TLESR, transient lower esophageal sphincter relaxation.

Transcription

1 GASTROENTEROLOGY 2010;139: CLINICAL Effects of Lesogaberan on Reflux and Lower Esophageal Sphincter Function in Patients With Gastroesophageal Reflux Disease GUY E. BOECKXSTAENS,*, HANNEKE BEAUMONT,* VEERLE MERTENS, HANS DENISON, MAGNUS RUTH, JOHN ADLER, DEBRA G. SILBERG, and DANIEL SIFRIM, *Academic Medical Centre, Amsterdam, The Netherlands; Department of Gastroenterology, University Hospital Leuven, Catholic University of Leuven, Leuven, Belgium; AstraZeneca R&D, Mölndal, Sweden; AstraZeneca R&D, Wilmington, Deleware; and Barts and The London School of Medicine and Dentistry, Queen Mary s College, University of London, London, United Kingdom This article has an accompanying continuing medical education activity on page e16. Learning Objective: Upon completion of this exercise, successful learners will be able to describe key aspects of the mechanisms underlying gastroesophageal reflux disease and its treatment. See editorial on page 377. BACKGROUND & AIMS: Transient lower esophageal sphincter relaxations (TLESRs) are a major mechanism behind reflux. This study assessed the effects of lesogaberan (AZD3355), a novel -aminobutyric acid type B receptor agonist, on reflux and lower esophageal sphincter (LES) function when used as add-on treatment in patients with reflux symptoms despite proton pump inhibitor (PPI) treatment. METHODS: In this randomized, double-blind, placebo-controlled, crossover study, patients received lesogaberan (65 mg) or placebo twice on day 1 (morning/evening) and once on day 2 (morning), in addition to existing PPI treatment. Patients consumed a standardized meal minutes after morning doses. Ambulatory impedance-ph monitoring was conducted for 24 hours after the first dose on day 1. Stationary manometry and impedance-ph monitoring was conducted for 4 hours after the third dose on day 2. RESULTS: Of 27 randomized patients, 21 were included in the per-protocol efficacy analysis. During the 24 hours after treatment start, lesogaberan reduced the mean number of reflux events by 35% compared with placebo. During the 3 postprandial hours on day 2, lesogaberan reduced the geometric mean number of TLESRs by 25% and increased geometric mean LES pressure by 28% compared with placebo. The most common adverse events were headache (placebo: 11/27 patients; lesogaberan: 8/25 patients) and paresthesia (transient; placebo: 3/27 patients; lesogaberan: 5/25 patients). CONCLUSIONS: In patients with reflux symptoms despite PPI treatment, lesogaberan decreased the number of TLESRs and reflux episodes, and increased LES pressure compared with placebo. These findings support further evaluation of lesogaberan as an add-on treatment in patients partially responding to PPIs. Keywords: AZD3355; Transient Lower Esophageal Sphincter Relaxation; Partial Response; Reflux Inhibitor. Transient lower esophageal sphincter relaxations (TLESRs) are considered to be a major mechanism behind acidic, weakly acidic, and weakly alkaline reflux episodes in both healthy individuals and those with gastroesophageal reflux disease (GERD). 1,2 Most evidence suggests that the frequency of TLESRs does not differ significantly between healthy individuals and those with GERD, 3,4 but TLESRs appear more likely to be associated with acid reflux in the latter. 3,5,6 TLESRs are triggered in response to the activation of stretch receptors in the stomach 7 and are thought to be mediated by a vago-vagal reflex pathway. 8,9 By targeting this pathway, it should be possible to reduce the number of TLESRs and hence inhibit all types of reflux. A promising approach is the use of agonists of the -aminobutyric acid type B (GABA B ) receptor. GABA B receptors act at several points along the vagal mechanoreceptor signaling pathway. 9 In patients with GERD, the GABA B -receptor agonist baclofen reduced the occurrence of TLESRs and reflux episodes, 10,11 reduced acid exposure, 10,12,13 and improved reflux symptoms. 13 However, baclofen has central nervous system (CNS) effects that limit its clinical value for treating GERD. Attention is Abbreviations used in this paper: CI, confidence interval; CNS, central nervous system; GABA, -aminobutyric acid; GMR, geometric mean ratio; GERD, gastroesophageal reflux disease; LES, lower esophageal sphincter; PPI, proton pump inhibitor; RDQ, reflux disease questionnaire; TLESR, transient lower esophageal sphincter relaxation by the AGA Institute /$36.00 doi: /j.gastro

2 410 BOECKXSTAENS ET AL GASTROENTEROLOGY Vol. 139, No. 2 now focusing on the development of new GABA B -receptor agonists that act primarily at peripheral sites and therefore have better tolerability. 14 In preclinical studies in dogs, the newly developed, peripherally acting GABA B -receptor agonist lesogaberan (AZD3355) inhibited TLESRs, and reduced esophageal acid exposure and the number of reflux episodes. 15,16 In healthy subjects, a single oral dose of lesogaberan (0.8 mg/kg) reduced the number of TLESRs and reflux episodes, and increased LES pressure compared with placebo, and had a favorable safety and tolerability profile. 