ORIGINAL ARTICLES ALIMENTARY TRACT. A Randomized, Comparative Study of Three Doses of AZD0865 and Esomeprazole for Healing of Reflux Esophagitis

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2007;5:1385 1391 ORIGINAL ARTICLES ALIMENTARY TRACT A Randomized, Comparative Study of Three Doses of AZD0865 and Esomeprazole for Healing of Reflux Esophagitis PETER J. KAHRILAS,* JOHN DENT, KARSTEN LAURITSEN, PETER MALFERTHEINER, HANS DENISON, STEFAN FRANZÉN, and GORAN HASSELGREN *Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Department of Gastroenterology, Hepatology and General Medicine, Royal Adelaide Hospital, Adelaide, Australia; Department of Gastroenterology, Odense Hospital, Odense, Denmark; Klinik für Gastroenterologie, Hepatologie und Infektiologie, Otto-von-Guericke-Universität Magdeburg, Magdeburg, Germany; and AstraZeneca Research & Development, Mölndal, Sweden Background & Aims: AZD0865 belongs to a new class of acid-suppressing agents with rapid onset of action and potent acid inhibition. We evaluated its effectiveness for healing reflux esophagitis. Methods: One thousand five hundred twenty-one patients with Los Angeles A-D esophagitis and heartburn of moderate or severe intensity for >4 days/week were randomized to AZD0865 25, 50, or 75 mg or esomeprazole 40 mg once daily for 4 8 weeks. The primary end point was esophagitis healing by AZD0865 at 4 weeks. Healing and control of heartburn were also assessed at 2, 4, and 8 weeks for AZD0865 and esomeprazole. Results: After 4 weeks of treatment, healing rates were similar among AZD0865 doses (76.9%; confidence interval [CI], 72.4% 81.1%); 78.2% (CI, 73.7% 82.3%), and 81.1% (CI, 76.7% 84.9%) for 25, 50, and 75 mg, respectively). The healing rate with esomeprazole at 4 weeks was similar (81.9%; CI, 77.6% 88.7%), and healing rates also were comparable among all treatments at 2 and 8 weeks. There were no significant differences in heartburn control among treatments. AZD0865 and esomeprazole were well-tolerated, although reversible increases in transaminases occurred in a small number of patients receiving AZD0865, especially at the 75-mg dose. Conclusions: AZD0865 25, 50, and 75 mg provided similar efficacy to esomeprazole 40 mg in terms of esophagitis healing and heartburn control. These findings suggest that increasing the degree of acid inhibition beyond that already achieved by esomeprazole 40 mg (or AZD0865 25 mg) does not translate into increased clinical efficacy in esophagitis patients. AZD0865 (8-[(2,6-dimethylbenzyl) amino]-n-(2-hydroxyethyl)- 2,3-dimethylimidazo [1,2-a]pyridine-6-carboxamide) is an acid-suppressing agent with a mechanism of action distinct from that of the proton pump inhibitors (PPIs). 1 It is a weak lipophilic base that concentrates in the highly acidic parietal cell canaliculus. Unlike PPIs, which bind covalently to cysteine residues in gastric H, K -adenosine triphosphatase, AZD0865 inhibits gastric H,K -adenosine triphosphatase by potassium-competitive binding at or near the potassium binding site of the enzyme. 2 4 In preclinical studies, AZD0865 has demonstrated a rapid onset of nearly complete inhibition of acid secretion, a long duration of effect, and a consistent effect on repeated dosing. 5 8 After single doses of AZD0865 (0.5 1.0 mg/kg) in healthy subjects, almost complete inhibition of acid production occurred within 1 hour of dosing and continued for the duration of the observation period (15 hours) with doses of 0.8 mg/kg and above. 9 On the basis of these phase I pharmacodynamic data it was hypothesized that in patients with reflux disease, treatment with AZD0865 could produce faster healing of esophagitis and faster, more effective symptom control than is achievable with current therapies. The majority of reflux esophagitis trials of PPIs have assessed healing rates at 4 or 8 weeks of treatment, with only limited data available on healing rates at earlier time points (eg, Castell et al 10 ). Consistent with this, the primary objective of the present study was to compare the reflux esophagitis healing rates of 3 different oral doses of AZD0865 at 4 weeks. However, to evaluate the potential for AZD0865 to facilitate faster healing, the current