lesogaberan and Gastroesophageal-Reflux

Lesogaberan, a γ-aminobutyric acid (GABA)B receptor agonist, was developed for the treatment of gastroesophageal reflux disease in patients with a partial response to proton pump inhibitor therapy. A high prevalence of paresthesia was observed in healthy individuals after dosing with lesogaberan in early-phase clinical trials. The aim of this review was to gain further insight into paresthesia caused by lesogaberan by summarizing the relevant preclinical and clinical data.. This study was a narrative review of the literature and unpublished data.. The occurrence of paresthesia may depend on the route or rate of drug administration; several studies were conducted to test this hypothesis, and formulations were developed to minimize the occurrence of paresthesia. Phase I clinical studies showed that, in healthy individuals, paresthesia occurred soon after administration of lesogaberan in a dose-dependent manner regardless of the route of administration. The occurrence of paresthesia could be decreased by fractionating the dose or reducing the rate of administration. These findings suggest that the initial rate of absorption plays an important part in the development of paresthesia. Modified-release formulations minimize the occurrence of paresthesia while retaining the anti-reflux activity of the drug, as measured by esophageal pH and the number of transient lower esophageal sphincter relaxations.. The development of lesogaberan was halted because the effect on gastroesophageal reflux disease symptoms observed in Phase II studies was not considered clinically meaningful in the target patient population. Nevertheless, it is an example of successful formulation development designed to minimize the occurrence of a compound's adverse effect while retaining its pharmacodynamic action.

Topics: GABA-A Receptor Agonists; Gastroesophageal Reflux; Humans; Paresthesia; Phosphinic Acids; Propylamines

The management of patients with refractory GERD (rGERD) is a major clinical challenge for gastroenterologists. In up to 30% of patients with typical GERD symptoms (heartburn and/or regurgitation), acid-suppressive therapy does not provide clinical benefit. In this Review, we discuss the current management algorithm for GERD and the features and management of patients who do not respond to treatment (such as those individuals with an incorrect diagnosis of GERD, inadequate PPI intake, persisting acid reflux and persisting weakly acidic reflux). Symptom response to existing surgical techniques, novel antireflux procedures, and the value of add-on medical therapies (including prokinetics and reflux inhibitors) for rGERD symptoms are discussed. Pharmaceutical agents targeting oesophageal sensitivity, a condition that can contribute to symptom generation in rGERD, are also discussed. Finally, on the basis of available published data and our expert opinion, we present an outline of a current, usable algorithm for management of patients with rGERD that considers the timing and diagnostic use of pH-impedance monitoring on or off PPI, additional diagnostic tests, the clinical use of baclofen and the use of add-on neuromodulators (tricyclic agents and selective serotonin reuptake inhibitors).

Topics: Alginates; Algorithms; Antacids; Baclofen; Chronic Disease; Esophagoscopy; Gastroesophageal Reflux; Gastrointestinal Agents; Gastroscopy; Humans; Isoxazoles; Muscle Relaxants, Central; Neurotransmitter Agents; Phosphinic Acids; Propylamines; Triazoles

The development of the novel γ-aminobutyric acid type-B receptor (GABAB) agonist lesogaberan is presented as an example of a partly successful translational strategy in the field of gastroenterology. Data on transient lower esophageal sphincter relaxations (TLESRs) and gastroesophageal reflux inhibition from preclinical models translated well to clinical studies in healthy volunteers and patients with gastroesophageal reflux disease (GERD). Animal models have also been used successfully to predict the effect of other target mechanisms on TLESRs in humans. However, while translation of physiology to symptomatology in patients with GERD was achieved, the effect size was too small to be of clinical significance. A deeper understanding of the cause of symptoms in different patient categories is therefore required.

Topics: Animals; Baclofen; Dogs; Drug Resistance; Esophageal Sphincter, Lower; GABA-B Receptor Agonists; Gastroesophageal Reflux; Gastrointestinal Agents; Humans; Muscle Relaxation; Neuromuscular Agents; Phosphinic Acids; Propylamines; Species Specificity; Translational Research, Biomedical

Gastroesophageal reflux disease (GERD) comprises all symptoms and clinical consequences in the context of reflux of stomach contents into the esophagus. The symptoms reported by patients include heartburn, regurgitation and sour taste in the mouth. In some cases atypical reflux associated symptoms such as asthma, laryngitis or recurrent pneumonias are reported. Pathophysiologically an incompetence of the lower esophageal sphincter and a disturbed clearance of the esophagus are the underlying mechanisms. Current treatment recommendations include a change of lifestyle and a drug treatment with proton pump inhibitors (PPI) being widely used. In patients with persistent symptoms other diagnoses like functional dyspepsia should be considered especially when additional symptoms like epigastric pain, postprandial fullness and nausea are present. This review summarizes the current understanding of the pathophysiology, the diagnosis and the treatment of GERD and gives an outlook on therapies currently developed for the treatment of reflux disease. A promising new drug, presently classified as being a reflux inhibitor, is lesogaberan. Lesogaberan is presently studied in phase II clinical trials.