17 The aim of the current study was to assess for the first time the effects of oral lesogaberan on lower esophageal sphincter (LES) function and reflux when added to current proton pump inhibitor (PPI) treatment in patients with GERD who experience reflux symptoms despite PPI treatment. Patients and Methods Patients Men and postmenopausal or surgically sterilized women with GERD who were experiencing reflux symptoms despite continuous treatment with any PPI at a dose approved for any GERD indication (as specified in the product label text) for at least 6 weeks before enrollment were eligible for inclusion. Patients were aged years and weighed kg, with at least 6 months history (consecutive or nonconsecutive) of reflux symptoms. Patients were recruited from the motility and outpatient units of the centers involved, using advertisements. The main exclusion criteria were as follows: history of clinically significant cardiovascular, respiratory, renal, hepatic, neurologic, mental or gastrointestinal disease other than GERD, although patients with uncomplicated and well-controlled diabetes mellitus or hypertension could be included; history of clinically significant orthostatic reactions; history or signs or symptoms of heart disease; prior surgery of the upper gastrointestinal tract; the need for concomitant medication with drugs that might interfere with the pharmacodynamic characteristics of the study drug (eg, baclofen) or influence gastrointestinal symptoms, except for the PPI used in the study and antacids; and a history of alcohol or substance misuse. This study was performed at 2 study centers: the University Hospital Leuven in Belgium and the Academic Medical Centre in Amsterdam, The Netherlands. The study was performed in accordance with the ethical principles of the Declaration of Helsinki and the International Conference on Harmonization/Good Clinical Practice and was approved by the Institutional Review Board of each of the 2 participating study centers. All participants provided written informed consent before any study-related activities or procedures. Figure 1. Study design showing (A) randomization schedule and visits and (B) schedule of dosing, standardized meals, and pharmacodynamic and symptom assessments. Patients received lesogaberan or placebo in addition to their current proton pump inhibitor therapy. Study Design This was a phase 2a, randomized, double-blind, placebo-controlled, crossover study conducted between February 2007 and February 2008 (study code D9120C00020; ClinicalTrials.gov identifier: NCT ). The randomization and visit schedule are shown in Figure 1. Screening Visit At the screening visit, patients underwent a physical examination, including measurement of vital signs, a 12- lead electrocardiogram, and a full laboratory screen. To assess eligibility, patients also completed the reflux disease questionnaire (RDQ) 18 using a hand-held electronic device. The RDQ evaluated symptoms during the past 7 days. Patients who reported a burning feeling behind the breastbone and/or unpleasant movement of material upwards from the stomach with at least mild intensity on at least 3 of the past 7 days were eligible for inclusion. Eligible patients also completed the gastrointestinal symptom rating scale 19 using a hand-held electronic device. In addition, a 15-minute manometric recording was performed to determine LES location and pressure, if these data were not available from assessments taken during the previous 6 months. Patients with fasting LES pressure below 5 mm Hg were excluded owing to the difficulty of identifying TLESRs at such low LES pressures. Study Visits Following the screening visit and a run-in period of up to 21 days, patients were randomized to receive 3 doses of either lesogaberan (65-mg capsule) or matching placebo, administered in the morning (09:00 hours) and evening (21:00 hours) on day 1, and in the morning (09:00 hours) on day 2. After a washout period of 5 28 days, patients crossed over to the opposite treatment arm. Patients then under-

3 August 2010 EFFECT OF LESOGABERAN ON REFLUX AND THE LES 411 went a follow-up visit 5 7 days after the second treatment period. In each treatment period, study medication was administered in addition to the patient s current PPI treatment, which was to be unchanged throughout the study. Study medication was taken each morning after an overnight fast. Patients received a standardized meal (100 g minced beef, 225 g potatoes, 10 g butter, 125 g banana, 200 ml soft drink; 2929 kj [30% fat]) 45 minutes after administration of the morning doses. Assignment and Blinding A treatment allocation list was generated by AstraZeneca R&D Mölndal using a validated computer program, and the randomization was performed within blocks of consecutive patient numbers. Treatment allocation was blinded for the patients and for study site personnel. Similarly, the tracings were coded so that investigators were blinded to treatment status. Pharmacodynamic Assessments Ambulatory impedance-ph recording was performed over the 24 hours following the first treatment dose on day 1. The catheter (Sleuth, Sandhill Scientific, Inc., Highlands Ranch, CO, or MMS, Enschede, The Netherlands) was positioned with the antimony ph sensor 5 cm above the LES; 6 electrode pairs measured intraluminal impedance at 3 17 cm above the LES. Patients recorded the times of reflux symptoms, meal intake, and periods in a supine position during this 24- hour period using a data logger and a diary card. On the second study day, the impedance-ph catheter was replaced with a manometric-impedance-ph catheter. A stationary combined manometric and impedance-ph recording was performed over the 4 hours following the third treatment dose (day 2) (for 1 hour before and 3 hours after the meal). Patients remained in a sitting position throughout the recording period. The manometric catheter (DentSleeve International Ltd, Mississauga, Ontario, Canada) was a perfused 12-channel silicone rubber assembly incorporating 1 gastric, 5 esophageal, and 4 pharyngeal side holes, and 1 side hole at the proximal border of the sleeve, which was positioned 1 cm above the LES. The sleeve and the gastric and esophageal side holes were perfused with degassed water at a rate of 0.2 ml/min using hydraulic flow restrictors (DentSleeve International Ltd). The optimum pharyngeal side hole to monitor swallows was identified and perfused with air at a rate of 0.8 ml/min. Efficacy Measures The primary efficacy variable was the number of postprandial TLESRs during the 3 hours after completion of the standardized meal on day 2 (ie, 1 4 hours after the third dose). The TLESRs were determined from manometric tracings according to previously published criteria. 