IW-3718 Reduces Heartburn Severity in Patients With Refractory Gastroesophageal Reflux Disease in a Randomized Trial.

BACKGROUND & AIMS: Refractory gastroesophageal reflux disease (GERD) reduces quality of life and creates significant financial burden on the health care system. Approximately 30% of patients with GERD who receive label-dose proton pump inhibitors (PPIs) still have symptoms. We performed a trial to evaluate the efficacy and safety of IW-3718, a bile acid sequestrant, as an adjunct to PPI therapy. METHODS: We performed a multicenter, double-blind, placebo-controlled trial, from March 2016 through April 2017, of 280 patients with confirmed GERD. The patients, stratified by esophagitis status, were randomly assigned (1:1:1:1) to groups given placebo or IW-3718 (500, 1000, or 1500 mg) twice daily, with ongoing label-dose PPI. The primary endpoint was percent change from baseline to week 8 in weekly heartburn severity score. We also analyzed percent change from baseline to week 8 in weekly regurgitation frequency score. RESULTS: Mean changes from baseline to week 8 in weekly heartburn severity scores were reductions of 46.0% in the placebo group, 49.0% in the 500 mg group, 55.1% in the 1000 mg group, and 58.0% in the 1500 mg IW-3718 group (dose-response P = .02). The treatment difference was 11.9% between the 1500 mg IW-3718 and placebo groups (P = .04, analysis of covariance). The mean change in weekly regurgitation frequency score from baseline to week 8 in the 1500 mg IW-3718 vs placebo groups was a reduction of 17.5% (95% confidence interval, reductions of 31.4% to 3.6%). The most common adverse event was constipation (in 8.1% of patients receiving IW-3718 and 7.1% of patients receiving placebo). There were no drug-related serious adverse events. CONCLUSIONS: In a randomized trial of patients with refractory GERD, adding 1500 mg IW-3718 to label-dose PPIs significantly reduced heartburn symptoms compared with adding placebo. Regurgitation symptoms also decreased. IW-3718 was well tolerated. (ClinicalTrials.gov, Number: NCT02637557).

Preclinical discovery and development of colesevelam for the treatment of type 2 diabetes.

Introduction: Type 2 diabetes (T2D) is a major global health challenge associated with increased cardiovascular morbidity and mortality. Intervention strategies managing multiple risk factors (hyperglycemia, hypertension and dyslipidemia) in patients with T2D can reduce the risk of cardiovascular disease by ~50%. Areas covered: Herein, the authors provide an update on the development and clinical potential of colesevelam as a glucose-lowering drug in T2D. Furthermore, they outline the pharmacokinetics, pharmacodynamics, and the clinical efficacy and safety data from the studies carried out to obtain market authorization for colesevelam. Expert opinion: Four phase III clinical trials provide evidence that colesevelam, as a monotherapy and add-on to various background glucose-lowering treatments, confers placebo-corrected reductions in HbA1c of ~5 mmol/mol. In addition, colesevelam reduces low-density lipoprotein (LDL) cholesterol and total cholesterol. Some antidiabetic agents seem superior to colesevelam in terms of clinical efficiency (HbA1c lowering), tolerability/convenience, and price. Nonetheless, colesevelam offers a clinically relevant combination of HbA1c- and LDL-lowering that in selected patients could be relevant as add-on treatment to other glucose-lowering drugs and a statin. Potential patients include those with renal impairment, and patients that are close to reaching their lipid and glycemic treatment goals but need further LDL and HbA1c reductions.