study assessed healing at 2 weeks in addition to the primary study end point of 4-week healing. Other secondary objectives of this phase II study included evaluation of the comparative efficacy of AZD0865 25, 50, or 75 mg and esomeprazole 40 mg in healing esophagitis at 2, 4, and 8 weeks, comparison of gastroesophageal reflux disease (GERD) symptom control between doses of AZD0865 and esomeprazole, and assessment of the safety and tolerability of AZD0865. Materials and Methods Patients Men and women aged 18 70 years with reflux symptoms and Los Angeles (LA) A D reflux esophagitis 11 were eligible for the study. Reflux esophagitis was categorized at the baseline endoscopy. Patients were required to have a minimum 6-month history of heartburn, defined as a burning feeling behind the breastbone, as their main GERD symptom. They also had to experience at least 4 days with episodes of heartburn of at least moderate intensity (ie, discomfort sufficient to cause interference with normal activities) during the 7 days before randomization. Abbreviations used in this paper: CI, confidence interval; GERD, gastroesophageal reflux disease; IBS, irritable bowel syndrome; LA, Los Angeles; PPI, proton pump inhibitor; ULN, upper limit of normal. 2007 by the AGA Institute 1542-3565/07/$32.00 doi:10.1016/j.cgh.2007.08.014

1386 KAHRILAS ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 5, No. 12 Exclusion criteria included current or historical evidence of esophageal stricture; primary esophageal motility disorder; systemic sclerosis; irritable bowel syndrome (IBS) (upper abdominal discomfort or pain that in the opinion of the investigator is likely to be due to IBS or fulfilling 2 or more of the criteria: relieved by defecation, associated with change in frequency of stools, associated with change in appearance of stools); inflammatory bowel disease; Zollinger-Ellison syndrome; gastric ulcer, duodenal ulcer, or duodenal erosions within the last 3 months. Subjects were also excluded if they had abnormalities of serum chemistry or blood count at the discretion of the site investigator, significant alarm symptoms, or a history of drug or alcohol abuse. There was no specified limit for any safety lab variable. However, an intensive monitoring program with repeat testing every third day had to be applied in patients with ALT, AST, or alkaline phosphatase 3 upper limit of normal (ULN) or bilirubin 1.5 ULN, which set the exclusion limit somewhat lower in practical terms. A clinical judgment rather than exact limit was considered appropriate because the clinical significance of abnormal lab tests must be evaluated individually for each patient. Other exclusion criteria included a history of heartburn that was not at least partially relieved within 2 weeks of treatment with PPIs or histamine 2 receptor antagonists and known or suspected hypersensitivity to PPIs or AZD0865. Concomitant therapy with other acid-suppressive therapy, gastroprotective agents, drugs that could alter AZD0865 pharmacokinetics (eg, CYP3A4 inducers or inhibitors), NSAIDs, bisphosphonates, or antineoplastic drugs was not permitted during the study. Patients who used a PPI or had continuous histamine 2 receptor antagonist treatment within the last 14 days of endoscopy and/or between endoscopy and the first dose of study drug were also excluded. Baseline assessment included Helicobacter pylori serology that was analyzed by a central laboratory, but a positive serology was not an exclusion criterion. Study Design This was a randomized, 4-arm parallel group, doubleblind, double-dummy, multicenter clinical study (Study no D9770C00012; ClinicalTrials.gov identifier: NCT00206245) to investigate the optimal dose, efficacy, and safety of treatment with AZD0865. The study was designed and performed according to the Declaration of Helsinki, International Conference on Harmonization guidelines and local ethics committee approval in participating countries. Written informed consent was required from all participants before study enrollment. The study was conducted in 188 centers in the USA, Canada, France, Germany, Norway, United Kingdom, Finland, Italy, Sweden, and Denmark between May 2004 March 2005. At an initial screening visit, patients rated the frequency and intensity of their GERD symptoms on a graded scale (none; mild: awareness of symptoms but easily tolerated; moderate: discomfort sufficient to cause interference with normal activities; severe: incapacitating, with inability to perform normal activities). The grading scale was taken from a previously validated reflux disease questionnaire. 