XP19986 Decreases Reflux and Is Well Tolerated in GERD Patients

Abstract

Purpose: XP19986 is a prodrug of R-baclofen, a GABA-b agonist. The primary objective of this study is to assess the efficacy and tolerability of a controlled-release formulation of XP19986 for decreasing the number of reflux episodes in patients with GERD. Methods: This is a multi-center, randomized, double-blind, placebo-controlled, crossover, study. Separate cohorts of patients are enrolled at each of four escalating dose levels. Enrolled patients have a history of GERD symptoms at least 3 times per week and ≥ 20 reflux episodes on impedance-pH monitoring over 2 hrs following a high-fat meal, and receive single doses of XP19986 or placebo in test periods separated by 4 to 7 days. High-fat meals are consumed at 2 and 6 hrs after dosing. Reflux episodes recorded and blood samples for XP19986 and R-baclofen levels collected through 12-hours post-dose. Other measures include GERD symptoms, vital signs, ECG, and clinical labs. Results: The primary endpoint for the clinical trial was the total number of reflux events over the 12-hour monitoring period following the dose of XP19986. For the combined 10, 20 and 40 mg groups (N = 35), the median number of reflux events during placebo treatment was 51.0, and there were fewer reflux events during XP19986 (median difference 7.0; Wilcoxon signed-rank p= 0.034). For the individual 10, 20 and 40 mg dosage groups, the median number of reflux events during placebo treatment was 79.0 (N = 12), 52.0 (N = 12) and 34.0 (N = 11), respectively. The median reduction during XP19986 treatment compared to placebo was 2.0 (p= 0.458), 11.5 (p= 0.210) and 10.0 (p= 0.051), respectively. In the 40 mg dose group, 9 of 11 patients had fewer reflux events after XP19986 treatment than after placebo treatment. XP19986 was well tolerated at all dose levels: no adverse event occurred in more than one patient on XP19986. Fatigue occurred in 1 patient each on placebo and XP19986. Nausea occurred in 3 patients on placebo and none on XP19986, headache in 3 on placebo and none on XP19986. Conclusions: The results for three dose levels of XP19986 are encouraging, both in terms of the efficacy in reducing reflux and the favorable tolerability of XP19986 in patients with GERD. Data for the 60 mg dose group and pharmacokinetic results will be available at the time of the meeting.