Lesogaberan development halts following disappointing results

Jul 10 2012

Lesogaberan is only marginally superior to placebo in gastroesophageal reflux disease (GERD) patients who are partially responsive to proton pump inhibitor (PPI) therapy, results show.

In a phase IIb study of the gamma-aminobutyric acid (GABA_B) receptor agonist, only the highest dose tested (240 mg) resulted in a statistically significant response over placebo. This translated to a small absolute increase in the proportion of responders, with a corresponding number needed to treat of 12.

Nicholas Shaheen (University of North Carolina, USA) and colleagues say "this degree of effectiveness is unlikely to be sufficient to make lesogaberan treatment a consideration for most physicians."

As published in Gut, 661 patients with ongoing reflux symptoms, despite at least 4 weeks of optimized PPI therapy, received add-on lesogaberan therapy for 4 weeks. A response was defined as at least 3 additional days on average per week with not more than mild intensity symptoms in any of the 13 items of the Reflux Symptom Questionnaire electronic Diary (RESQ-eD).

The proportion of patients who responded at twice-daily doses of 60, 120, 180 and 240 mg were 20.9%, 25.6%, 23.5%, and 26.2%, respectively, in comparison to 17.9% in the placebo group.

The authors also assessed RESQ-eD results for each of the symptoms individually. The proportion of days with not more than mild regurgitation, burping, heartburn, and overall symptoms compared with baseline was significantly increased relative to placebo for all doses of at least 120 mg. However, these declines resulted in less than 1 additional day per week with not more than mild symptoms.

The development of lesogaberan was part of ongoing efforts to provide a treatment option to the 20-30% of GERD sufferers who fail to fully respond to PPI therapy. The GABA_B agonist baclofen is effective in these patients, but is associated with substantial adverse effects. Lesogaberan was developed as a potentially effective treatment for GERD with limited access to the central nervous system.

Disappointingly, the findings of this study echo similarly modest results in the earlier phase IIa trial, in which patients received a substantially lower dose of only 65 mg. As a result, AstraZeneca has halted the development of lesogaberan in this group of patients.

The authors say further research is required and that development of an effective alternative therapy "would be aided by a better understanding of the pathophysiology of the condition… and better identification of the proportion of these patients whose symptoms are functional or non-reflux related."

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