tmax (h)
`0.73
`0.47
`0.64
`Interpatient variability in AUC
`AUC: Area under the curve of plasma drug concentration versus time; Cmax: Peak drug concentration in plasma; Interpatient variability in AUC: Standard deviation
`based on log-transformed values; T½λz: Plasma terminal elimination half-life; Tmax: Time to Cmax.
`*Significantly different versus omeprazole 20 mg, p < 0.0001.
`
`4.4 Special populations
`An understanding of the pharmacokinetics of this agent in
`patients with impaired hepatic function is important because
`esomeprazole is extensively metabolised by the liver. Mild or
`moderate hepatic impairment did not substantially alter the
`pharmacokinetic profile of esomeprazole 40 mg o.d. for
`5 days in patients with cirrhosis of the liver [40]. In patients
`with severe disease (Child–Pugh class C), AUC values were
`∼ 2 – 3 times higher than in a control group of 36 patients
`with symptomatic GERD and normal hepatic function.
`Esomeprazole dosage adjustment is not necessary for patients
`with Child–Pugh class A or B hepatic insufficiency [40], but a
`maximum esomeprazole dose of 20 mg o.d. is recommended
`in patients with Child–Pugh class C hepatic insufficiency [24].
`As < 1% of esomeprazole is excreted unchanged in the urine,
`the pharmacokinetic profile of esomeprazole in patients with
`renal impairment is unlikely to be altered relative to those in
`healthy volunteers [24].
`
`5. Pharmacodynamics
`
`5.1 Antisecretory activity
`Maintenance of intragastric pH > 4 is critical to ensure symp-
`tom control and healing in patients with GERD [41].
`Esomeprazole 40 mg, the recommended healing dose, sup-
`presses intragastric acidity more effectively than the standard
`healing doses of rabeprazole (20 mg), lansoprazole (30 mg),
`pantoprazole (40 mg) or omeprazole (20 mg) when adminis-
`tered for 1 or 5 days (Table 2) [42-45]. The pharmacodynamic
`studies that compared esomeprazole with omeprazole, listed in
`Table 1, were conducted in healthy volunteers [44,46,47] or in
`patients with symptoms of GERD [39,42,44,45].
`Esomeprazole 40 mg provided significantly faster suppres-
`sion of gastric acid secretion than rabeprazole and lansoprazole
`in two comparative controlled investigations. In one study, the
`proportion of time with pH > 4 in the first 4 h after dosing on
`day 1 was 23.2% for esomeprazole 40 mg versus 11.0% for rab-
`eprazole 20 mg (p = 0.006) [43]. In the other study, the propor-
`tion of time with pH > 4 in the first 24 h after dosing on day 1
`
`was 40.6 versus 33.4% in esomeprazole 40 mg and lansoprazole
`30 mg recipients, respectively (p = 0.0182) [48].
`The pharmacodynamic effects of esomeprazole relative to
`other PPIs are strongly related to its pharmacokinetic proper-
`ties. The higher AUC values for esomeprazole lead to
`increased drug delivery at the canalicular lumen and thus
`more pronounced inhibition of acid secretion, as demon-
`strated in the combined pharmacokinetic and pharmacody-
`namic studies by Lind et al. (Tables 1 and 2) [39].
`
`5.2 Other pharmacodynamic effects
`Chronic PPI use causes an increase in serum gastrin concen-
`trations. The effect of esomeprazole on fasting serum gastrin
`levels was evaluated in a number of clinical trials lasting
`between 6 and 12 months [8,9,49]. The mean fasting gastrin
`level increased in the early weeks of treatment with esomepra-
`zole in a dose-dependent fashion, then reached a plateau after
`2 – 3 months of therapy. Serum gastrin levels decreased to
`baseline values within 4 weeks of discontinuation of therapy.
