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Sirs, We read with great interest and excitement the recent article by Zerbib et al. that evaluated the effect of ADX10059, an mGluR5 inhibitor in patients with gastro-oesophageal reflux disease (GERD) who were responsive to proton pump inhibitor (PPI) treatment. We congratulate the authors for a study well done.1

ADX10059 is one of less than a handful of TLESR-reducer compounds currently under development. This line of drugs was launched with great fanfare, because it is the first to specifically target TLESR, the underlying mechanism of GERD. However, drug development thus far for TLESR reducers has been plagued by many obstacles including modest clinical efficacy and high level of adverse events.2, 3

While TLESR reducers have been primarily niched in patients who failed PPI treatment, the authors included only patients who demonstrated complete symptomatic response to PPIs, enriching the study population with true refluxers. Interestingly, the mean number of GERD symptom-free days, which was the primary clinical endpoint of the study, was modestly greater in the ADX10059 group when compared with placebo (week 2 – 0.9 days, 2 weeks – 0.6 days). It is possible that the full clinical effect of ADX10059 is not achievable after only 2 weeks of treatment.

Unfortunately, 62% of those who received ADX10059 developed side effects (when compared to 28% in the placebo group). Many are centrally mediated (dizziness, vertigo and sleep disorders), which may impede long-term usage of the drug.

Overall, in this well-designed and -executed study, the authors were able to demonstrate the clinical efficacy of ADX10059 when compared with placebo. Unfortunately, the authors stated that further development was halted because of safety issues observed in another longer-term trial. This statement, in addition to the recent decision to discontinue development of lesogaberan, raises the concern that development of this valuable class of drugs may have hit a ‘brick wall’.

Acknowledgement

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  2. Acknowledgement
  3. References

Declaration of personal and funding interests: None.

References

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  2. Acknowledgement
  3. References
  • 1
    Zerbib F, Bruley des Varannes S, Roman S, et al. Randomised clinical trial: effects of monotherapy with ADX10059, a mGluR5 inhibitor, on symptoms and reflux events in patients with gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2011; 33: 91121.
  • 2
    Boeckxstaens GE, Beaumont H, Mertens V, et al. Effects of lesogaberan on reflux and lower esophageal sphincter function in patients with gastroesophageal reflux disease. Gastroenterology 2010; 139: 40917.
  • 3
    Gerson LB, Huff FJ, Hila A, et al. Arbaclofen placarbil decreases postprandial reflux in patients with gastroesophageal reflux disease. Am J Gastroenterol 2010; 105: 126675.