Abstract
Disclosure: R. Pivonello: Consulting Fee; Self; Corcept Therapeutics, Recordati AG, Crinetics Pharmaceuticals, H. Lundbeck A/S. Other; Self; Corcept- Research Funding, Neurocrine Biosciences- Research Funding, Recordati AG- Research Funding, Strongbridge Biopharma- Research Funding. G. Arnaldi: Advisory Board Member; Self; Recordati Rare Disease, HRA Pharmaceuticals. R.J. Auchus: Consulting Fee; Self; Quest Diagnostics, Corcept Therapeutics, Crinetics Pharmaceuticals, Xeris Pharmaceuticals, Adrenas Therapeutics, Novo Nordisk, Neurocrine Biosciences/Diurnal LTD, Recordati Rare Diseases, H Lundbeck A/S, Sparrow Pharmaceuticals. Other; Self; Neurocrine Biosciences/Diurnal LTD- Contracted Research, Spruce Biosciences- Contracted Research, Corcept Therapeutics- Contracted Research, Crinetics Pharmaceuticals- Contracted Research, Recordati Rare Diseases- Contracted Research. C.P. Badiu: Research Investigator; Self; Corcept Therapeutics, Novo Nordisk, Lundbeck. Speaker; Self; Pfizer, Inc., Ipsen, Merck. S. Cannavo: Advisory Board Member; Self; Novo Nordisk, Recordati, Camurus, Amryt. Consulting Fee; Self; Lundbeck. U. Dischinger: Advisory Board Member; Self; Recordati Rare Disease. Speaker; Self; MSD, Alnylam. Other; Self; Novo Nordisk- Scientific Support. G.A. Dobri: Advisory Board Member; Self; Camurus, Recordati, Xeris. A. Elenkova: Advisory Board Member; Self; Novartis Pharmaceuticals. Research Investigator; Self; Novartis Pharmaceuticals, Recordati, Xeris, Crinetics. P.K. Fazeli: Advisory Board Member; Self; Crinetics, Xeris, Amryt, Camurus. Consulting Fee; Self; Regeneron Pharmaceuticals, Quest Diagnostics. Research Investigator; Self; Corcept Therapeutics, Crinetics. R.A. Feelders: Consulting Fee; Self; Corcept Therapeutics, Recordati. Grant Recipient; Self; Corcept Therapeutics, Recordati. R. Garcia-Centeno: Advisory Board Member; Self; Recordati, Ipsen, Novartis Oncology. Speaker; Self; Recordati, Novo Nordisk, Sanofi, Ipsen. A. Gilis-Januszewska: None. O. Hamidi: Advisory Board Member; Self; Corcept Therapeutics, Neurocrine Biosciences, Recordati Rare Diseases, Lantheus, Xeris, Amryt Pharma. Z.C. Hannoush: None. H.J. Miller: None. A. Ranetti: None. M. Recasens: None. M. Reincke: Advisory Board Member; Self; Recordati, Ipsen, Crinetics, HRA Pharmaceuticals, Lundbeck. Speaker; Self; Recordati, HRA Pharmaceuticals. S. Rovner: Speaker; Self; Corcept Therapeutics, Novo Nordisk, Lilly, Bayer, Inc., Amgen Inc. R. Salvatori: Advisory Board Member; Self; Novo Nordisk, Recordati, Camurus, Amryt. Consulting Fee; Self; Lundbeck. J.M. Silverstein: Consulting Fee; Self; Xeris Biopharma. A. Stigliano: Advisory Board Member; Self; HRA Pharmaceuticals, Recordati Rare Disease. M. Terzolo: Advisory Board Member; Self; HRA Rare Diseases, Corcept Therapeutics. C. Wang: None. K.C. Yuen: Advisory Board Member; Self; Novo Nordisk, Ascendis, Ipsen, Chiesi, Recordati, Crinetics, Xeris, Neurocrine. Speaker; Self; Novo Nordisk, Recordati. Other; Self; Ascendis- Research grants to Barrow Neurological Institute, Corcept- Research grants to Barrow Neurological Institute, Chiesi- Research grants to Barrow Neurological Institute, Sparrow- Research grants to Barrow Neurological Institute. A.L. Hand: Employee; Self; Corcept Therapeutics. I. Tudor: Employee; Self; Corcept Therapeutics. K.A. Araque: Employee; Self; Corcept Therapeutics. A.G. Moraitis: Employee; Self; Corcept Therapeutics. The selective glucocorticoid receptor modulator relacorilant was designed to decrease excess cortisol activity and improve clinical signs and symptoms of endogenous hypercortisolism (Cushing syndrome [CS]). GRACE, the largest prospective, interventional CS study to date, is a 2-part phase 3 study of relacorilant in patients (pts) with CS of all etiologies and uncontrolled hypertension (HTN) and/or hyperglycemia (DM/IGT). It consists of a 22-week open-label (OL) phase followed by a 12-week, double-blind, placebo-controlled randomized withdrawal (RW) phase. 152 pts (n=31 with HTN; n=50 with DM/IGT; n=71 with both) were enrolled in the OL phase and received relacorilant 100 mg QD titrated up to 400 mg QD as tolerated. 63% of pts achieved HTN and/or hyperglycemia control at their last OL assessment (week 22/early termination). Of those who completed the OL phase, 65% continued to the RW phase. Here we report efficacy and safety results from the OL phase. The pts had a mean age of 50.4 years, mean weight of 93.8 kg, and mean body mass index (BMI) of 34.7 kg/m(2) at baseline. 83.6% were women and 77.6% had ACTH-dependent CS. Rapid and sustained improvements in HTN and hyperglycemia were observed. In pts with HTN with or without DM/IGT (n=102), systolic and diastolic blood pressure (SBP, DBP; assessed by ambulatory blood pressure monitoring) were significantly reduced from baseline to week 22 (mean change ± standard deviation SBP: -7.9 ± 9.8 mm Hg, DBP: -5.4 ± 7.0 mm Hg; P<0.0001). In pts with DM/IGT with or without HTN (n=121), significant improvements in various glycemic parameters were observed, including significant declines in AUC(glucose) (-3.3 ± 6.7 h*mmol/L; P<0.0001) and HbA1c (-0.3 ± 1.0%; P=0.03). In pts who entered the RW phase, even greater improvements were seen (SBP: -12.6 ± 6.5 mm Hg; DBP: -8.3 ± 4.9 mm Hg; AUC(glucose): -6.2 ± 6.5 h*mmol/L; HbA1c: -0.7 ± 1.1%; P<0.0001 for all). Improvements in other signs and symptoms of CS were also observed, including weight loss (-3.3 ± 5.9 kg), reduction in waist circumference (-2.8 ± 6.2 cm), and improvement in quality of life (+7.4 ± 14.6 points on Cushing QoL normalized total score) (P<0.0001 for all). Due to relacorilant’s unique mechanism of action, the observed efficacy was seen without increases in cortisol concentrations and associated hypokalemia, and no cases of drug-induced endometrial hyperplasia with or without vaginal bleeding or independently confirmed QT prolongation were reported. Adverse events (AEs) were consistent with the known safety profile of relacorilant (Pivonello et al. 2021); no new safety concerns were identified. The most frequently reported AEs in the OL phase (≥20%) were nausea, peripheral edema, pain in extremity, back pain, and fatigue. In summary, relacorilant showed clinically and statistically significant improvements in HTN, hyperglycemia, and across other manifestations of cortisol excess with a favorable safety profile. Presentation: 6/3/2024