`In a study of 808 patients with erosive oesophagitis who
`received 12 months of maintenance treatment with esomepra-
`zole 40 mg (twice the recommended dose), mean gastrin lev-
`els increased from baseline by 21.6 – 80.9 ng/l, with
`considerable intraindividual variability [49].
`In rats, dose-related morphologic changes in the gastric
`mucosa, including enterochromaffin-like (ECL) cell hyperpla-
`sia and carcinoid tumours, have been observed in 24-month
`carcinogenicity studies of omeprazole [24]. In humans, the
`incidence of ECL cell hyperplasia increased with time in gas-
`tric biopsy specimens obtained from > 3000 patients receiving
`long-term omeprazole therapy [50]. However, neither ECL
`dysplasia nor carcinoid tumours of the gastric mucosa were
`observed in patients treated with omeprazole, nor did they
`occur in > 800 patients treated with esomeprazole 40 mg o.d.
`for ≤ 12 months [49].
`Esomeprazole given orally at doses of 20 or 40 mg for 4 weeks
`has no apparent effect on thyroid function and, based on ome-
`prazole studies, esomeprazole is expected to have no effect on car-
`bohydrate metabolism or circulating levels of parathyroid
`
`256
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`
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`Table 2. Comparison of the effect of esomeprazole and other proton pump inhibitors on suppression of intragastric acidity
`in healthy volunteers or patients with symptoms of gastro-oesophageal reflux disease. (Adapted with permission from [18]).
`
`Study
`
`No. and characteristics
`of evaluable patients
`
`Treatment
`regimen
`
`Mean percentage of
`24-h period with pH > 4
`
`Mean 24-h
`median pH
`
`Percentage of patients
`with pH > 4
`for ≥ 12 h for ≥ 16 h
`
`Ref.
`
`Johnson
`
`Comparisons with omeprazole
`Lind et al.
`36 patients with GERD
`
`Esomeprazole
`40 mg
`Esomeprazole
`20 mg
`Omeprazole
`20 mg
`115 patients with GERD Esomeprazole
`40 mg
`
`Röhss et al.
`
`69.8* (day 5)
`
`4.9‡ (day 5)
`
`92 (day 5)
`
`56 (day 5)
`
`[39]
`
`53.0‡ (day 5)
`
`4.1*(day 5)
`
`54 (day 5)
`
`24 (day 5)
`
`43.7 (day 5)
`
`3.6 (day 5)
`
`44 (day 5)
`
`14 (day 5)
`
`48.6** (day 1)
`68.4** (day 5)
`
`50¶ (day 1)
`88¶ (day 5)
`
`16 (day 1)
`55§ (day 5)
`
`[45]
`
`Comparisons with lansoprazole
`Thomson
`48 healthy volunteers
`et al.
`
`Wilder-Smith
`et al.
`
`27 healthy volunteers
`
`Comparison with pantoprazole
`Wilder-Smith
`31 patients with GERD
`et al.
`
`Omeprazole
`40 mg
`
`40.6 (day 1)
`62.0 (day 5)
`
`Esomeprazole
`40 mg
`Lansoprazole
`30 mg
`Esomeprazole
`20 mg
`Lansoprazole
`15 mg
`
`57.2¶ (day 1)
`65.4** (day 5)
`51.8 (day 1)
`53 (day 5)
`50.4§ (day 5)
`
`43.0 (day 5)
`
`Esomeprazole
`40 mg
`Pantoprazole
`40 mg
`
`50** (day 1)
`66** (day 5)
`29 (day 1)
`44 (day 5)
`
`3.86**
`(day 1)
`4.78**
`(day 5)
`3.41 (day 1)
`4.50 (day 5)
`
`NR
`
`NR
`
`NR
`
`NR
`
`34 (day 1)
`75 (day 5)
`
`10 (day 1)
`44 (day 5)
`
`71 (day 1)
`90 (day 5)
`61 (day 1)
`55 (day 5)
`50 (day 5)
`
`36 (day 1)
`35 (day 5)
`21 (day 1)
`5 (day 5)
`23 (day 5)
`
`35 (day 5)
`
`15 (day 5)
`
`3.9** (day 1)
`4.7** (day 5)
`2.9 (day 1)
`3.7 (day 5)
`
`39 (day 1)
`90 (day 5)
`10 (day 1)
`30 (day 5)
`
`26 (day 1)
`50 (day 5)
`3 (day 1)
`10 (day 5)
`
`[44]
`
`[46]
`
`[42]
`
`Comparisons with rabeprazole
`Wilder-Smith
`23 healthy volunteers
`et al.