Topics: Antacids; Drug Resistance; GABA Antagonists; Gastroesophageal Reflux; Histamine H2 Antagonists; Humans; Phosphinic Acids; Propylamines; Proton Pump Inhibitors; Receptors, GABA-A

Topics: Baclofen; GABA-B Receptor Agonists; Gastroesophageal Reflux; Humans; Phosphinic Acids; Propylamines; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate

The γ-aminobutyric acid type B-receptor agonist lesogaberan (AZD3355) has been developed for use in patients with gastroesophageal reflux disease (GERD) symptoms despite proton pump inhibitor (PPI) therapy (partial responders). This study aimed to explore the dose-response effect of lesogaberan on reflux episodes in partial responders.. In this randomized, single-centre, double-blind, crossover, placebo-controlled study, partial responders taking optimised PPI therapy were given 30, 90, 120 and 240 mg doses of lesogaberan. Each dose was given twice (12 h apart) during a 24-h period, during which impedance-pH measurements were taken.. Twenty-five patients were included in the efficacy analysis and 27 in the safety analysis. The effect of lesogaberan on the mean number of reflux episodes was dose-dependent, and all doses significantly reduced the mean number of reflux episodes relative to placebo. Lesogaberan also dose-dependently reduced the mean number of acid reflux episodes (except the 30 mg dose) and weakly acid reflux episodes (all doses) significantly, relative to placebo. Regardless of dose, lesogaberan had a similar effect on the percentage of time with esophageal pH < 4 [mean reduction: 68.5% (30 mg), 54.2% (90 mg), 65.9% (120 mg), 72.1% (240 mg); p < 0.05 except 90 mg dose]. No adverse events led to discontinuation and no serious adverse events occurred during active treatment.. Lesogaberan inhibited reflux in a dose-dependent manner in partial responders taking optimised PPI therapy, and these effects were significant versus placebo. All lesogaberan doses were well tolerated and were not associated with clinically relevant adverse events.. ClinicalTrials.gov identifier: NCT01043185.

Topics: Adult; Aged; Dose-Response Relationship, Drug; Double-Blind Method; Esophagus; Female; GABA-A Receptor Agonists; Gastroesophageal Reflux; Gastrointestinal Agents; Headache; Humans; Hydrogen-Ion Concentration; Male; Middle Aged; Nausea; Phosphinic Acids; Propylamines; Young Adult

Lesogaberan (AZD3355) is a novel γ-aminobutyric acid B-type receptor agonist designed to treat gastro-oesophageal reflux disease (GERD) by inhibiting transient lower oesophageal sphincter relaxations. A randomised, double-blind, placebo-controlled, multi-centre phase IIb study was performed to assess the efficacy and safety of lesogaberan as an add-on to proton pump inhibitor (PPI) therapy in patients with GERD who are partially responsive to PPI therapy (ClinicalTrials.gov reference: NCT01005251).. In total, 661 patients were randomised to receive 4 weeks of placebo or 60, 120, 180 or 240 mg of lesogaberan twice daily, in addition to ongoing PPI therapy. Symptoms were measured using the Reflux Symptom Questionnaire electronic Diary. Response to treatment was defined as having an average of ≥ 3 additional days per week of not more than mild GERD symptoms during treatment compared with baseline.. In the primary analysis, 20.9%, 25.6%, 23.5% and 26.2% of patients responded to the 60, 120, 180 and 240 mg twice daily lesogaberan doses, respectively, and 17.9% responded to placebo. The response to the 240 mg twice daily dose was statistically significantly greater than the response to placebo using a one-sided test at the predefined significance level of p < 0.1. However, the absolute increases in the proportions of patients who responded to lesogaberan compared with placebo were low. Lesogaberan was generally well tolerated, although six patients receiving lesogaberan developed reversible elevated alanine transaminase levels.. In patients with GERD symptoms partially responsive to PPI therapy, lesogaberan was only marginally superior to placebo in achieving an improvement in symptoms.

