Management of Gastroesophageal Reflux Disease that does not Respond Well to Proton Pump Inhibitors

Tiberiu Hershcovici and Ronnie Fass


Curr Opin Gastroenterol. 2010;26(4):367-378. 

In This Article

Future Therapy

Several directions in drug development have been pursued in patients who failed PPI treatment. These include more early and profound acid suppression, reduction in the rate of TLESRs, improving esophageal and/or gastric motility, attenuation of esophageal pain and mucosal coating of the esophagus.

Vecam, a combination of a PPI and succinic acid (an acid pump activator, VB101), is a drug that has meal-independent antisecretory effect. Oral administration of succinic acid in humans has the same acid-stimulating activity as pentagastrin, and succinic acid given to rats augments PPI antisecretory effects.[94]

AGN 201904-Z is a slowly absorbed, acid-stable pro-PPI that rapidly converts to omeprazole in the systemic circulation. A single oral dose provides continued metered absorption (CMA) that prolongs plasma residence time. Consequently, the activated proton pumps are exposed over longer period of time to the drug. In a 5-day phase I study, AGN 201904-Z produced a significantly greater acid suppression than esomeprazole 40 mg per day. Nocturnal acid suppression also was significantly greater for AGN 201904-Z, which reduced the proportion of patients exhibiting NAB (25 vs. 100%).[95]

Tenatoprazole is an imidazopyridine-based PPI with a prolonged plasma half-life. Tenatoprazole 40 mg daily provides better night-time acid control than esomeprazole 40 mg once daily. In a single-center, double-blind, double-dummy, randomized, four-way cross-over study that was conducted in 32 healthy male individuals, S-tenatoprazole-sodium produced significantly greater and more prolonged 24-h and nocturnal acid suppression than esomeprazole 40 mg.[96]

Several new compounds that combine a PPI with an H2RA have been recently evaluated. All are still in early stages of development. The fast-dissolving OX 17 is a fixed-dose combination of omeprazole and famotidine. This drug has undergone several phase II/III clinical trials.[97] In addition, a combination of an H2RA with tenatoprazole has been recently patented.[98] Further studies are needed to determine the value of these compounds in refractory GERD patients.