20 Secondary efficacy variables were the mean LES pressure during the 3 hours following the standardized meal on day 2 (ie, 1 4 hours after the first dose) and the number of swallows during this period. LES pressure was evaluated every 15 minutes and expressed as the mean difference between the end-expiration LES pressure and the end-expiration intragastric pressure over 1 minute. A swallow was defined as a fast increase in pressure in the pharyngeal channel clearly distinguishable from baseline activity. Further secondary variables were reflux parameters assessed during both the 24-hour ambulatory impedance-ph recording and the 3 postprandial hours during the stationary manometric and impedance-ph recordings. Acidic, weakly acidic, and weakly alkaline reflux episodes were defined as episodes lasting longer than 5 seconds with esophageal ph 4, ph 4 to 6.5, and ph 6.5, respectively. 21 The number of each type of episode was recorded and calculated as a percentage of total number of episodes. The number of acid reflux episodes longer than 5 minutes was also recorded. In addition, acid clearance time (ie, the mean duration of an acid reflux episode) and esophageal acid exposure or fraction time (percentage of registration time with esophageal ph 4) were calculated. The composition of reflux episodes (liquid, gas, or mixed gas/liquid) was evaluated for 24 hours after the first dose and 4 hours after the third dose using impedance data. A reflux episode was defined as a period when impedance dropped below 50% of baseline level (liquid episode) or increased to above 50% of baseline level (gas episode), propagating arboreally from the most distal channel. Mixed episodes showed both gas and liquid criteria in the same episode. The duration of these episodes (bolus clearance time), the proximal extent of reflux, and the number of proximal reflux events ( 15 cm above the LES) were also recorded. Safety and Tolerability Assessments Adverse events were recorded during each treatment period (ie, from the first dose to 24 hours after the third dose) and during the washout/follow-up periods. Physical examination, measurements of vital signs, 12- lead electrocardiography, and assessment of laboratory parameters were performed at regular intervals during the study. Statistical Analyses A sample size of 30 patients randomized to treatment was planned to ensure that at least 24 patients completed the study, and 20 patients had evaluable manometric recordings after both treatment periods. The analysis of the pharmacokinetic and pharmacodynamic variables was based on the per protocol set of patients. If possible, the geometric mean ratio (GMR) was estimated based on logarithmically transformed data. However, this was not possible if any patient had no events for any variable, in which case the difference in arithmetic means was estimated based on untransformed data. Log-trans-

4 412 BOECKXSTAENS ET AL GASTROENTEROLOGY Vol. 139, No. 2 formed data were analyzed using an analysis of variance model with treatment, period, and sequence as fixed effects and patient as a random effect. The confidence interval (CI) limits were transformed back to the original scale to give CIs for the geometric mean for each treatment and the GMR between treatments. The analyses were not adjusted for multiplicity. Statistical analyses were performed using SAS, version 8.2 (SAS Institute, Cary, NC). Results Patient Disposition Forty-two patients were enrolled in the study, 27 of whom were randomized to study treatment; 25 completed the study. Of the 15 patients who were not randomized, 9 did not meet the criteria for inclusion based on the RDQ screen, 4 had a LES pressure of less than 5 mm Hg, 1 tested positive for cannabinoids, and 1 was not deemed suitable for the study according to the investigator. Two patients discontinued prematurely, 1 because of catheter problems and low LES pressure, the other because of nausea, and a further 2 patients were excluded from the efficacy analysis (because of a dosing error and catheter problems). In addition, 2 patients had insufficient recording time after the first dose and were excluded from the ambulatory impedance-ph efficacy analyses. Two patients were excluded from the stationary combined manometric and impedance-ph efficacy analyses after the third dose because of multiple swallowing and low LES pressure. Thus, 21 patients were included in the per protocol efficacy analysis groups after the first and third treatment doses. Patient Demographics and Baseline Characteristics Overall, 16 men and 11 women were randomized to treatment (Table 1). All were white subjects, and their mean age was 51.6 years. In all, 17 patients (63%) reported a history of GERD lasting 5 years or longer. A history of hiatus hernia and of reflux esophagitis was each reported by more than half of the patients. Symptom burden at screening was considerable despite PPI treatment (Table 1). Almost half of the patients reported daily symptoms of at least 1 of the primary RDQ items (ie, a burning feeling behind the breastbone and unpleasant movement of material upwards from the stomach ) over the 7 days prior to screening. Almost all patients had reflux symptoms of at least moderate intensity. Among patients in the per protocol efficacy analysis group, omeprazole (10 40 mg per day) was