The Safety, Tolerability, Systemic Exposure, and Effect on Bowel Habits of Single and Multiple Doses of the Intestinal Sodium Re-Uptake Inhibitor RDX5791 in Normal Healthy Volunteers

Abstract

Purpose: RDX5791 is a first-in-class minimally systemic, small molecule NHE3 inhibitor in clinical development for the treatment of IBS-C and other constipation-related diseases. The intestinal Na+/H+ antiport protein NHE3 plays a key role in the uptake of sodium, and thus water, from the intestinal lumen. RDX5791 increases intestinal sodium leading to enhanced intestinal fluid volume and transit. RDX5791 has also been shown to have an anti-nociceptive effect in an IBS animal model of visceral pain. The purpose of this study was to evaluate the safety, tolerability, systemic exposure and pharmacodynamics of RDX5791, after single and 7 daily oral doses to healthy volunteers. Methods: A randomized, double-blind, placebo-controlled, study was performed in 80 healthy male and female volunteers at single ascending doses of 10, 50, 150, 450, and 900 mg (6 treated, 2 placebo/group) and multiple ascending doses of 3, 10, 30, and 100 mg (8 treated, 2 placebo). Safety assessments were performed routinely and included vital signs, ECGs, hematology, and serum chemistry evaluations as well as adverse event assessments. The pharmacodynamics of RDX5791 on bowel habits was assessed by recording stool frequency (time), weight, and consistency utilizing the Bristol Stool Form Scale (BSFS). Results: RDX5791 was very well tolerated and exhibited minimal systemic absorption. There were no SAEs observed and very few adverse events. In the single-dose phase, there was no RDX5791 detectable in plasma samples at doses of 10 and 50 mg (LOQ 0.5 ng/mL) and transient amounts (0.5 to 1ng/mL) at one time point in 11 of 18 subjects at doses of 150, 450 and 900 mg. In the multiple-dose phase, only 2 of 576 plasma samples had any detectable RDX5791 (< 1 ng/mL). In the single-dose phase, RDX5791 caused a decrease in time to first stool (TTFS) in all dose groups, most notably at 50 mg, (4.3 ± 2.4 hr versus 23.2 ± 7.8 hr for placebo). RDX5791 also caused statistically significant increases from placebo in BSFS (at 50 mg) and stool weight (at 150 mg). In the multiple-dose phase, RDX5791 caused a dose-related increase in BSFS with no increase in stool frequency as compared to placebo. RDX5791 also caused a decrease in TTFS and an increase in the % of days with a spontaneous bowel movement. Conclusion: RDX5791 is a minimally systemic, first-in-class inhibitor of NHE3, that was well tolerated at all doses tested (10-900 mg). RDX5791 exhibited pharmacodynamic activity in healthy volunteers consistent with its mechanism of action. Preclinical and clinical data corroborate the potential of RDX5791 for the treatment of IBS-C and other constipation-related diseases. In addition to the study described here, a phase 2 study to assess the efficacy of RDX5791 in IBS-C is ongoing. Disclosure: All authors are employees of Ardelyx, the sponsor of the clinical trial This research was supported by an industry grant from Ardelyx.