A long‐acting GDF15 analog causes robust, sustained weight loss and reduction of food intake in an obese nonhuman primate model

Abstract

Abstract Growth Differentiation Factor‐15 (GDF15) is a circulating polypeptide linked to cellular stress and metabolic adaptation. GDF15's half‐life is ~3 h and activates the glial cell line‐derived neurotrophic factor family receptor alpha‐like (GFRAL) receptor expressed in the area postrema. To characterize sustained GFRAL agonism on food intake (FI) and body weight (BW), we tested a half‐life extended analog of GDF15 (Compound H [CpdH]) suitable for reduced dosing frequency in obese cynomolgus monkeys. Animals were chronically treated once weekly (q.w.) with CpdH or long‐acting GLP‐1 analog dulaglutide. Mechanism‐based longitudinal exposure‐response modeling characterized effects of CpdH and dulaglutide on FI and BW. The novel model accounts for both acute, exposure‐dependent effects reducing FI and compensatory changes in energy expenditure (EE) and FI occurring over time with weight loss. CpdH had linear, dose‐proportional pharmacokinetics (terminal half‐life ~8 days) and treatment caused exposure‐dependent reductions in FI and BW. The 1.6 mg/kg CpdH reduced mean FI by 57.5% at 1 week and sustained FI reductions of 31.5% from weeks 9–12, resulting in peak reduction in BW of 16 ± 5%. Dulaglutide had more modest effects on FI and peak BW loss was 3.8 ± 4.0%. Longitudinal modeling of both the FI and BW profiles suggested reductions in BW observed with both CpdH and dulaglutide were fully explained by exposure‐dependent reductions in FI without increase in EE. Upon verification of the pharmacokinetic/pharmacodynamic relationship established in monkeys and humans for dulaglutide, we predicted that CpdH could reach double digit BW loss in humans. In summary, a long‐acting GDF15 analog led to sustained reductions in FI in overweight monkeys and holds potential for effective clinical obesity pharmacotherapy.