12 The rating of symptom frequency and intensity was made by patients with a site-based computer and was done independently of investigators. Patients who met the eligibility criteria underwent endoscopy according to routine practice at the study center to determine the presence or absence of reflux esophagitis. At this baseline visit, the LA grade of esophagitis was determined by the investigator and photographically documented. Patients who did not have esophagitis entered an alternative study of symptom relief in nonerosive reflux disease (d9770c00011). Investigators then randomized patients to receive AZD0865 25, 50, or 75 mg or esomeprazole 40 mg orally once daily to be taken 30 minutes before breakfast. The study population was randomly divided into halves on the basis of study centers to minimize the number of endoscopies for individual patients. One half (group A) was treated for up to 4 weeks and the other half (group B) for up to 8 weeks. Each center was randomly allocated to conduct either the 4-week or 8-week protocol to minimize complexity. The randomization list was generated using a validated computer program (Grand, AstraZeneca R&D, Mölndal, Sweden) with a block size of 4, with corresponding drug packs. The allocation code was not broken, except in case of medical emergencies, until the preplanned analyses. A subgroup of patients selected from 17 predesignated centers underwent ambulatory ph monitoring after 14 days of therapy. Assessments The primary outcome was the comparative healing of esophagitis with 3 doses (25, 50, and 75 mg) of AZD0865 at 4 weeks. Endoscopy of the esophagus, stomach, and duodenum was performed in group A at 2 and 4 weeks and in group B at weeks 4 and 8. Patients whose esophagitis was classified as healed were considered to have completed the study, and the observations were carried forward. As secondary outcomes at 2, 4, and 8 weeks, the esophagitis healing rates among AZD0865 doses and between each dose and esomeprazole 40 mg were compared. Patients assessed a range of GERD symptoms (a burning feeling behind the breastbone [ie, heartburn], pain behind the breastbone, a burning feeling in the center of the upper stomach, pain in the center of the upper stomach, acid taste in the mouth, and unpleasant movement of material upwards from the stomach) for up to 8 weeks of treatment. 12 Patients used electronic diaries to record their symptoms twice daily (in the morning close to the time of intake of study medication and just before bedtime in the evening). Patients reported the intensity of symptoms by using a 4-point graded scale (none to severe). Evaluation of patient-reported symptom control was based on the following variables: time to sustained absence of symptoms (time to the first of 7 consecutive symptom-free days), of which the sustained absence of heartburn was considered to be the most informative variable; and the proportion of patients with absence of individual symptoms on the first, second, and fourth weeks of treatment. In addition, investigators questioned patients during clinic visits at the end of the first, second, and fourth weeks of treatment and recorded symptom intensity for each patient during the preceding 7 days for the same set of symptoms as in the patient assessment. The investigator-reported assessment of symptoms was based on the proportion of patients without individual symptoms. Safety and tolerability were assessed on the basis of adverse events, laboratory values, vital signs, electrocardiogram, and physical examination. Physical examinations, vital signs, and electrocardiograms were assessed at baseline and at week 4 (group A) or week 8 (group B). Laboratory screens were conducted in both groups before enrollment, at baseline, at weeks 1, 2, and 4, as well as at week 8 in group B.

