A long-acting GDF15 analog causes robust, sustained weight loss and reduction of food intake in an obese non-human primate model.

GDF15 (Growth Differentiation Factor-15) is a circulating polypeptide linked to cellular stress and metabolic adaptation. GDF15's half-life is ~3h and activates the GFRAL (glial cell line-derived neurotrophic factor family receptor alpha-like) 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 (QW) with CpdH or long-acting GLP-1 analog dulaglutide. Mechanism-based longitudinal exposure-response (E-R) 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 (t 1/2 ~8 days) and treatment caused exposure-dependent reductions in FI and BW. 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 pharmacokinetic/pharmacodynamic relationship established in monkeys and human 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.