used by 9 patients, esomeprazole (20 40 mg) by 7 patients, pantoprazole (20 40 mg) by 6 patients, and lansoprazole (30 mg) by 1 patient. Table 1. Demographic and Baseline Characteristics of the Randomized Patient Population Characteristics All patients (n 27) Sex, n (%) Male 16 (59) Female 11 (41) Age, y Range Body mass index, kg/m History of reflux disease, y, n(%) 0.5 to 1 1 (4) 1to 5 9 (33) 5to 10 4 (15) (48) History of erosive esophagitis, n (%) Yes 17 (63) No 8 (30) Unavailable 2 (7) History of hiatus hernia, n (%) Yes 14 (52) No 8 (30) Unknown 5 (19) Positive for Helicobacter pylori, n(%) a 3 (12) Primary RDQ items at screening b Days with symptoms/week, n (%) 7 days 12 (46) 5 6 days 5 (19) 3 4 days 9 (35) Maximum symptom intensity, n (%) Moderate severe 25 (96) NOTE. Values are means standard deviation unless otherwise stated. a Data unavailable/not evaluable for 2 patients. b Recorded at the screening visit based on patient recall of symptoms over the past 7 days (n 26). Efficacy: Stationary Assessment of Number of TLESRs, LES Pressure, and Reflux Episodes, Day 2 TLESRs. Lesogaberan reduced the geometric mean number of TLESRs by 25% (GMR, 0.75; 95% CI, ) compared with placebo in the 3 postprandial hours (1 4 hours after the third dose). The geometric mean number of TLESRs during this period was 11.6 with lesogaberan and 15.5 with placebo. Overall, 16 of 21 patients had fewer TLESRs with lesogaberan than with placebo, 2 patients had the same number with both interventions, and 3 patients had fewer TLESRs with placebo than with lesogaberan. The number of TLESRs varied widely between patients, as illustrated in Figure 2A. The relative reduction in the number of TLESRs with lesogaberan compared with placebo remained similar before the meal and for the 3 hours after the meal (Figure 2B). LES pressure. Geometric mean LES pressure was increased with lesogaberan by an average of 28% (GMR, 1.28; 95% CI, ) over placebo during the 3 postprandial hours. Increases in LES pressure with lesogaberan peaked around 1 hour after the meal and persisted until at least 3 hours after the meal (Figure 3).

5 August 2010 EFFECT OF LESOGABERAN ON REFLUX AND THE LES 413 Figure 2. Number of TLESRs with lesogaberan or placebo (A) for individual patients 0 3 hours after the standardized meal consumed 1 hour after the third dose and (B) hourly geometric means over the 4 hours after the third dose. Error bars show 95% CIs. Reflux episodes and swallows. Lesogaberan reduced the total number of reflux episodes by approximately 47% compared with placebo in the 3 postprandial hours (arithmetic mean difference, 10; 95% CI, 15 to 4.8), and had the greater effect on acid reflux (Figure 4A). During the 4 hours of the stationary assessment after the third dose, there were fewer pure liquid and mixed gas/liquid reflux episodes (but not pure gas episodes) with lesogaberan than with placebo (Figure 4C). There were also fewer proximal reflux events, and acid exposure and clearance times were shorter with lesogaberan than with placebo during this assessment period (Table 2). The number of swallows during the 3 postprandial hours was similar with lesogaberan and placebo (GMR, 0.97; 95% CI, ). Ambulatory 24-Hour Assessment of Reflux Episodes and Symptoms, Day 1 During the ambulatory impedance-ph study starting on day 1, lesogaberan reduced the total number of reflux episodes over 24 hours by approximately 35% compared with placebo (arithmetic mean difference, 22; 95% CI, 28 to 15). The effects of lesogaberan were more pronounced for acid reflux episodes than for either weakly acidic or weakly alkaline episodes (Figure 4B). The arithmetic mean differences for lesogaberan compared with placebo were 16 (95% CI, 23 to 8.3) for acid reflux, 6.5 (95% CI, 12 to 0.53) for weakly acidic reflux, and 0.64 (95% CI, 2.1 to 3.34) for weakly alkaline reflux. With both treatments, more reflux episodes occurred when upright than while supine. There were fewer acid reflux episodes with lesogaberan than with placebo while upright (mean: lesogaberan, 12.5; placebo, 25.0) and while supine (lesogaberan, 1.0; placebo, 4.3). Esophageal acid exposure time was reduced with lesogaberan compared with placebo, as was supine mean acid clearance time over 24 hours (Table 2). There were also fewer pure liquid and mixed gas/liquid reflux episodes (but not pure gas episodes) with lesogaberan than with placebo; the differences between the treatment groups were more pronounced in an upright than in a supine position (Figure 4C). There were fewer proximal reflux events with lesogaberan than with placebo (Table 2). The mean bolus clearance time while supine was less with lesogaberan than with placebo during the 24-hour ambulatory assessment (Table 2). The number of reflux symptom episodes reported by patients over the 24 hours after the first dose was similar with lesogaberan and placebo (mean number of episodes 4.6 vs 4.9, respectively, P.815). The total number of symptom episodes related to reflux episodes was 33 with lesogaberan vs 57 with placebo (P.092); for acid reflux, this was 17 vs 36 (P.065), respectively, and, for weakly acidic/alkaline reflux, 16 vs 21 (P.754), respectively. Reflux episodes were significantly associated with reflux symptoms in similar numbers of patients during lesogaberan and placebo treatment (symptom association probability 95% in 4 vs 7 patients for heartburn and 5 vs 3 patients for regurgitation). Safety and Tolerability The number of patients reporting adverse events during active treatment was similar with lesogaberan Figure 3. Mean LES pressure with lesogaberan and placebo during the stationary assessment 4 hours after the third treatment dose. Error bars show upper or lower extent of 95% CIs.

