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

OBJECTIVE: The hormone peptide YY (PYY; cleaved into Y-selective form PYY) 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 analogue (PYY1875) alone and as an add-on to semaglutide for treatment of obesity. METHODS: 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. RESULTS: 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). CONCLUSIONS: PYY1875 showed modest efficacy as an add-on to semaglutide for weight management in people with obesity, but the treatment was not well tolerated.