Relacorilant tied to sustained cardiometabolic improvements in Cushing’s syndrome
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Key takeaways:
- Adults with Cushing’s syndrome had declines in BP and glucose with relacorilant therapy in the GRACE trial.
- Those who continued on relacorilant were less likely to lose BP control than those on placebo.
PHILADELPHIA — Adults with Cushing’s syndrome who responded to relacorilant had sustained improvements in blood pressure and glucose levels through 34 weeks, according to findings from a phase 3 trial.
As Healio previously reported, top-line results from the phase 3 GRACE trial showed relacorilant (Corcept Therapeutics), a selective cortisol modulator, reduced BP for adults with hypertension and Cushing’s syndrome and lowered glucose among those with Cushing’s syndrome and impaired glucose tolerance or diabetes. Reductions were sustained during a randomized withdrawal phase of the trial. The findings were encouraging due to the effect that comorbidities can have on adults with Cushing’s syndrome, according to Rosario Pivonello, MD, PhD, professor of endocrinology at the University of Naples in Italy and principal investigator of the GRACE trial.
“It’s known that patients with Cushing’s syndrome have a very complicated disease,” Pivonello said during a presentation at the Heart in Diabetes CME Conference. “Patients have [poor] quality of life and also increased mortality, especially from cardiovascular events. This is a very severe disease.”
In the phase 3 GRACE study, 152 adults aged 18 to 80 years with Cushing’s syndrome and either hypertension, hyperglycemia or both received relacorilant for 22 weeks during an open-label phase (mean age, 50.4 years; 83.6% women). Hyperglycemia was defined as having diabetes or impaired glucose tolerance. Participants received 100 mg relacorilant once daily at the start of the trial, with titration up to 400 mg based on tolerability and efficacy. At 22 weeks, participants who achieved prespecified criteria for hypertension or hyperglycemia control were eligible to enter a randomized withdrawal phase. In that phase, participants were randomly assigned, 1:1, to continue relacorilant or switch to placebo for an additional 12 weeks.
Open-label findings
Of the study group, 71 adults had hypertension and hyperglycemia, 50 had hyperglycemia only and 31 had hypertension only. During the open-label phase of the trial, participants with hypertension had a reduction in systolic BP of 7.9 mm Hg and a diastolic BP decrease of 5.1 mm Hg from baseline to 22 weeks (P < .001 for both). Reductions were observed regardless of BP medication use and among adults with systolic and diastolic hypertension.
Among adults who met the trial’s hypertension response criteria and entered the randomized withdrawal phase, systolic BP decreased by 12.6 mm Hg and diastolic BP declined by 8.3 mm Hg from baseline to 22 weeks.
Adults with hyperglycemia had a 2.7 h*mmol/L decrease in area under the curve glucose from baseline to 22 weeks (P < .0001). Among adults diagnosed with diabetes, AUC glucose declined by 3.8 h*mmol/L from baseline to 22 weeks (P < .0001). A 6.2 h*mmol/L decline in AUC glucose was observed for participants meeting the hyperglycemia response criteria and entering randomized withdrawal phase. Improvements in HbA1c, fasting plasma glucose and 2-hour oral glucose tolerance test were also seen for adults with hyperglycemia.
Among all adults participating in the open-label phase, improvements were seen in body weight (mean change, 3.3 kg; P < .0001), waist circumference (mean change, 2.8 cm; P < .0001), tissue fat mass as measured by DXA scan (mean change, 1.8%; P < .0001), tissue lean mass (mean change, 1.8%; P < .0001) and sit-to-stand test (mean change, 1.5 seconds; P < .01).
“Patients with Cushing’s syndrome do not just have hyperglycemia or hypertension.” Pivonello said. “There are many other comorbidities associated. ... “[Relacorilant] significantly decreased body weight and waist circumference, which is an expression of additional fat, which is a real problem in patients with Cushing’s syndrome.”
During the open-label portion of the trial, treatment-emergent adverse events occurred among 96.7% of participants. At least one treatment-emergent adverse event of grade 3 or higher was reported by 24.3% of adults, and 4.6% reported a serious treatment-emergent adverse events. Pivonello noted most adverse events were mild or moderate in severity and no new safety signals were found.
“Due to relacorilant’s specificity for the glucocorticoid receptor and its unique mechanism of action, the observed efficacy was seen without cases of relacorilant-induced irregular vaginal bleeding, without increases in cortisol and relacorilant-induced hypokalemia, and also without adrenal insufficiency and QT prolongation,” Pivonello said.
Randomized withdrawal data
There were 62 adults who continued to the randomized withdrawal phase of the trial, with 30 adults receiving relacorilant (mean age, 45.6 years; 73.3% women) and 32 receiving placebo (mean age, 48.8 years; 81.3% women). Adults receiving relacorilant were less likely to have loss of hypertension control compared with placebo (OR = 0.17; 95% CI, 0.04-0.77; P = .02). No change in systolic or diastolic BP was seen for the relacorilant group, whereas the placebo group had increases in both measures from the start of the randomized withdrawal phase until week 12.
“Patients receiving relacorilant had almost six times higher probability to maintain hypertension control,” Pivonello said. “These results were consistent in all types of populations that have been analyzed during the study, emphasizing and reinforcing the results.”
The relacorilant group had no changes in AUC glucose or HbA1c from baseline to 12 weeks of the randomized withdrawal phase. Among adults receiving placebo, AUC glucose increased by 4.9 h*mmol/L (P = .0003) and HbA1c increased by 0.3 percentage points (P = .03) from baseline to 12 weeks.
Body weight declined by 1.2 kg for the relacorilant group during the randomized withdrawal phase, whereas the placebo group had a 0.5 kg increase in weight. Increases in waist circumference and tissue fat mass, and a decrease in tissue lean mass was seen in the placebo group, whereas the relacorilant group had no change in any of the measures.
Adverse events occurred at similar rates among the relacorilant and placebo groups during the randomized withdrawal phase. Back pain was the most common adverse event, occurring in 16.7% of the relacorilant group and 18.8% of the placebo group.
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Pivonello R, et al. Session 6: Medical treatment of hypercortisolism with relacorilant: Final results of the phase 3 GRACE study. Presented at: Heart in Diabetes CME Conference; June 7-9, 2024; Philadelphia.
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