6 414 BOECKXSTAENS ET AL GASTROENTEROLOGY Vol. 139, No. 2 Figure 4. Mean number of reflux episodes with lesogaberan and placebo (A) during the stationary assessment 0 3 hours after the meal consumed 1 hour after the third dose and (B) during the ambulatory assessment 0 24 hours after the first dose. (C) Mean number of pure liquid, mixed gas/liquid, and pure gas reflux episodes with lesogaberan and placebo, during the stationary assessment 0 4 hours after the third treatment dose and during the ambulatory assessment 0 24 hours after the first dose. Error bars show 95% CIs. (n 18) and placebo (n 20) (Table 3). One patient discontinued the study early because of an adverse event (nausea) while receiving placebo. There were no serious adverse events or deaths during the study period, including follow-up. The most commonly reported adverse events during active treatment were headache, paresthesia, and nausea (Table 3). A similar pattern of adverse events was observed during the washout/follow-up period (data not shown). During active treatment, headache and nausea were reported by similar numbers of patients receiving lesogaberan and placebo. Paresthesia was reported by 3 patients only during lesogaberan treatment (1 of whom reported 2 episodes), by 1 patient only while taking placebo, and by 2 patients during both treatments. Paresthesia events starting after treatment was given were transient and mostly mild in intensity. One patient experienced intermittent paresthesia that started 3 days before the first treatment period and continued throughout the study. In 3 of the patients who reported paresthesia with lesogaberan treatment, the symptom began minutes after the first dose and lasted for 8 15 minutes. One patient reported a tingling sensation that began 52 minutes after the first dose of lesogaberan and continued intermittently until the following day. In no case was paresthesia accompanied by any neurologic findings. No clinically significant changes in vital signs, electrocardiogram, or laboratory hematology or clinical chemistry values were observed during the study. Discussion This study is the first to evaluate the effects of the novel GABA B -receptor agonist lesogaberan on reflux and

7 August 2010 EFFECT OF LESOGABERAN ON REFLUX AND THE LES 415 Table 2. Proximal Reflux Events and Acid Exposure Parameters 0 to 4 Hours After the Third Treatment Dose on Day 2, and 0 to 24 Hours After the First Treatment Dose on Day 1 Lesogaberan (n 21) Placebo (n 21) 0 to 4 hours after third dose Acid exposure (%) a Acid clearance time (s) Proximal reflux events (n) Bolus clearance time (s) to 24 hours after first dose Acid exposure (%) a Upright Supine Acid clearance time (s) Upright Supine Number of proximal reflux events Upright Supine Bolus clearance time (s) Upright Supine NOTE. Values are means standard deviation. a Percentage of assessment period (ie, 4 or 24 hours) with esophageal ph 4. LES function in patients with GERD who have persistent reflux symptoms despite PPI treatment. Compared with placebo, oral lesogaberan (65 mg twice daily) reduced the number of TLESRs, increased LES pressure, and decreased the number of reflux episodes when added to existing PPI treatment. Acid exposure and the number of proximal reflux events were also reduced with lesogaberan treatment compared with placebo. Lesogaberan was well tolerated in this patient population. TLESRs are thought to be a major mechanism behind reflux episodes, 1,2 and studies with a number of pharmacologic agents have shown that reducing the number of TLESRs can decrease the occurrence of reflux episodes in healthy subjects and in patients with GERD. 8,22 Lesogaberan reduced the number of postprandial TLESRs by 25% compared with placebo in this study, in line with the reduction seen in healthy subjects (36%) 17 and with the centrally acting GABA B -agonist baclofen in patients with GERD (40%). 11 However, there was considerable variability between individuals in the number of TLESRs, particularly with placebo. The reduction in the number of TLESRs was sustained during the 4 hours after dosing. Of greatest interest from a clinical perspective is the effect of lesogaberan on the number of reflux episodes, and, indeed, this was more marked (47% reduction over 3 hours) than the effect on TLESRs. Because the decrease in reflux episodes cannot be explained by the decrease in TLESRs alone, lesogaberan may inhibit reflux via more than one mechanism. The increase in LES pressure seen with lesogaberan, although moderate, may have been sufficient to keep nadir LES pressure above the level at which increased intra-abdominal pressure and low resting LES pressure, rather than TLESRs, cause reflux events. 