ADX10059 in GERD

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In data from Addex Phase IIa trial, released in April 2007, ADX10059 reduced the extent of esophageal acid exposure compared to placebo. The primary endpoint, the percentage of time that esophageal pH (a measure of acidity) was less than 4 during a 24-hour period, was statistically significantly improved during ADX10059 treatment compared to placebo administration. Importantly, night time reflux, which is often poorly controlled by conventional acid-suppressing therapies and causes sleep disturbance and increased risk of esophageal damage, was also significantly reduced by ADX10059 (see Fig. 2.1).

ADX10059 also reduced exposure of the esophagus to acid during the critical periods following meals, when GERD can be most troublesome and most resistant to marketed therapies (see Fig. 2.2).

The benefits on the physiological measures of reflux were also observed as a reduction in clinical symptoms. Patients reported fewer and shorter episodes of GERD symptoms on the active treatment day. Specifically, on the placebo treatment day, patients experienced an average of 7 symptomatic episodes, each lasting an average of 14 minutes. These were reduced to an average of 2 episodes, each lasting 5 minutes during treatment (see Fig. 2.3).

ADX10059 Phase IIa GERD data were presented at the 2007 United European Gastroenterology Week, a peer reviewed clinical research conference in October 2007.

Although ADX10059 demonstrated clinically and statistically significant efficacy, some CNS side effects were observed in Phase IIa testing, including dizziness, drunk feeling and flushing. Addex hypothesized in 2007 that the cause of these side effects was the rapid absorption of ADX10059 and subsequently developed a modified release formulation that would slow the rate of absorption.

The new formulation entered Phase I testing (studies 104 & 105) in 2008 and, in September 2008, Addex confirmed that it slowed the rate of absorption, reduced peak plasma concentration levels and stayed in the body longer than the unformulated version, which was simply the active pharmaceutical ingredient in capsules. (Click on the bottom right graphic "Part One Results: mean plasma profile" to enlarge it)

Part One of Study 104 was a single-dose, three-way crossover trial in 12 healthy volunteers where the pharmacokinetics, safety and tolerability of two modified release (MR) formulations of ADX10059 250 mg were compared to the original 250mg API filled capsules used in Phase IIa. No adverse events were observed with the formulation selected for Phase IIb testing. In contrast, seven of 12 subjects taking the original ADX10059 250mg API in capsules experienced side effects like dizziness, drunk feeling and flushing.

Part Two of Study 104 showed that ADX10059 MR continued to show clinically and statistically significant activity despite its dramatically improved tolerability profile. Specifically, after six days of ADX10059 MR (50mg, 125mg or 250mg) statistically significant dose-dependent treatment effects were observed during the reflux provocation test for the percentage of total acid exposure (p = 0.0483) and the post-prandial number of weakly acid reflux episodes (p = 0.0411) compared to placebo. Efficacy was measured in 24 healthy volunteers using impedence/pH-metry after GERD was induced using a high fat, large volume meal. This human model of GERD is well established and considered predictive for GERD patients.

In addition, statistically significant effects (p<0.05) were seen for the ADX10059 125 mg dose compared to placebo for impedance measured reflux, weakly acidic reflux, acid exposure percent, and bolus exposure percent. Statistically significant results (p<0.05) also were seen for various pharmacodynamic measures with the 250 mg dose compared to placebo. The 250mg dose did not demonstrate an advantage over the 125 mg dose. Decreases in some reflux parameters were apparent for the 50mg dose group compared to placebo but did not achieve statistical significance.

Study 105 was a Phase I three-way crossover study in 15 healthy volunteers of the interaction of a single 250mg dose of the modified release formulation ADX10059 with food and with the proton pump inhibitor esomeprazole. Data from Study 105 show that neither food nor esomeprazole significantly altered the absorption of ADX10059.

The pharmacokinetics observed in Studies 104 and 105 confirmed satisfactory drug exposure with twice daily oral dosing. As in all previous studies, all safety monitoring parameters were unaffected by ADX10059.

More recently, Phase IIb data from study 204, have shown that ADX10059 worked to reduce reflux and patient reported symptoms. However, data from study 206, a 3-month study in migraine, have shown liver toxicity and led Addex to end development of the long-term use of ADX10059.