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LOS ANGELES -- The investigational agent relacorilant significantly improved excess cortisol in patients with endogenous hypercortisolism, researchers reported here.

In a multicenter phase II study, about 64% of patients who had confirmed Cushing's syndrome plus hypertension responded to high-dose treatment -- defined as a ≥5mmHg drop in mean systolic or diastolic blood pressure (BP) -- after 16 weeks of treatment with the selective glucocorticoid receptor modulator, according to Rosario Pivonello, MD, PhD, of Università Federico Il di Napoli in Italy, and colleagues.

Around 42% of patients with comorbid hypertension responded to low-dose relacorilant treatment after 12 weeks of therapy, they reported at the American Association of Clinical Endocrinologists (AACE) annual meeting.

"Clearly there was a dose-dependent effect," co-author Andreas Moraitis, MD, of Corcept Therapeutics in Menlo Park, California, explained. "We saw, actually unexpectedly, quite significant efficacy even in the low-dose. But in the high-dose group, the results were quite impressive."

Looking at patients in the cohort who had confirmed Cushing's syndrome plus hyperglycemia, half of patients on a high-dose course of relacorilant therapy for 16 weeks were considered "responders" to treatment, defined as a ≥0.5% decrease in HbA1c, normalization of ≥50 mg/dL decrease in 2-hour oral glucose tolerance test glucose levels, or a ≥25% decrease in their daily dose of insulin or ≥50% decrease in sulfonylurea.

However, only about 15% of the group who had Cushing's plus impaired glucose tolerance of type 2 diabetes responded to low-dose treatment after 12 weeks.

The open-label study had 35 adult patients with confirmed Cushing's plus uncontrolled hypertension (n=23) and/or hyperglycemia (n=25). Cushing's syndrome was confirmed with biochemical analysis according to . They also exhibited at least two signs or symptoms of Cushing's syndrome at baseline. Patients with severely uncontrolled diabetes (A1c >12%), or severally uncontrolled hypertension (BP >170/100 mmHg) were excluded from the study, as were those with uncontrolled hypothyroidism or hyperthyroidism.

At baseline, the entire cohort had an average adrenocorticotropic hormone of 54.1 pg/mL, a 24-hour urine free cortisol of 207.68 µg/24 hours, and late-night salivary cortisol levels of 0.34 µg/dL.

Patients in the low-dose group received 100 mg/day for 4 weeks that was then increased to 150 mg/day for an additional 4 weeks, and then escalated to 200 mg/day for another 4 weeks. Those in the high-dose group were given 250 mg/day for 4 weeks, followed by 300 mg/day, 350 mg/day, and 400 mg/day, respectively, each given for 4 weeks.

An interesting secondary finding was that 60% of patients on the high-dose group experienced an average weight loss of 11.2 lbs (5.1 kg), while the low-dose group saw an average weight loss of 4.9 lbs (2.2 kg).

Among the entire cohort, significant decreases were also seen in the area under the curve for glucose, fructosamine, alanine aminotransferase, aspartate aminotransferase, Factor VIII percentage, platelet count, and Beck Depression Inventory-II total score. Significant increases were seen in serum osteocalcin, absolute eosinophils, activated partial thromboplastin time, and Cushing's quality of life score.

As for safety, there were five serious treatment emergent adverse events (AEs) reported, four of which were in a high-dose regimen patient. These included myopathy, polyneuropathy, MI, hypertension, and a pilonidal cyst. However, there weren't any drug-induced reports of abnormal vaginal bleeding or hypokalemia.

"We didn't see something we were expecting to see based on our experience with mifepristone. We didn't see hypokalemia," Moraitis noted, explaining that this didn't occur with relacorilant because it didn't cause any significant increases in cortisol levels as seen with mifepristone (Korlym, Mifeprex). "This is a huge advantage of this compound compared to mifepristone."

The most common AEs reported with the drug included back pain, headache, edema peripheral, nausea, pain, diarrhea, and dizziness, most of which were associated with cortisol withdrawal, Moraitis noted, adding that a phase III study is in progress.

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