Topics: Adult; Dose-Response Relationship, Drug; Double-Blind Method; Drug Monitoring; Drug Therapy, Combination; Esophageal Sphincter, Lower; Female; GABA-A Receptor Agonists; Gastroesophageal Reflux; Humans; Male; Middle Aged; Phosphinic Acids; Propylamines; Proton Pump Inhibitors; Treatment Outcome

Approximately 20-30% of patients with gastroesophageal reflux disease (GERD) do not experience complete symptom resolution during proton pump inhibitor (PPI) therapy. The aim of this study was to determine the prevalence of esophageal mucosal breaks among patients who have a partial response to PPI therapy.. This was an analysis of data from a phase 2b clinical trial carried out to assess the efficacy and safety of a reflux inhibitor, lesogaberan (AZD3355), as an add-on to PPI therapy in this patient population (clinicaltrials.gov reference: NCT01005251). A total of 661 patients with persistent GERD symptoms who had received a minimum of 4 weeks of PPI therapy were included in the study. The prevalence of esophageal mucosal breaks was assessed according to (i) the most recent endoscopy results from within the previous 24 months, if available ("historical" endoscopies), and (ii) the results of endoscopies performed at study baseline ("baseline" endoscopies). Baseline endoscopies were not carried out in patients who had a historical endoscopy showing an absence of esophageal mucosal breaks.. Historical endoscopy results were available for 244 patients, of whom 48 (19.7%) had esophageal mucosal breaks. Baseline endoscopies were carried out in 465 patients, of whom 146 (31.4%) had esophageal mucosal breaks. Sensitivity analyses showed a prevalence of esophageal mucosal breaks of 20-30%. In both the historical and baseline endoscopies, most esophageal mucosal breaks were Los Angeles grades A or B.. In patients with GERD symptoms partially responsive to PPI therapy, mild-to-moderate severity esophageal mucosal breaks are common (prevalence 20-30%), and may contribute to symptom etiology.

Topics: Adult; Drug Therapy, Combination; Endoscopy; Esophagitis, Peptic; Female; Gastroesophageal Reflux; Humans; Male; Middle Aged; Phosphinic Acids; Prevalence; Propylamines; Proton Pump Inhibitors; Treatment Outcome

o evaluate the efficacy and tolerability of add-on treatment with lesogaberan (AZD3355), a novel reflux inhibitor, in patients with persistent gastro-oesophageal reflux disease (GORD) symptoms despite proton pump inhibitor (PPI) therapy.. double-blind, placebo-controlled, randomised, parallel-group, multicentre phase IIA study was carried out in outpatient clinics. The study group comprised 244 adult patients with persistent GORD symptoms (heartburn and/or regurgitation) of at least mild intensity and for 3 days of 7 days before enrolment, despite ≥6 weeks of continuous PPI therapy. Patients received either lesogaberan (65 mg twice daily) or placebo in addition to PPI therapy for a period of 4 weeks. Symptom intensity, based on the Reflux Disease Questionnaire, was recorded twice daily. Treatment response (defined as at most one 24 h period with heartburn or regurgitation of not more than mild intensity during the last 7 days of treatment). Time to response, proportion of symptom-free days and measures of tolerability were also analysed.. total of 232 (114 lesogaberan- and 118 placebo-treated patients) of the 244 randomised patients were analysed for efficacy. Treatment with lesogaberan, compared with placebo, resulted in a significantly larger proportion of responders to treatment (16% vs 8% of patients; p=0.026) and cumulative proportion of responders over time (log-rank p=0.0195). Lesogaberan was well tolerated: adverse events of mostly mild to moderate intensity were reported in 45% of patients on lesogaberan and in 37% on placebo.. esogaberan add-on therapy to PPIs significantly improved heartburn and regurgitation symptoms; however, the proportion of responders was small. Clinical trial number NCT00394472.