`
`Wilder-Smith
`et al.
`
`35 patients with GERD
`
`Esomeprazole
`40 mg
`Rabeprazole
`20 mg
`41.5¶ (day 1)
`Esomeprazole
`3.4¶ (day 1)
`40 mg
`4.4** (day 5)
`59.4** (day 5)
`2.7 (day 1)
`29.4 (day 1)
`Rabeprazole
`3.5 (day 5)
`44.5 (day 5)
`20 mg
`All drugs were given orally once-daily for 5 days. ∗Significantly different versus OMP and ESO 20 mg, p < 0.001; ‡ Significantly different versus OMP, p < 0.01;
`§ Significantly different versus comparators, p < 0.05; ¶ Significantly different versus comparators, p < 0.01; ** Significantly different versus comparators, p < 0.001.
`ESO: Esomeprazole; GERD: Gastro-oesophageal reflux disease; NR: Not reported; OMP: Omeprazole.
`
`61¶ (day 5)
`
`45.1 (day 5)
`
`NR
`
`NR
`
`77 (day 5)
`
`32 (day 5)
`
`[47]
`
`36 (day 5)
`
`5 (day 5)
`
`NR
`
`NR
`
`NR
`
`NR
`
`[43]
`
`hormone, cortisol, estradiol, testosterone, prolactin, cholecystoki-
`nin or secretin [24].
`
`6. Clinical efficacy
`
`The clinical efficacy of esomeprazole has been studied for
`the acute treatment of GERD with and without erosive
`
`oesophagitis, as well as for maintenance of healed erosive
`oesophagitis. The efficacy of esomeprazole in the acute and
`long-term management of erosive oesophagitis has been
`compared with that of other proton pump inhibitors
`[21-23,51]. Studies aimed at eradication of H. pylori using tri-
`ple therapy involving esomeprazole in combination with
`amoxicillin and clarithromycin have also been completed
`
`Expert Opin. Pharmacother. (2003) 4(2)
`
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`
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`

`

`*
`
`‡
`
`*
`
`*
`
`Esomeprazole 40 mg
`
`Esomeprazole 20 mg
`
`Omeprazole 20 mg
`
`Lansoprazole 30 mg
`
`Esomeprazole
`
`96
`
`94
`
`92
`
`90
`
`88
`
`86
`
`84
`
`82
`
`80
`
`78
`
`Percentage of patients with healing
`
`Kahrilas et al.
`
`Richter et al.
`
`Castell et al.
`
`Study
`
`Figure 2. Life-table estimated healing rates in patients with endoscopically confirmed healing of oesophagitis during
`randomised double-blind, multi-centre, 8-week trials evaluating the efficacy of esomeprazole 20 or 40 mg compared with
`omeprazole 20 mg or lansoprazole 30 mg [21-23].
`*p < 0.001 versus omeprazole 20 mg or lansoprazole 30 mg. ‡p < 0.05 versus omeprazole 20 mg.
`
`[52-54]. Unless otherwise specified, reported data are for
`intention-to-treat groups.
