Long-acting PYY₃ _-36 analogue with semaglutide for obesity: from preclinical assessment through randomized clinical studies.

Abstract

The hormone peptide YY (PYY; cleaved into Y₂-selective form PYY_3-36) is an attractive candidate for use as a complementary pharmacotherapy for obesity along with glucagon-like peptide-1 (GLP-1) receptor agonists. This series of studies investigated a novel long-acting PYY_3-36 analogue (PYY1875) alone and as an add-on to semaglutide for treatment of obesity. Weight loss and food intake were first investigated in obese male rats, followed by phase 1 and 2 clinical studies investigating efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of PYY1875 as monotherapy and in combination with semaglutide in participants with overweight or obesity. PYY1875 induced additional body weight loss in semaglutide-treated obese rats. In the phase 1 study, all doses of PYY1875 alone and coadministered with semaglutide were tolerated. In the phase 2 study, a modest but not clinically meaningful treatment effect of PYY1875 1.0 mg versus placebo as an add-on to semaglutide 2.4 mg was observed. However, gastrointestinal-related adverse events were common with the 1.0-mg PYY1875 dose, and the 2.0-mg PYY1875 dose escalation regimen was not tolerated (both as add-ons to semaglutide). PYY1875 showed modest efficacy as an add-on to semaglutide for weight management in people with obesity, but the treatment was not well tolerated.