OR12-05 Effects of Relacorilant on Body Weight and Body Composition in Patients With Endogenous Hypercortisolism in the Phase 3 GRACE and GRADIENT Studies

Abstract Disclosure: O. Hamidi: Corcept Therapeutics, Lantheus, Recordati Rare Diseases, Neurocrine Biosciences, Crinetics Pharmaceuticals, Camurus. R.J. Auchus: Neurocrine Biosciences/Neurocrine UK, LTD, Spruce Biosciences, Corcept Therapeutics, Crinetics Pharmaceuticals, Recordati Rare Diseases, Adrenas Therapeutics, Mineralys Pharmaceuticals, Quest Diagnostics, Xeris Pharmaceuticals, Novo Nordisk, H Lundbeck A/S, Sparrow Pharmaceuticals, Astellas Pharmaceuticals, Acerand Therapeutics. R.S. Busch: Corcept Therapeutics, Novo Nordisk, Lilly USA, LLC, Novartis Pharmaceuticals, AstraZeneca, Amgen Inc, Bayer, Inc. H. East: Corcept Therapeutics, Amgen Inc, BI/Lilly. R.A. Feelders: Corcept Therapeutics, Recordati. A. Gilis-Januszewska: Recordati, Novo Nordisk, Ipsen, Pfizer, Inc.. R. Giordano: None. Z.C. Hannoush: None. A.M. Isidori: Corcept Therapeutics, Recordati Rare Diseases Pharma, Neurocrine, Crinetics Pharma. S. Jabbour: Eli Lilly & Company, Sanofi. M. Reincke: Crinetics, HRA Pharmaceuticals, Ipsen, Lundbeck, Recordati. S. Rovner: Amgen Inc, Bayer, Inc., Corcept Therapeutics, Eli Lilly & Company, Novo Nordisk. R. Salvatori: Camurus, Chiesi, Crinetics, Lundbeck. J. Silverstein: Camurus, Corcept Therapeutics, Xeris, Abbvie, Amryt, Ascendis, Bayer, Inc., Fractyl, Recordati, Sparrow. M. Terzolo: HRA Pharmaceuticals, Corcept Therapeutics. C. Wang: None. A.L. Hand: Corcept Therapeutics. K.A. Araque: Corcept Therapeutics. A. Moraitis: Corcept Therapeutics. Relacorilant is a selective glucocorticoid receptor modulator in development for the treatment of endogenous hypercortisolism (Cushing syndrome). Relacorilant has been studied in the phase 3 GRACE study in patients with endogenous hypercortisolism of any etiology (NCT03697109) and the phase 3 GRADIENT study in patients with adrenal hypercortisolism (NCT04308590). GRACE comprised a 22-week open-label phase followed by a 12-week double-blind, placebo-controlled randomized-withdrawal phase. GRADIENT was a 22-week, randomized, double-blind, placebo-controlled study. In both studies, participants received relacorilant 100-400 mg QD. Here, we report the effects of relacorilant on body weight and body composition. GRADIENT enrolled 137 patients, of which 68 received relacorilant and 69 received placebo. At baseline, mean ± SD body weight was 89.6 ± 20.5 kg (relacorilant) and 85.9 ± 20.9 kg (placebo), visceral adipose tissue mass was 1359.7 ± 726.4 g (relacorilant) and 1571.8 ± 981.8 g (placebo), and visceral adipose tissue volume was 1452.9 ± 767.8 mL (relacorilant) and 1674.8 ± 1036.4 g (placebo) (both measured by DXA scan). After 22 weeks of treatment, body weight was reduced by -3.6 ± 4.3 kg (relacorilant, P<0.0001) vs +0.0 ± 3.4 kg (placebo, P=ns), with a least-squares mean (LSM) difference from placebo of -3.9 kg (P<0.0001). Significant reductions in weight were observed by week 6. Visceral adipose tissue mass and volume were reduced by -161.5 ± 182.3 g and -173.3 ± 195.1 mL with relacorilant (both P=0.0001) vs increases of +14.1 ± 256.0 g and +15.3 ± 271.6 mL with placebo (both P=ns). The LSM differences from placebo were -169.5 g and -182.3 mL, respectively (both P=0.02). The GRACE open-label phase included 152 patients. At baseline, mean ± SD body weight was 93.8 ± 24.7 kg, which was reduced by -3.3 ± 5.9 kg by week 22 (P<0.0001). Significant reductions in weight were observed by week 10. At baseline, tissue fat and lean mass (by DXA scan) were 46.4 ± 8.4% and 53.6 ± 8.4%, which were improved by -1.8 ± 2.7% and +1.8 ± 2.7%, respectively, by week 22 (both P<0.0001). Improvements in body weight and composition observed in the GRACE open-label phase were maintained in patients who continued treatment with relacorilant in the randomized withdrawal phase, while deteriorations were observed in those switched to placebo. These results suggest that treatment with relacorilant can lead to clinically and statistically significant improvements in body weight and composition in patients with endogenous hypercortisolism of any etiology, in addition to the previously reported improvements in blood pressure and other comorbidities (Pivonello et al. Am Heart J. 2024;278[Suppl]:10-11). These improvements may occur as early as after 6-10 weeks of treatment. Importantly, lean mass was preserved in both studies, in contrast to the reductions in lean mass reported with the most common classes of weight-loss agents. Presentation: Sunday, July 13, 2025