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Investigational Cushing’s syndrome medication reduces BP, glucose in open-label trial

Investigational Cushing’s syndrome medication reduces BP, glucose in open-label trial

Adults with endogenous Cushing’s syndrome had reductions in blood pressure and glucose at 22 weeks of treatment with a selective cortisol modulator, according to topline results from the open-label portion of the GRACE phase 3 trial.

Relacorilant (Corcept Therapeutics) is a medication currently under investigation for multiple disorders, including Cushing’s syndrome and ovarian, adrenal and prostate cancer. The phase 3 GRACE trial included two parts, the first of which was an open-label portion in which 152 adults with Cushing’s syndrome and either hypertension, hyperglycemia or both received relacorilant for 22 weeks. Participants who achieved prespecified improvements for either symptom were invited to the trial’s randomized double-blind withdrawal phase in which adult were randomly assigned, 1:1, to relacorilant or placebo for 12 weeks. The topline results announced by Corcept Therapeutics are only from the open-label portion of the trial.

All adults with hypertension had a rapid decrease in systolic and diastolic BP at 6 weeks that was maintained through the end of the open-label phase. At 22 weeks, participants with hypertension had a 7.9 mm Hg decrease in systolic BP and a 5.4 mm Hg decline in diastolic BP (P < .0001 for both). Of adults with hypertension, 63% met the study’s response criteria. Adults who entered the randomized withdrawal phase had a 12.6 mm Hg improvement in systolic BP and an 8.3 mm Hg decrease in diastolic BP from baseline to 22 weeks (P < .0001 for both).

Adults with hyperglycemia included those with diabetes and people with impaired glucose tolerance. The hyperglycemia group had improvements in multiple measures of glucose metabolism from baseline to 22 weeks. Mean HbA1c declined by 0.3 percentage points and mean fasting glucose decreased by 12.4 mg/dL from baseline to 22 weeks (P = .03 for both). Mean glucose area under the curve also declined from baseline to 22 weeks (P < .0001). Half of adults with hyperglycemia met the study’s response criteria. Adults who enrolled in the randomized portion of the trial had a reduction in HbA1c of 0.7 percentage points (P < .0001) and fasting glucose of 25.2 mg/dL (P = .006) from baseline to 22 weeks. Glucose AUC also declined at 22 weeks (P < .0001).

Relacorilant was deemed well tolerated in the trial. The most common adverse events were nausea, edema, back and extremity pain and fatigue, all of which were mild or moderate in nature and are consistent with symptoms people experience after surgery or the start of therapy to treat hypercortisolism. No increases in cortisol levels or relacorilant-induced hypokalemia were observed. There were no cases of relacorilant-induced endometrial hypertrophy with or without vaginal bleeding, adrenal insufficiency or QT prolongation

Richard Auchus: “These open-label results are compelling, and they provide important information about the treatment of hypercortisolism,” Richard Auchus, MD, PhD, professor of internal medicine in the division of metabolism, endocrinology and diabetes at the University of Michigan and chief of the endocrinology and metabolism section at the Ann Arbor VA Medical Center, said in a press release. “Patients showed marked improvement across a broad range of signs and symptoms, without significant safety burden. Due to relacorilant’s unique mechanism of action, we are not observing other toxicities seen with current therapies, which positions relacorilant to potentially become a new standard of care for patients with this disease.”

Corcept Therapeutics plans to present data on both the open-label and randomized withdrawal phases of the trial in June and submit a new drug application to the FDA in the second quarter of this year.

April 24, 2024

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