1 In addition, lesogaberan could, in theory, have affected contraction of esophageal longitudinal muscle and the crus diaphragmatica (which has recently been shown to be innervated in a similar way to the LES 23 ), which could have affected LES opening because of reduced esophageal shortening and compliance, respectively. LES pressure tends to decrease after a meal even among patients with normal LES pressure at other times, as shown in Figure 3. This can make TLESRs more difficult to identify after rather than before a meal. It could therefore be possible that some TLESRs were not recorded and that this could contribute to the observed greater effect of lesogaberan on the number of reflux episodes than on the number of TLESRs. Interestingly, lesogaberan treatment had a more pronounced effect on acid reflux episodes than on weakly acidic and alkaline reflux episodes. The reasons for this are unclear, given that inhibition of reflux episodes is thought to be independent of gastric ph. However, baclofen has also been shown to reduce acid reflux to a greater extent than refluxate of a higher ph. 24 Differential effects of treatment on the inhibition of liquid, gas, or mixed gas/liquid reflux events could have an impact because liquid content is more typically associated with acid reflux. 25 Lesogaberan was not shown to reduce the Table 3. Number of Patients Reporting Adverse Events During Active Treatment Lesogaberan (n 25) Placebo (n 27) Any adverse event Serious adverse event 0 0 Discontinuations because of adverse 0 1 event Most frequently reported adverse events ( 2 patients in either treatment arm) Nervous system disorders Dizziness 3 1 Headache 8 11 Paresthesia 5 3 Gastrointestinal disorders Abdominal distension 3 1 Flatulence 2 1 Nausea 2 5 General disorders and administration site conditions Feeling hot 2 1 Skin and subcutaneous tissue disorders Hyperhidrosis 0 2 Vascular disorders Hot flush 3 1 Infections and infestations Nasopharyngitis 1 2 NOTE. Table reflects number of patients reporting adverse events during active treatment until 24 hours after the last dose.

8 416 BOECKXSTAENS ET AL GASTROENTEROLOGY Vol. 139, No. 2 number of pure gas reflux episodes but showed similar reductions relative to placebo in liquid and in mixed gas/liquid reflux events. Another possibility is that GABA B -receptor agonists could affect the amount or distribution of acid in the stomach, leading to a differential effect on the types of reflux episodes. 13,26,27 The fact that there was a reduction in the number of liquid reflux episodes, but not in the number of gas reflux episodes may also indicate an effect on gastric distribution. Lesogaberan treatment was associated with fewer proximal reflux events and lower esophageal acid exposure, which are likely to result from a reduction in the number of acid reflux events. However, a reduction in refluxate volume could also provoke these effects, and this idea is supported by the reduced acid clearance times found with lesogaberan compared with placebo. It is possible that GABA B agonists have an effect on gastric acid secretion either alone or by potentiating the effect of the PPI. 13 This could explain the preferential decrease of acid reflux and decrease in refluxate volume with lesogaberan. A high proximal extent of reflux has been strongly associated with the perception of clinical symptoms during reflux episodes in patients with GERD receiving PPI treatment Thus, by reducing the number of proximal events as well as total reflux time, lesogaberan would be expected to provide relief from symptoms of GERD. Although lesogaberan demonstrated beneficial effects on the number of TLESRs and reflux episodes, and on esophageal acid exposure, no significant effects were observed on the number of GERD symptom episodes. However, the study was not designed to be able to detect differences between the treatments. A larger randomized trial, which included 232 patients in the efficacy analysis, showed a significant difference in symptom response with lesogaberan compared with placebo. 31 Lesogaberan demonstrated a good safety and tolerability profile in this study. None of the patients experienced serious adverse events, and only 1 patient discontinued because of an adverse event (nausea), which occurred with placebo. Headache and transient, mostly mild, paresthesia were the most frequently reported adverse events during study treatment. The underlying cause of paresthesia associated with the intake of lesogaberan is not known, but the observed rapid onset of paresthesia could be a result of lesogaberan stimulating GABA B receptors located in peripheral cutaneous afferents, causing changes in membrane potential and an imbalance in the sensory input. 32,33 Few patients reported CNS-related adverse events such as dizziness and somnolence, and the number of these events was similar with lesogaberan and with placebo. The study has some limitations. Because lesogaberan was investigated as an add-on treatment to each patient s usual treatment with a PPI, the PPI regimen varied between patients. The design of the study meant that the effect of lesogaberan on symptoms could not be fully evaluated, although this has been assessed elsewhere. 