`
`6.1 Gastro-oesophageal reflux disease
`6.1.1 Healing erosive oesophagitis
`Oesophagitis was healed more rapidly and effectively with ther-
`apeutic doses of esomeprazole than with omeprazole [22,23] or
`lansoprazole [21] in patients with GERD enrolled in three large,
`double-blind, multi-centre trials (Figure 2). Patients with endo-
`scopically proven erosive oesophagitis were treated with esome-
`prazole 20 or 40 mg, lansoprazole 30 mg or omeprazole 20 mg
`o.d. for 4 – 8 weeks. In two studies comparing esomeprazole
`with omeprazole, esomeprazole 40 mg (n = 1870) produced a
`healing rate (based on life table estimates) of 94% compared
`with 84.2 – 86.9% with omeprazole 20 mg (n = 1859;
`p < 0.001) [22,23]. An evidence-based analysis of pooled data
`from these two studies found that one treatment failure could
`be prevented for every 11 patients treated with esomeprazole
`40 mg daily compared with omeprazole 20 mg (number
`needed to treat [NNT] = 11) [55]. In two other trials that evalu-
`ated healing rates after ≤ 8 weeks of esomeprazole (20 or
`40 mg) compared with omeprazole 20 mg, healing rates with
`esomeprazole were consistently > 90%, although the differences
`between the two agents did not reach statistical significance [24].
`In another large, well-designed, randomised trial, the week 8
`healing rates based on life-table estimates were 92.6 and 88.8%
`for esomeprazole 40 mg (n = 2624) and lansoprazole 30 mg
`(n = 2617), respectively (p = 0.0001) [21]. In three primary
`
`trials, esomeprazole produced consistently high healing rates
`across all baseline grades of oesophagitis (assessed using the Los
`Angeles Classification system), whereas the efficacy of omepra-
`zole and that of lansoprazole relative to esomeprazole deterio-
`rated with worsening severity of baseline disease (esomeprazole
`and lansoprazole data shown in Figure 3) [21-23]. A pooled anal-
`ysis of data from patients participating in trials in which they
`received esomeprazole 20 or 40 mg or omeprazole 20 mg o.d.
`confirmed that, in contrast to omeprazole, the severity of base-
`line erosive oesophagitis did not significantly affect healing
`rates with esomeprazole [56].
`Secondary end points from these three primary studies showed
`that esomeprazole 40 mg resolved heartburn in the majority of
`patients with erosive oesophagitis and that esomeprazole 40 mg
`was significantly more effective than omeprazole and lansopra-
`zole in this regard (Table 3) [21-23]. At 4 weeks, resolution of
`heartburn, defined as no heartburn on a 4-point symptom sever-
`ity scale over 7 days, occurred in 64.7 – 68.3% of patients receiv-
`ing esomeprazole 40 mg compared with 57.2 – 58.1% of those
`receiving omeprazole 20 mg (p < 0.05 to < 0.001) [22,23]. Simi-
`larly, heartburn had completely resolved at 4 weeks in signifi-
`cantly more patients treated with esomeprazole than in those
`receiving lansoprazole (62.9 versus 60.2%, respectively; p < 0.05)
`[21]. Heartburn symptoms resolved significantly earlier with
`esomeprazole 40 mg than with either omeprazole 20 mg or lan-
`soprazole 30 mg [21,23]. Sustained resolution of heartburn
`occurred in a median of 5 days with esomeprazole versus 8 days
`with omeprazole (p ≤ 0.0005) [57].
`
`258
`
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`
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`IPR2017-01995
`
`

`

`Johnson
`
`Esomeprazole 40 mg
`
`Lansoprazole 30 mg
`
`A
`
`B
`
`C
`
`D
`
`Los Angeles grade of erosive oesophagitis
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`Percentage of patients healed at week 8
`
`Figure 3. Estimated healing rates of erosive oesophagitis by baseline Los Angeles classification following treatment for
`≤ 8 weeks with either esomeprazole 40 mg or lansoprazole 30 mg [21].
`
`Table 3. Secondary (heartburn) efficacy end points after 4 weeks of treatment with esomeprazole 40 mg, omeprazole
`20 mg or lansoprazole 30 mg during randomised, double-blind, multi-centre trials [21-23].