December 2007 DOSE RANGING STUDY OF AZD0865 IN REFLUX ESOPHAGITIS 1387 In a subgroup of patients from selected centers, 24-hour ambulatory intraesophageal and intragastric ph monitoring was performed at week 2, while on continued therapy, to study the relationship between intraesophageal and intragastric ph and control of symptoms. However, patients were not disqualified or discontinued if they declined the ph monitoring study. Each study center used its standard equipment for ambulatory ph monitoring. Patients fasted for at least 4 hours before ph monitoring. A dual antimony electrode ph-monitoring catheter with electrodes spaced approximately 15 cm apart was positioned manometrically so that the esophageal electrode was 5 cm above the proximal margin of the lower esophageal sphincter by using a validated technique. 13 During ph monitoring, patients continued their normal daily activities. The percentage of time during which intragastric ph was 4 and the percentage of time with intraesophageal ph 4 for the total period (0 24 hours) were calculated. Statistical Analyses Consistent with existing data, this study assumed that esomeprazole 40 mg would achieve an 80% healing rate after 4 weeks. 14 16 On the basis of a model of the relationship between healing rates and intragastric ph holding times, 17 it was estimated that the greater degree of acid suppression with the 75-mg dose of AZD0865 would translate to a healing rate of 89% at 4 weeks. Thus, a total of 300 patients per treatment group were needed to show superiority of AZD0865 75 mg to esomeprazole 40 mg, with a 5% significance level for a two-sided 2 test with 80% power. With adjustment for a 10% dropout rate, a total sample size of 1400 was required. The primary and secondary esophagitis healing-related end points were analyzed with a Mantel-Haenszel-Cochran test stratified by baseline LA grade and the confidence interval (CI) estimated on the basis of normal approximations. The only adjustment for multiple comparisons in the study was in testing the primary outcome, the comparison of the 3 AZD0865 doses. The analysis of these was performed with a closed test procedure in which the hypothesis of all 3 dose groups being equal was tested first at the 5% alpha level. Only if this test was significant could any of the treatment arm pairs be tested, each at a 5% alpha level. Secondary end points were analyzed with Wilcoxon tests (the proportion of patients with the absence of individual symptoms) or Kaplan-Meier or life table estimates (time to sustained absence of heartburn). All patients who received at least one dose of study medication were included in the intention-to-treat set. Results Patient Characteristics Of 1524 patients enrolled in the study, 1521 were randomized. The intention-to-treat population included 1514 patients; 7 randomized patients did not receive study drug and were excluded (Figure 1). The overall number of discontinuations and the reasons for discontinuation (ie, eligibility criteria not fulfilled, adverse event, lack of therapeutic response, patient not willing to continue study, and other) were comparable among treatment groups. At baseline, there were no marked differences in demographic characteristics among treatment groups. The majority had a history of GERD for longer than 12 months, and there were no major differences in LA grade among the treatment groups, with approximately one fourth having grade C or D Figure 1. Patient disposition.