Topics: Adolescent; Adult; Aged; Drug Administration Schedule; Drug Therapy, Combination; Epidemiologic Methods; Female; GABA-A Receptor Agonists; Gastroesophageal Reflux; Gastrointestinal Agents; Humans; Male; Middle Aged; Phosphinic Acids; Propylamines; Proton Pump Inhibitors; Time Factors; Treatment Outcome; Young Adult

Transient lower oesophageal sphincter relaxations (TLESRs) are a major mechanism behind gastro-oesophageal reflux disease (GERD).. To assess the effect of lesogaberan (AZD3355) - a novel peripherally active GABA(B) receptor agonist - on TLESRs.. Twenty-four healthy men were enrolled in this single-blind, placebo-controlled, randomized, single-centre, three-period crossover phase 1 study. Subjects were randomized to receive single oral doses of lesogaberan (0.8 mg/kg), baclofen (40 mg) and placebo, separated by washout periods of < or = 7 days. Subjects finished a meal 1 h after the dose. Oesophageal manometry and pH-metry measurements were taken during the 3 h after the meal.. Twenty-one subjects completed the study. Compared with placebo, lesogaberan 0.8 mg/kg significantly reduced the number of TLESRs by 36% [geometric mean ratio (GMR): 0.64; 95% confidence interval (CI): 0.51-0.82] and significantly reduced the number of acid reflux episodes (mean reduction: 1.6; 95% CI: 0.34-2.9). Lesogaberan also significantly increased lower oesophageal sphincter (LES) pressure by 39% compared with placebo (GMR: 1.39; 95% CI: 1.18-1.64). Comparable results were observed with baclofen. Similar numbers of adverse events were reported by subjects taking lesogaberan and placebo.. Compared with placebo, lesogaberan significantly reduced TLESRs and acid reflux episodes and increased LES pressure.

Topics: Adolescent; Adult; Baclofen; Cross-Over Studies; Esophageal Sphincter, Lower; GABA Agonists; Gastroesophageal Reflux; Humans; Male; Manometry; Middle Aged; Muscle Relaxation; Phosphinic Acids; Propylamines; Young Adult

Transient lower esophageal sphincter relaxations (TLESRs) are a major mechanism behind reflux. This study assessed the effects of lesogaberan (AZD3355), a novel gamma-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.. 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 45-60 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.. 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 approximately 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).. 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.

Topics: Administration, Oral; Adult; Aged; Belgium; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Esophageal pH Monitoring; Esophageal Sphincter, Upper; Female; GABA Agonists; Gastroesophageal Reflux; Humans; Male; Manometry; Middle Aged; Netherlands; Phosphinic Acids; Postprandial Period; Pressure; Propylamines; Proton Pump Inhibitors; Time Factors; Treatment Outcome

Proton pump inhibitors (PPIs) are the gold standard treatment for gastroesophageal reflux disease. In clinical practice, failure of PPIs occurs frequently, and may affect up to 30% of patients in a typical gastroenterology practice. Multichannel impedance monitoring combined with pH monitoring helps to detect nonacid reflux, and if symptoms correlate with these nonacid reflux episodes, nonacid reflux disease can be diagnosed. In contrast to PPIs, reflux inhibitors target transient lower esophageal sphincter relaxations, which are involved in the pathophysiology of reflux disease and may be the appropriate future treatment for nonacid reflux disease. The present article discusses the current understanding of nonacid reflux disease, its diagnosis and treatment.

Topics: Baclofen; Esophageal Sphincter, Lower; Gastroesophageal Reflux; Humans; Phosphinic Acids; Propylamines; Proton Pump Inhibitors; Receptors, GABA-A

While patients with symptoms of gastroesophageal reflux disease generally respond well to proton pump inhibitors, 20-30% continue to experience troublesome symptoms. In such cases, agents that target transient lower esophageal sphincter (LES) relaxation may be useful as add-on therapy to proton pump inhibitors. The GABAB receptor agonist baclofen inhibits transient LES relaxation but it is not an ideal agent due to central nervous system activity. Lesogaberan (AZD3355) is a peripherally restricted GABAB receptor agonist with limited central nervous system activity that inhibits transient LES relaxation in dogs. In the present study, the comparative effects of lesogaberan (7 micromol/kg) and baclofen (2.8 micromol/kg) on reflux were studied in dogs using 24-h pHmetry. Drugs (or vehicle control) were administered orally prior to the first meal of the day, and the number of reflux episodes (pH<4 for > or = 5 s) and acid exposure time were computed for the 24-h monitoring period. The mean (S.E.M.) number of reflux episodes/24 h was 4.6 (0.4) and 6.4 (0.6) for lesogaberan and baclofen, respectively, versus 10.7 (0.5) for control (P<0.0001 for both). Acid exposure time was 51.2 (4.5) min for control versus 23.6 (3.8) min for lesogaberan (P<0.0001) and 35.4 (6.5) min with baclofen (P=0.05). It is concluded that lesogaberan significantly reduces acid reflux in dogs, with comparable efficacy to baclofen.

