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The FDA approved a new treatment for adults with endogenous hypercortisolemia related to Cushing's syndrome, late last week.

The oral drug levoketoconazole (Recorlev) is indicated for the treatment of endogenous hypercortisolemia in adults with Cushing's syndrome for whom surgery is not an option or has not been curative.

Acting as a cortisol synthesis inhibitor, levoketoconazole is a pure 2S,4R enantiomer of ketoconazole, a steroidogenesis inhibitor.

While rare, endogenous Cushing's syndrome is caused by chronic elevated cortisol exposure, typically due to a benign tumor of the pituitary gland. This condition is three times more common in women and often occurs between the ages of 30 to 50.

"Levoketoconazole (Recorlev) is an important and welcome new therapeutic option for clinicians to help manage patients with endogenous Cushing's syndrome, a severe, potentially life-threatening rare disease, if not appropriately treated, with multisystem signs and symptoms," said Maria Fleseriu, MD, of the Oregon Health & Science University in Portland, in a statement. "In prospective clinical studies, treatment with levoketoconazole was shown to be effective for reducing and normalizing cortisol."

The phase III SONICS and studies led to the drug's approval. Comprised of a combined 166 participants, both studies met primary and key secondary endpoints. In the SONICS study, led by Fleseriu, levoketoconazole significantly reduced and normalized mean urinary free cortisol concentrations in 81% of patients. The LOGICS study confirmed the drug's efficacy, demonstrating a loss of cortisol response in 55% of patients who withdrew to placebo.

The drug's label suggests that patients be started on an oral 150-mg twice-daily dose, with or without food. The dosage should then be titrated by 150 mg daily, no more frequently than every 2 to 3 weeks. The maximum recommended dosage is 1,200 mg daily, administered as 600 mg twice daily.

A boxed warning also appears on the label, regarding possible hepatotoxicity and QT prolongation. It also points out the agent is not approved for the treatment of fungal infections.

Adverse reactions reported in more than 20% of patients included nausea and vomiting, hypokalemia, hemorrhage and contusion, systemic hypertension, headache, hepatic injury, abnormal uterine bleeding, erythema, fatigue, abdominal pain/dyspepsia, arthritis, upper respiratory infection, myalgia, arrhythmia, back pain, insomnia/sleep disturbances, and peripheral edema.

The approval came after the drug snagged orphan drug designation from the FDA and the European Medicines Agency for the treatment of endogenous Cushing's syndrome. Xeris noted that the drug is expected to hit shelves in the first quarter of 2022.

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