1388 KAHRILAS ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 5, No. 12 Table 1. Patient Demographics and Baseline Characteristics AZD0865 25 mg AZD0865 50 mg AZD0865 75 mg Esomeprazole 40 mg Age (y) N 386 377 375 376 Mean 47.3 47.4 45.8 46.5 SD 12.1 12.2 13.1 13.2 Male, n 233 (60.4) 245 (65.0) 236 (62.9) 243 (64.6) Race, n White 342 (88.6) 340 (90.2) 326 (86.9) 328 (87.2) Black 11 (2.9) 11 (2.9) 16 (4.3) 12 (3.2) Asian 1 (0.3) 2 (0.5) 3 (0.8) 1 (0.3) Other 32 (8.3) 24 (6.4) 30 (8.0) 35 (9.3) History of GERD, n 6 12 mo 14 (3.6) 19 (5.0) 26 (6.9) 14 (3.7) 12 mo 372 (96.4) 358 (95.0) 349 (93.1) 362 (96.3) H pylori, n Negative 329 (85.2) 313 (83.0) 328 (87.7) 316 (84.0) Positive 55 (14.3) 57 (15.1) 42 (11.2) 54 (14.4) Missing 2 (0.5) 7 (1.9) 4 (1.1) 6 (1.6) LA grade of esophagitis, N A 132 (34.2) 127 (33.7) 144 (38.4) 131 (34.8) B 166 (43.0) 153 (40.6) 145 (38.7) 156 (41.5) C 69 (17.9) 73 (19.4) 65 (17.3) 73 (19.4) D 19 (4.9) 24 (6.4) 21 (5.6) 16 (4.3) Barrett s esophagus No 347 (89.9) 342 (90.7) 349 (93.1) 349 (92.8) Yes 39 (10.1) 33 (8.8) 26 (6.9) 27 (7.2) SD, standard deviation. esophagitis (Table 1). Treatment compliance, assessed by pill count, was 75% in 94% of patients. Healing of Esophagitis After 4 weeks of treatment, healing rates were similar among AZD0865 doses (76.9%, CI, 72.4% 81.1%; 78.2%, CI, 73.7% 82.3%; and 81.1%, CI, 76.7% 84.9% for AZD0865 25, 50, and 75 mg, respectively) (Figure 2). The 4-week healing rate with esomeprazole 40 mg was 81.9% (CI, 77.6% 85.7%) (Figure 2) and was not significantly different from the rate observed with any dose of AZD0865. At 2, 4, and 8 weeks, there were no consistent significant differences in healing rates between any dose of AZD0865 and esomeprazole 40 mg. Thus, although there appeared to be a significant difference in favor of esomeprazole 40 mg in a pairwise comparison with AZD0865 50 mg at week 2 (P.041), the failure to reject the hypothesis that there was any difference in healing rate among AZD0865 doses suggests this to be a type I statistical error in the face of multiple comparisons (Figure 2). Stratification according to LA grade of esophagitis at baseline revealed no consistent significant differences in healing rates between the 3 doses of AZD0865 and esomeprazole 40 mg at week 4 (Table 2) or at weeks 2 and 8 (data not shown). There appeared to be a significant difference in favor of esomeprazole 40 mg versus AZD0865 25 mg for LA grade B at week 4 (P.022); however, this difference was not apparent at earlier or later time points, and again this result should be viewed as likely a consequence of a type I statistical error in the context of multiple comparisons. Symptom Control The time taken for patients to achieve sustained absence of heartburn was virtually identical among the doses of AZD0865 and esomeprazole 40 mg (Figure 3). During the first, second, and fourth weeks of treatment, increasing proportions of patients in each treatment group reported freedom from heartburn (Table 3). Once again, the apparent significant difference observed at week 4 between AZD0865 25 mg and AZD0865 75 mg (P.04) should be viewed as likely a consequence of a type I statistical error in the context of multiple comparisons, because the primary hypothesis of there being any difference among AZD0865 doses was rejected. There were no significant differences in either the time to sustained absence or the proportion of patients free of other Figure 2. Healing rates with 95% CI at weeks 2, 4, and 8 for AZD0865 25 mg (white bar), AZD0865 50 mg (light grey shaded bar), AZD0865 75 mg (dark grey shaded bar), and esomeprazole 40 mg (black bar).

December 2007 DOSE RANGING STUDY OF AZD0865 IN REFLUX ESOPHAGITIS 1389 Table 2. Healing Rate at Week 4 by Baseline LA Grade Baseline LA grade Treatment arm (n) Healing rate (95% CI) P value A AZD0865 25 mg (132) 84.1 (76.7 89.9).599 AZD0865 50 mg (127) 85.0 (77.6 90.7).721 AZD0865 75 mg (144) 83.3 (76.2 89.0).403 Esomeprazole 40 mg (131) 87.0 (80.0 92.3) B AZD0865 25 mg (166) 76.5 (69.3 82.7).022 AZD0865 50 mg (153) 77.8 (70.4 84.1).053 AZD0865 75 mg (145) 82.8 (75.6 88.5).424 Esomeprazole 40 mg (156) 86.5 (80.2 91.5) C AZD0865 25 mg (69) 73.9 (61.9 83.7).579 AZD0865 50 mg (73) 72.6 (60.9 82.4).717 AZD0865 75 mg (65) 83.1 (71.7 91.2).051 Esomeprazole 40 mg (73) 68.5 (56.6 78.9) D AZD0865 25 mg (19) 42.1 (20.3 66.5).505 AZD0865 50 mg (24) 62.5 (40.6 81.2).750 AZD0865 75 mg (21) 47.6 (25.7 70.2).743 Esomeprazole 40 mg (16) 43.8 (19.8 70.1) P values relate to comparisons of AZD0865 vs esomeprazole. patient-reported symptoms, either among AZD0865 doses or compared with esomeprazole 40 mg. Similarly, investigators reported a similar pattern of