`
`Study
`
`Treatment
`
`Median time
`to sustained
`resolution*
`(days)
`
`Sustained
`resolution* at
`week 4
`(% patients)
`
`% Heartburn-free
`days at week 4
`
`% Heartburn-free
`nights at week 4
`
`Kahrilas et al. 2000
`
`Richter et al. 2001
`
`Castell et al. 2001
`
`84.7‡
`72.7§
`64.7§
`5‡
`Esomeprazole 40 mg
`80.1
`67.1
`57.2
`9
`Omeprazole 20 mg
`90.8‡
`74.9‡
`68.3‡
`5‡
`Esomeprazole 40 mg
`87.9
`69.7
`58.1
`8
`Omeprazole 20 mg
`7§
`Esomeprazole 40 mg
`87.1§
`72.5
`62.9§
`85.8
`70.9
`60.2
`8
`Lansoprazole 30 mg
`*Defined as seven consecutive days without heartburn on a 4-point severity scale. ‡p ≤ 0.001 versus omeprazole 20 mg or lansoprazole 30 mg.§p < 0.05 versus
`omeprazole 20 mg or lansoprazole 30 mg.
`
`Resolution of heartburn occurred concurrently with heal-
`ing of oesophagitis in the majority of patients treated with
`esomeprazole [21-23], suggesting that resolution of heartburn
`could be used as a marker for healing. Furthermore, analysis
`of pooled data showed that 83.4% of patients who had no
`heartburn symptoms were healed after treatment with esome-
`prazole 40 mg compared with 75.4% of those treated with
`omeprazole (p < 0.001) [58].
`During the 8-week, open-label phase of a trial, in which
`patients with endoscopically confirmed oesophagitis received
`treatment with esomeprazole 40 mg o.d., patients’ QoL was
`substantially improved [59]. At baseline, 80% of patients had
`impairment in at least one QoL dimension because of GERD,
`as assessed with the QoL in reflux and dyspepsia (QOLRAD)
`questionnaire. After treatment with esomeprazole, only
`1 – 6% of patients had GERD-induced impairment of QoL.
`
`6.1.2 Maintaining healing of erosive oesophagitis
`Treatment with esomeprazole 10, 20 or 40 mg o.d. was effec-
`tive in maintaining healing of oesophagitis in a dose-depend-
`ent manner in two 6-month, randomised, double-blind,
`placebo-controlled trials (Figure 4) [8,9]. Patients enrolled in
`these trials (n = 693, combined) had endoscopically con-
`firmed healing of erosive oesophagitis following treatment
`with esomeprazole or omeprazole in 8-week acute healing
`trials and were subsequently enrolled in either of the two
`maintenance trials. The mean duration of remission among
`patients in whom erosive oesophagitis recurred was longer
`among those receiving esomeprazole relative to those treated
`with placebo (40 mg: 163 days; 20 mg 115 days; 10 mg:
`78 days; placebo: 34 days) [8]. At 1 month, heartburn was
`absent or mild in a significantly higher proportion of patients
`treated with esomeprazole than placebo (Figure 5) [8,9].
`
`Expert Opin. Pharmacother. (2003) 4(2)
`
`259
`
`Page 8 of 13
`
`Patent Owner Ex. 2056
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`*
`
`*
`
`*
`
`*
`
`Placebo
`
`Esomeprazole 10 mg
`
`Esomeprazole 20 mg
`
`Esomeprazole 40 mg
`
`*
`
`*
`
`Esomeprazole
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Percentage of patients
`
`Johnson et al. (2001)
`
`Vakil et al. (2001)
`
`Figure 4. Percentage of patients in whom healed erosive oesophagitis was maintained after 6 months of therapy with
`esomeprazole 10, 20 or 40 mg in randomised, double-blind, placebo-controlled trials [8,9].
`*p < 0.001 versus placebo.
`
`*
`
`*
`
`*
`
`*
`
`*
`