31 Entry to the study was based on symptom assessment. Therefore, although more than 60% of patients reported a history of reflux esophagitis, it is possible that a proportion of patients had functional heartburn rather than GERD. This study indicates that lesogaberan has a similar pharmacodynamic effect on reflux parameters to baclofen. However, in contrast to baclofen, lesogaberan has a low incidence of CNS-related adverse effects. PPI treatment has been shown to provide high rates of symptom improvement and healing of reflux esophagitis in patients with GERD. 34,35 However, 20% 30% of patients with GERD experience persistent reflux symptoms despite taking a PPI daily In clinical practice, the proven efficacy of PPIs means that they should continue to be the mainstay of treatment for GERD. Residual symptoms in patients with a partial response to PPIs are most likely related to weakly acidic reflux, weakly alkaline reflux, esophageal hypersensitivity to refluxate, or a combination of these factors. 39 By targeting the LES, lesogaberan offers an alternative mode of action to PPIs and could be used as an add-on treatment in patients with a partial response to a PPI. In conclusion, the oral GABA B -receptor agonist lesogaberan (65 mg twice daily) reduced the number of TLESRs, increased LES pressure, and decreased reflux episodes when added to existing PPI treatment in patients with reflux symptoms despite PPI treatment. Lesogaberan was well tolerated, with a low incidence of CNS-related adverse effects. These results support future assessment of how the effects of lesogaberan on reflux and LES function might translate into symptomatic relief in patients with GERD who show a partial response to PPI treatment. References 1. Dodds WJ, Dent J, Hogan WJ, et al. Mechanisms of gastroesophageal reflux in patients with reflux esophagitis. N Engl J Med 1982;307: Dent J, Dodds WJ, Friedman RH, et al. Mechanism of gastroesophageal reflux in recumbent asymptomatic human subjects. J Clin Invest 1980;65: Trudgill NJ, Riley SA. Transient lower esophageal sphincter relaxations are no more frequent in patients with gastroesophageal reflux disease than in asymptomatic volunteers. Am J Gastroenterol 2001;96: Sifrim D, Holloway R. Transient lower esophageal sphincter relaxations: how many or how harmful? Am J Gastroenterol 2001;96: Mittal RK, Holloway RH, Penagini R, et al. Transient lower esophageal sphincter relaxation. Gastroenterology 1995;109: Kahrilas PJ. GERD pathogenesis, pathophysiology, and clinical manifestations. Cleve Clin J Med 2003;70(Suppl 5):S4 S Penagini R, Carmagnola S, Cantu P, et al. Mechanoreceptors of the proximal stomach: role in triggering transient lower esophageal sphincter relaxation. Gastroenterology 2004;126: Hirsch DP, Tytgat GN, Boeckxstaens GE. Transient lower oesophageal sphincter relaxations a pharmacological target for gastrooesophageal reflux disease? Aliment Pharmacol Ther 2002;16: Blackshaw LA. Receptors and transmission in the brain-gut axis: potential for novel therapies. IV. GABA(B) receptors in the braingastroesophageal axis. Am J Physiol Gastrointest Liver Physiol 2001;281:G311 G315.

9 August 2010 EFFECT OF LESOGABERAN ON REFLUX AND THE LES van Herwaarden MA, Samsom M, Rydholm H, et al. The effect of baclofen on gastro-oesophageal reflux, lower oesophageal sphincter function and reflux symptoms in patients with reflux disease. Aliment Pharmacol Ther 2002;16: Zhang Q, Lehmann A, Rigda R, et al. Control of transient lower oesophageal sphincter relaxations and reflux by the GABA(B) agonist baclofen in patients with gastro-oesophageal reflux disease. Gut 2002;50: Cange L, Johnsson E, Rydholm H, et al. Baclofen-mediated gastro-oesophageal acid reflux control in patients with established reflux disease. Aliment Pharmacol Ther 2002;16: Ciccaglione AF, Marzio L. Effect of acute and chronic administration of the GABA B agonist baclofen on 24-hour ph metry and symptoms in control subjects and in patients with gastro-oesophageal reflux disease. Gut 2003;52: Alstermark C, Amin K, Dinn SR, et al. Synthesis and pharmacological evaluation of novel -aminobutyric acid type B (GABA B ) receptor agonists as gastroesophageal reflux inhibitors. J Med Chem 2008;51: Brändén L, Carlsson A, Jensen J, et al. The novel GABA(B) receptor agonist AZD3355 inhibits acid reflux and reduces esophageal acid exposure as measured by 24-hour ph metry in dogs (abstract). Gastroenterology 2008;134(4 Suppl 1):A Lehmann A, Brändén L, Carlsson A, et al. AZD3355, a novel GABA(B) receptor agonist, inhibits transient lower esophageal sphincter relaxations in the dog. Gastroenterology 2008;134(4 Suppl 1):A Boeckxstaens GE, Rydholm H, Adler J, et al. Effect of AZD3355, a novel GABA(B) receptor agonist, on transient lower esophageal sphincter relaxations in healthy subjects. Gastroenterology 2009;136(Suppl 1): Shaw MJ, Talley NJ, Beebe TJ, et al. Initial validation of a diagnostic