heartburn control to that reported by patients, with no differences between AZD0865 doses and esomeprazole 40 mg. Intragastric and Intraesophageal ph Intragastric ph data were available from 85 patients and intraesophageal ph data from 77 patients. A number of patients declined to undergo ph monitoring, although they continued in the study. Furthermore, not all ph data were evaluable because of technical failures. Also, owing to the large number of unevaluable esophageal ph recordings, these data were viewed to be unreliable. Nonetheless, a trend toward an intragastric ph dose-response was identified for AZD0865 in Table 3. Proportion of Patients Free From Heartburn During the First, Second, and Fourth Treatment Weeks (Investigator Assessed) Week Treatment arm (n) Estimate (CI) 1 AZD0865 25 mg (310) 16.8 (12.6 20.9) AZD0865 50 mg (302) 20.2 (15.7 24.7) AZD0865 75 mg (284) 20.1 (15.4 24.7) Esomeprazole 40 mg (293) 17.8 (13.4 22.1) 2 AZD0865 25 mg (327) 35.2 (30.0 40.3) AZD0865 50 mg (319) 34.2 (28.7 39.4) AZD0865 75 mg (306) 40.9 (35.3 46.4) Esomeprazole 40 mg (314) 35.4 (30.1 40.6) 4 AZD0865 25 mg (165) 52.7 (45.1 60.4) AZD0865 50 mg (155) 57.4 (49.6 65.2) AZD0865 75 mg (159) 63.5 (56.0 71.0) Esomeprazole 40 mg (157) 54.1 (46.4 61.9) terms of mean percentage time that intragastric ph was 4 (ie, mean standard deviation %: 25 mg, 65.6% 20.8%, n 24; 50 mg, 74.3% 17.7%, n 22; 75 mg, 77.0% 18.3%, n 19), but this did not achieve statistical significance (AZD0865 75 mg vs 25 mg, P.058). There were no significant differences in mean percentage time that intragastric ph was 4 for any AD0865 dose versus esomeprazole 40 mg (67.3% 20.2%, n 15). Safety and Tolerability Overall, AZD0865 and esomeprazole 40 mg were welltolerated. Similar proportions of patients in the AZD0865 and esomeprazole 40 mg study groups (approximately 30%) had an adverse event. The most commonly reported adverse events were headache (4.7% 7.4%), diarrhea (2.4% 4.1%), and nausea (1.9% 3.9%), and the frequency was comparable among treatment groups. Four patients had serious adverse events during treatment, assessed by investigators as unrelated to the study drug. There were few discontinuations (2.1% 3.2%) as a result of adverse events in all treatment groups and no apparent difference between the groups. The most common reasons for discontinuation were gastrointestinal disorders (1.1% 1.3%) and nervous system disorders (0.3% 1.0%). Reversible increases in liver transaminases were observed with all treatments, although ALT increases 3 ULN occurred almost exclusively in patients receiving AZD0865 (Table 4). Abnormalities were observed at week 1 in 2 patients, week 2 in 2 patients, and weeks 4 8 in 13 patients. The 17 AZD0865-treated patients Table 4. Number of Patients With Maximal Values 3 ULN of Normal in Serum Liver Enzymes During Treatment Lab variable AZD0865 25 mg, n AZD0865 50 mg, n AZD0865 75 mg, n Esomeprazole 40 mg, n Figure 3. Cumulative incidence of sustained absence of heartburn (P.05 for all comparisons with log-rank test) with AZD0865 25 mg (grey line), ADZ0865 50 mg (thin black line), AZD0865 75 mg (thick black line), and esomeprazole 40 mg (dotted line). ALT 3 ULN 3 (0.8) 6 (1.7) 8 (2.2) 1 (0.3) 5 ULN 2 (0.5) 4 (1.1) 5 (1.4) 0 (0) AST 3 ULN 4 (1.1) 5 (1.4) 5 (1.4) 0 (0) ALP 3 ULN 1 (0.3) 0 (0) 0 (0) 0 (0)

1390 KAHRILAS ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 5, No. 12 with ALT 3 ULN were followed up, and in general, their levels returned to normal or back to baseline within 1 3 weeks either during continued treatment (4 patients) or after stopping study treatment (13 patients). Six patients had bilirubin values 1.5 ULN before the start of treatment; however, there was no increase in these values during treatment. There were no significant changes in other liver function tests in any of these patients during the study. No clinically meaningful change in any other laboratory test parameter or vital signs was seen. Discussion The major findings of this study were that treatment with all 3 doses of AZD0865 resulted in healing of esophagitis