Gastro-oesophageal reflux disease, or GERD, is the result of stomach acid backing up into the oesophagus, damaging the mucosa. It is commonly caused by the lower oesophageal sphincter relaxing and failing to keep the stomach closed. If left untreated, in the worst case scenario it can lead to cancer of the oesophagus.
Treatment generally relies on using proton pump inhibitors such as omeprazole to reduce the acid, and in some cases surgery can help, but this rarely provides a long-term solution. Not all patients respond to PPI drugs, though, and another strategy would be to use a drug that inhibits the transient lower oesophageal sphincter relaxation (TLESR) that allows the acid to exit the stomach upwards, and the γ-aminobutyric acid B receptor agonist baclofen has this effect. The CNS side-effects of baclofen render it far from ideal as a long-term treatment option, and a new GABAB agonist with a better side-effect profile, lesogaberan, is being developed by AstraZeneca.1
In a single blind, placebo-controlled crossover Phase I trial, 24 healthy male subjects were given 0.8mg/kg single doses of lesogaberan, 40mg baclofen or placebo followed by a meal after an hour, separated by washout periods of up to seven days.2 Lesogaberan reduced the number of TLESRs; comparable results were seen to baclofen, but the side-effect profile of lesogaberan was comparable to placebo.
A double blind, placebo-controlled trial was carried out in 27 patients with GERD. They were given 65mg lesogaberan or placebo twice on day one and once on day two in addition to PPI therapy, and ate 45-60 mins after the morning dose.3 In the first 24 hours, lesogaberan reduced the mean number of reflux events by about a third, with the most common adverse events being headache and paraesthesia, with similar incidences in both placebo and treatment groups.
A double blind, placebo-controlled, parallel group Phase IIa study has also been carried out in 244 patients whose GERD symptoms persisted despite PPI therapy.4 Subjects were given 65mg lesogaberan or placebo plus PPIs for four weeks, and symptom intensity recorded twice a day. Of the 232 evaluable patients, 16% of the lesogaberan group responded, compared with 8% of the placebo group. Those who did respond had a significant improvement in their heartburn and regurgitation symptoms, and adverse events were largely mild to moderate.
references
1. C. Alstermark et al. J. Med. Chem. 2008, 51, 4315
2. G.E. Boeckxstaens et al. Aliment. Pharmacol. Ther. 2010, 31, 1208
3. G.E. Boeckxstaens et al. Gastroenterol. 2010, 139, 409
4. G.E. Boeckxstaens et al. Gut 2011, epub ahead of print, 14 Mar 2011