Topics: Animals; Baclofen; Dogs; Esophagus; Female; GABA Agonists; GABA-B Receptor Agonists; Gastric Acid; Gastroesophageal Reflux; Hydrogen-Ion Concentration; Male; Manometry; Phosphinic Acids; Pilot Projects; Propylamines; Receptors, GABA-B; Time Factors

Proton pump inhibitors are highly successful in treating gastroesophageal reflux disease, but a significant proportion of patients have persistent symptoms from weakly or nonacidic reflux. Transient lower esophageal sphincter relaxation (TLESR) represents the dominant mechanism of gastroesophageal reflux and has therefore become the most intensely investigated therapeutic target. The triggering of TLESR involve the vagal pathways and the gamma-aminobutyric type B (GABA(B)) and metabotropic glutamate type 5 (mGluR5) receptors. Baclofen is a GABA(B) receptor agonist that is effective in inhibiting TLESR and reducing the number of reflux episodes, but is associated with significant central nervous system (CNS) side effects. The newer GABA(B) agonists, such as AZD9343 and AZD3355, and mGluR5 antagonists, such as 2-methyl-6-(phenylethynyl)-pyridine (MPEP), have been shown in small, randomized, controlled trials to have comparable efficacy to baclofen, but possibly a more favorable CNS side effect profile. Cannibinoid agonists, such as Delta(9)-THC, have also been demonstrated to reduce TLESRs and reflux events respectively. Macrolide antibiotics (eg, erythromycin) show early promise in a select group of patients with possible reflux associated post-lung transplant problems.

Topics: Animals; Baclofen; Cannabinoid Receptor Agonists; Dogs; Dronabinol; Erythromycin; GABA Agonists; GABA-B Receptor Agonists; Gastroesophageal Reflux; Gastrointestinal Agents; Humans; Phosphinic Acids; Propylamines; Proton Pump Inhibitors; Pyridines; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate

Topics: Drug Therapy, Combination; Esophageal Sphincter, Upper; GABA Agonists; Gastroesophageal Reflux; Humans; Muscle Relaxation; Phosphinic Acids; Pressure; Propylamines; Proton Pump Inhibitors; Time Factors; Treatment Outcome

Lesogaberan, under development by AstraZeneca plc, is a GABA(B) agonist for the potential treatment of gastroesophageal reflux disease (GERD). In vitro, lesogaberan was an efficient GABA(B) agonist and was taken up by GABA(B) receptors, thereby maintaining low extracellular levels of lesogaberan in the CNS and avoiding the serious CNS side-effect profile of the GABA(B) agonist baclofen. In phase I and IIa clinical trials, lesogaberan treatment was well tolerated, and resulted in a substantial reduction in reflux episodes by decreasing the frequency of transient lower esophageal sphincter relaxations. At the time of publication, a phase IIa trial was ongoing in patients with GERD that was partially refractive to standard proton pump inhibitor (PPI) therapy. Lesogaberan may have potential to be used as an add-on therapy to PPIs. However, the safety, efficacy and advantages of lesogaberan compared with existing therapies remain to be established in phase IIb and III trials.

Topics: Animals; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drug Therapy, Combination; Esophageal Sphincter, Lower; GABA Agonists; GABA-B Receptor Agonists; Gastroesophageal Reflux; Humans; Phosphinic Acids; Propylamines; Proton Pump Inhibitors; Receptors, GABA-B; Tissue Distribution

We have previously demonstrated that the prototypical GABA B receptor agonist baclofen inhibits transient lower esophageal sphincter relaxations (TLESRs), the most important mechanism for gastroesophageal reflux. Thus, GABA B agonists could be exploited for the treatment of gastroesophageal reflux disease. However, baclofen, which is used as an antispastic agent, and other previously known GABA B agonists can produce CNS side effects such as sedation, dizziness, nausea, and vomiting at higher doses. We now report the discovery of atypical GABA B agonists devoid of classical GABA B agonist related CNS side effects at therapeutic doses and the optimization of this type of compound for inhibition of TLESRs, which has resulted in a candidate drug ( R)- 7 (AZD3355) that is presently being evaluated in man.

Topics: Animals; Dose-Response Relationship, Drug; GABA Agonists; GABA-B Receptor Agonists; Gastroesophageal Reflux; Humans; Magnetic Resonance Spectroscopy; Spectrometry, Mass, Fast Atom Bombardment