in a high proportion of patients after 4 weeks (all approximately 80%), but there were no significant differences in healing rates among AZD0865 doses or between each AZD0865 dose and esomeprazole 40 mg at 2, 4, or 8 weeks. In fact, the proportion of patients healed with esomeprazole was numerically greater than for all 3 AZD0865 doses at all 3 time points. Similar to the healing data, the 3 doses of AZD0865 were no more effective than esomeprazole 40 mg at achieving sustained absence of heartburn. Pharmacodynamic data from phase I studies of AZD0865 at doses of 0.8 mg/kg and above suggested that the drug could inhibit acid secretion more rapidly and completely than would be expected with PPIs. 9 Extrapolating that pharmacodynamic effect into the well-known model of the relationship between gastric acid suppression and esophagitis healing proposed by Bell et al, 17 it was hypothesized that AZD0865 might exhibit clinical advantages with respect to the rapidity of esophagitis healing. Esomeprazole 40 mg was chosen as the comparator to AZD0865 because earlier studies have associated it with higher esophagitis healing rates than lansoprazole, omeprazole, or pantoprazole, 14,15,18 23 establishing it as the most formidable comparator for a new compound with potentially superior acid inhibition characteristics. However, none of the AZD0865 doses achieved faster healing rates than esomeprazole 40 mg at 2 weeks (63% 67% vs 69%) or achieved faster sustained absence of heartburn. Also, there were not any consistent, significant differences in esophagitis healing rates after 4 weeks of treatment with AZD0865 and esomeprazole 40 mg in patient subgroups stratified for esophagitis severity according to LA grade. Furthermore, the results obtained in the present study for esomeprazole 40 mg are consistent with data from previous esomeprazole studies with the same clinical end points, 14 16,21,22 as were the demographic characteristics, relative disease severity, and H pylori prevalence rates of the patients studied, 16,21 arguing against this being a spurious result. Previous studies of PPIs suggest that large differences in the time that intragastric ph is maintained 4 are reflected in differences in healing rates. 18,24 However, as the potency of the comparator compounds increases, these clinical differences become numerically small and only demonstrable with very large sample size exemplified by the lansoprazole versus esomeprazole trial enrolling more than 5000 patients. 16 The magnitude of difference in acid inhibition between treatment arms was not well-demonstrated in the current study. In fact, the pharmacodynamic data in the current study did not demonstrate pharmacodynamic differences between treatment arms as might have been predicted from available phase I data. However, these nonsignificant differences between treatment arms in gastric ph control are likely attributable to the small sample size (n 18 24 per group), which made it unlikely to detect a significant difference, on the basis of the sample size calculation in other pharmacodynamic studies, suggesting that a minimum of 30 per group is usually needed with a parallel study design. Although it has been assumed for some time now that more is better when it comes to clinical efficacy in the treatment of GERD, the potential for AZD0865 (or other antisecretory drugs potentially more potent than esomeprazole 40 mg) to hasten esophagitis healing might ultimately be limited by the relatively slow rate of epithelial cell turnover in the squamous epithelium of the esophagus. 25 Although decreased exposure to acid and active pepsin is necessary to promote healing of reflux esophagitis, the restoration of the integrity of the esophageal mucosa also depends on the biology of the epithelium itself and might ultimately be constrained by the time it takes for the epithelial cells to be replaced. Likewise, the speed of heartburn control might be limited by the rate of healing of acid-induced microscopic lesions in the esophageal squamous epithelium (ie, dilated intercellular spaces or microerosions) that are thought to be sensitive to acid and trigger some GERD symptoms. 