questionnaire for gastroesophageal reflux disease. Am J Gastroenterol 2001;96: Revicki DA, Wood M, Wiklund I, et al. Reliability and validity of the gastrointestinal symptom rating scale in patients with gastroesophageal reflux disease. Qual Life Res 1998;7: Holloway RH, Penagini R, Ireland AC. Criteria for objective definition of transient lower esophageal sphincter relaxation. Am J Physiol 1995;268:G128 G Sifrim D, Castell D, Dent J, et al. Gastro-oesophageal reflux monitoring: review and consensus report on detection and definitions of acid, non-acid, and gas reflux. Gut 2004;53: Lehmann A. Novel treatments of GERD: focus on the lower esophageal sphincter. Eur Rev Med Pharmacol Sci 2008;12: Young RL, Cooper NJ, Blackshaw LA. Anatomy of vagal afferent innervation of the crural diaphragm. Gastroenterology 2008; 134(4 Suppl 1):A Vela MF, Tutuian R, Katz PO, et al. Baclofen decreases acid and non-acid post-prandial gastro-oesophageal reflux measured by combined multichannel intraluminal impedance and ph. Aliment Pharmacol Ther 2003;17: Sifrim D, Holloway R, Silny J, et al. Composition of the postprandial refluxate in patients with gastroesophageal reflux disease. Am J Gastroenterol 2001;96: Del Tacca M, Blandizzi C, Bernardini MC. Central GABA A excitatory and GABA B inhibitory receptors regulate gastric acid secretion in rats. Eur J Pharmacol 1990;177: Blandizzi C, Bernardini MC, Natale G, et al. Phaclofen-sensitive GABA-B receptors do not mediate excitatory effects of baclofen on gastric secretion. Pharmacology 1991;42: Tutuian R, Vela MF, Hill EG, et al. Characteristics of symptomatic reflux episodes on acid suppressive therapy. Am J Gastroenterol 2008;103: Zerbib F, Duriez A, Roman S, et al. Determinants of gastrooesophageal reflux perception in patients with persistent symptoms despite proton pump inhibitors. Gut 2008;57: Bredenoord AJ, Weusten BL, Curvers WL, et al. Determinants of perception of heartburn and regurgitation. Gut 2006;55: Boeckxstaens GE, Beaumont H, Hatlebakk JG, et al. Efficacy and tolerability of the novel reflux inhibitor, AZD3355, as add-on treatment in GERD patients with symptoms despite proton pump inhibitor therapy. Gastroenterology 2009;136(Suppl 1):M Mogyoros I, Bostock H, Burke D. Mechanisms of paresthesias arising from healthy axons. Muscle Nerve 2000;23: Brown DA, Adams PR, Higgins AJ, et al. Distribution of GABAreceptors and GABA-carriers in the mammalian nervous system. J Physiol (Paris) 1979;75: Donnellan C, Sharma N, Preston C, et al. Medical treatments for the maintenance therapy of reflux oesophagitis and endoscopic negative reflux disease. Cochrane Database Syst Rev 2005;4: CD van Pinxteren B, Numans ME, Bonis PA, et al. Short-term treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-oesophageal reflux disease-like symptoms and endoscopy negative reflux disease. Cochrane Database Syst Rev 2004:CD Armstrong D, Pare P, Pericak D, et al. Symptom relief in gastroesophageal reflux disease: a randomized, controlled comparison of pantoprazole and nizatidine in a mixed patient population with erosive esophagitis or endoscopy-negative reflux disease. Am J Gastroenterol 2001;96: Hatlebakk JG, Hyggen A, Madsen PH, et al. Heartburn treatment in primary care: randomised, double blind study for 8 weeks. BMJ 1999;319: Meineche-Schmidt V, Hauschildt Juhl H, Ostergaard JE, et al. Costs and efficacy of three different esomeprazole treatment strategies for long-term management of gastro-oesophageal reflux symptoms in primary care. Aliment Pharmacol Ther 2004; 19: Fass R, Sifrim D. Management of heartburn not responding to proton pump inhibitors. Gut 2009;58: Received February 15, Accepted April 29, Reprint requests Address requests for reprints to: Guy E. Boeckxstaens, MD, Department of Gastroenterology, University Hospital Leuven, Catholic University of Leuven, Herestraat 49, 3000 Leuven, Belgium. guy.boeckxstaens@med.kuleuven.be; fax: (32) Acknowledgments Writing support was provided by Dr Catherine Henderson (Research Evaluation Unit, Oxford PharmaGenesis Ltd, Oxford, UK), funded by AstraZeneca R&D Mölndal, Sweden. The statistical analysis pertaining to efficacy and safety has been independently confirmed by a biostatistician who is not employed by AstraZeneca. The corresponding author had full access to all of the data and takes full responsibility for the veracity of the data and analysis. Authors employed by AstraZeneca R&D were involved in the concept and design of the study and in the analysis and interpretation of the data. Conflicts of interest The authors disclose the following: Dr Boeckxstaens has received an unrestricted grant, has participated in advisory boards of, and is/has been a consultant for AstraZeneca. Drs Denison, Ruth, Adler, and Silberg are employees of AstraZeneca. Dr Sifrim has received grant/research support from AstraZeneca. The remaining authors have no conflicts to disclose. Funding Supported by AstraZeneca R&D Mölndal, Sweden.