Levoketoconazole Offers New Option for Cushing's Syndrome

LOS ANGELES — The investigational cortisol synthesis inhibitor levoketoconazole (Recorlev, Strongbridge Biopharma) is showing promise as an alternative treatment option for endogenous Cushing's syndrome, new data indicate.

Secondary endpoints from the phase 3, multicenter, open-label SONICS trial were presented April 25 here at the American Association of Clinical Endocrinologists (AACE) 2019 Annual Scientific & Clinical Congress by Maria Fleseriu, MD, professor of medicine and neurological surgery director, Northwest Pituitary Center, Oregon Health and Science University, Portland.

Levoketoconazole, the pure 2S,4R enantiomer of ketoconazole, has received an orphan drug designation from the US Food and Drug Administration and European Medicines Agency for the treatment of endogenous Cushing's syndrome.

The syndrome is a rare but serious and potentially lethal endocrine disease. Individuals with the syndrome can develop moon face, facial plethora, supraclavicular fat pads, buffalo hump, truncal obesity, and purple striae, and often complain of proximal muscle weakness, easy bruising, weight gain, hirsutism, and, in children, growth retardation. Hypertension, osteopenia, diabetes, and impaired immune function may occur.

Treatment options include surgery, radiation therapy, and drug treatment.

SONICS Data

SONICS was a single-arm, open-label dose titration study that included 94 patients (77 women, 17 men) with elevated mean 24-hour urinary free cortisol (mUFC) levels at or above 1.5 times the upper limit of normal.

Patients received levoketoconazole orally, starting at 300 mg twice daily, titrated up to a maximum of 600 mg twice daily (a reduction to 150 mg once daily was allowed to resolve tolerability issues).

Of the 94 patients, 77 completed dose titration and 61 completed a 6-month maintenance phase.

Fleseriu presented the secondary endpoint data for the first time at AACE 2019, showing that levoketoconazole significantly reduced scores of acne (P = .0063), peripheral edema (P = .0295), and hirsutism (P = .0008) in women following the maintenance phase.

Mean free testosterone levels in women dropped (from 0.32 to 0.12 ng/dL; P < .0001), which was accompanied by improvements in clinical signs of hyperandrogenism. In men there was a nonsignificant rise in mean free testosterone (from 5.1 to 5.8 ng/dL). Quality of life and depression scores also improved with the drug.

"Despite the availability of newly approved treatments, with the first medications approved for Cushing's syndrome in 2012, medical needs in Cushing's syndrome remain high. This study demonstrates that levoketoconazole can suppress both cortisol and testosterone syntheses, translating into potential clinical benefits and improvement in symptoms related to cortisol excess, but also related to hyperandrogenism in women," Fleseriu told Medscape Medical News.

Fleseriu had previously presented the primary SONICS results at the European Neuroendocrine Association meeting in Wrocław, Poland, in October 2018, and reviewed them briefly here at AACE 2019.

The primary endpoint of mUFC normalization without a dose increase during a 6-month maintenance phase was achieved in 30% of patients, and another 8% achieved mUFC normalization with dose increases. Cardiovascular risk biomarkers also improved significantly.

The most commonly reported adverse events were nausea (31.9%), headache (27.7%), peripheral edema (19.1%), hypertension (17.0%), and fatigue (16.0%).

Serious adverse events considered related to the drug were reported in four patients, including elevated liver function in one, prolonged QTc interval in two, and adrenal insufficiency in one. Liver monitoring detected mildly to moderately elevated enzymes in 15% of participants, and a similar proportion, 13%, discontinued the drug because of treatment-related adverse events.

"A New Potentially Safer Medication"

Asked to comment on the data, session moderator David Lieb, MD, associate professor of internal medicine and program director of the endocrinology fellowship program at Eastern Virginia Medical School, Norfolk, told Medscape Medical News that levoketoconazole "offers another medical therapy for Cushing's."

"Many of our patients will still have elevated cortisol concentrations after surgery and still have all of the symptoms and adverse effects that are associated with that."

Current medications used to treat Cushing's syndrome all have downsides, Lieb noted. Ketoconazole carries a risk for hepatotoxicity, pasireotide (Signifor, Novartis) can lead to diabetes, and mifepristone has several drug interactions.

"It's nice to have a new potentially safer medication in your armamentarium to treat people, especially because some may respond better to this than to one of the other...drugs that are available...and also to have some data showing that they improve the side effects of having Cushing's syndrome that are troubling to patients."

Fleseriu commented, "The improvements in both clinician- and patient-reported signs and symptoms of Cushing's syndrome provide further support for the potential utility of levoketoconazole as a treatment option in Cushing's syndrome."

The study was funded by Cortendo, a subsidiary of Strongbridge. Fleseriu has reported receiving research funding for Oregon Health and Science University from Novartis, Millendo, and Strongbridge, and scientific consulting fees from Novartis and Strongbridge. Lieb has reported no relevant financial relationships.

AACE 2019. Presented April 25, 2019.

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