26,27 Within this context, the results of the current study suggest that although the strategy of increased acid inhibition in the management of GERD has proved very effective, it is ultimately limited by a ceiling effect, and that ceiling was achieved by all 4 treatment arms of this study. Hence, there is the absence of a dose-response curve for AZD0865 despite a 3-fold range in dose. AZD0865 was generally well-tolerated, although reversible increases of transaminases were observed in some AZD0865- treated patients. Elevated transaminase values were observed more commonly with the higher doses, and for the most part they did not develop until after at least 4 weeks of treatment. Fortunately, they were also rapidly reversible with discontinuation of the treatment. The mechanism underlying these increases is unclear, although hepatic effects have also been documented with other agents sharing the imidazopyridine ring structure, suggesting a potential chemical class effect. 28,29 In conclusion, this study failed to demonstrate that the theoretical advantages related to superior pharmacodynamic properties of acid inhibition of AZD0865 translated into improved efficacy in the treatment of esophagitis patients. AZD0865 25 mg, 50 mg, and 75 mg were all similar in the magnitude of treatment effect and did not provide greater efficacy than esomeprazole 40 mg in terms of esophagitis healing, in the rapidity with which heartburn control was achieved, or in the degree of GERD symptom control. References 1. Vakil N. Review article: new pharmacological agents for the treatment of gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2004;19:1041 1049. 2. 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December 2007 DOSE RANGING STUDY OF AZD0865 IN REFLUX ESOPHAGITIS 1391 AZD0865, an H,K -ATPase selective, potassium-competitive acid blocker. Gastroenterology 2004;126:A333. 5. Holstein B, Florentzson M, Andersson M, et al. AZD0865, a potassium-competitive acid blocker (P-CAB), has a long duration of effect in the rat. Am J Gastroenterol 2004;99(Suppl 10):S8. 6. Holstein B, Holmberg A, Florentzson M, et al. AZD0865, a potassium-competitive acid blocker (P-CAB), provides predictable inhibition of acid secretion with repeated dosing in the dog. Eur J Pharm Sci 2004;23(Suppl 1):S8. 7. Holstein B, Florentzson M, Andersson K. Consistent inhibition of acid ouput with repeated dosing of AZD0865 in rats. Clin Pharmacol Ther 2005;77:P55. 8. Holstein B, Holmberg A, Florentzson M, et al. AZD0865 a new potassium-competitive acid blocker -exhibits maximal gastric antisecretory effects from first dose. Gastroenterology 2004;126:A334. 9. Nilsson C, Albrektson E, Rydholm H, et al. 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Expert Opin Investig Drugs 2005;14:411 421. 29. Karsenti D, Blanc P, Bacq Y, et al. Hepatotoxicity associated with zolpidem treatment. BMJ 1999;318:1179. Address requests for reprints to: Dr Peter James Kahrilas, Feinberg School of Medicine, Northwestern University, 676 N St Clair St, Suite 1400, Chicago, Illinois 60611-2951. e-mail: p-kahrilas@northwestern.edu; fax: 312-695- 3999. Supported by AstraZeneca, who were involved in the study design, data collection, analysis, and interpretation and in the writing of the report and the decision to submit for publication. Dr Kahrilas serves as a consultant for AstraZeneca. Professor John Dent serves as a consultant for AstraZeneca and receives research support from AstraZeneca. Professor Peter Malfertheiner serves as a consultant for AstraZeneca. Dr Hans Denison is a research physician for AstraZeneca. Dr Stefan Franzén is an employee of AstraZeneca and owns a small number of shares in AstraZeneca. Dr Goran Hasselgren is an employee of AstraZeneca. We thank the investigators, their co-investigators and study coordinators, and the patients who participated in this trial. We also wish to acknowledge Christopher Langford of PAREXEL MMS for medical writing support on behalf of AstraZeneca.