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New phase III clinical trial data suggests that an investigational oral drug, levoketoconazole, might be a useful therapeutic option for patients with Cushing syndrome, the study's authors said.

The open-label, non-randomized trial included 94 patients and found the drug normalized cortisol levels in 77 (81%). The normalization was sustained for 6 months in 29 patients (31%), a research team led by Maria Fleseriu, MD, of the Oregon Health & Science University in Portland, reported online in .

Additionally, patients experienced improvements in cardiovascular risk factors, including significant mean reductions from baseline in LDL cholesterol (–37.3 mg/dL, 95% CI –45.1 to –29.6), glycated hemoglobin (–0.39%, 95% CI–0.61% to –0.18%), and body weight (-5.1 kg, 95% CI -7.3 to -3.0) (P <0.0001 for all). However, there were no improvements in blood pressure and a slight but significant mean decrease in HDL cholesterol (-7.7 mg/dL, 95% CI -11.6 to -3.9), the study found.

Levoketoconazole is the 2S,4R enantiomer of ketoconazole (Xolegel), which is currently used off-label to treat Cushing syndrome, and is more potent than the racemic drug. It therefore might be used at lower doses, Fleseriu's team explained. (Besides its antifungal effect, ketoconazole is believed to lower cortisol levels by inhibiting enzymes involved in steroidogenesis.)

"The findings from this study show the sustained clinical benefits of twice-daily oral levoketoconazole," they continued, "including improvements in cardiovascular risk factors as well as normalisation of cortisol concentrations in some patients. Levoketoconazole might represent a useful therapeutic option for the medical treatment of Cushing syndrome."

Of the 94 patients in the trial, 80 (85%) had pituitary Cushing syndrome. Mean urinary free cortisol at baseline was 671.4 nmol/24 h, which is 4.9 times the upper limit of normal. Patients were initially treated with oral levoketoconazole 150 mg twice daily, and during a titration phase that lasted 2 to 21 weeks, the dose was increased by 150 mg increments until urinary free cortisol was normalized or a maximum dose of 600 mg was reached.

The 77 patients who achieved normal cortisol levels continued to receive the drug without any additional dose increase for a maintenance phase that lasted 6 months. The primary outcome was the proportion of patients with normal cortisol at the end of the maintenance phase. Prespecified adverse events of special interest were liver toxicity, corrected QT prolongation, and adrenal insufficiency.

The most common adverse events were nausea (32%) and headache (28%). Serious adverse events included one patient with an abnormal liver function test, one with adrenal insufficiency, and two with a prolonged QT interval. A total of 12 patients (13%) discontinued the study because of adverse events, the researchers reported.

The primary treatment for Cushing syndrome is surgery, noted Ashley Grossman, MD, of the University of Oxford in England, in an . However, sometimes surgery is delayed, contraindicated, or unsuccessful. In these cases, Grossman explained, options are limited, but one of the most commonly used treatments is ketoconazole, which has been shown to normalize cortisol in about 50% of patients. Ketoconazole is approved for this indication in the U.K., though not in the U.S.

The biggest limitation of the study was the lack of comparison to ketoconazole or any other alternative treatment, Grossman said. The study authors acknowledged this limitation, but they explained that because of the rarity of Cushing syndrome, gathering enough patients for a head-to-head trial would be impractical.

"Do these findings represent an improvement on racemic ketoconazole?" Grossman asked. "This question is difficult to answer, but the urinary free cortisol normalisation rate in those with moderate cortisol excess (i.e., from two to less than five times the upper limit of normal) was 49% and therefore not dissimilar to racemic ketoconazole."

However, "[i]n the absence of a head-to-head trial, which is unlikely to be done, it is difficult to know whether levoketoconazole is indeed a real advance over racemic ketoconazole," Grossman said. "Nevertheless, one would hope that more data will appear over time comparing the merits of the two formulations, and in any case such competition should be reflected in price competitiveness, to the benefit of health systems."

Fleseriu and colleagues argued that one strength of the study -- the first phase III trial for levoketoconazole -- was its use of "a robust, conservative analytical approach that counted all patients who discontinued from the study as treatment failures, irrespective of the reason, as well as all patients with missing data at the 6-month assessment."

The study authors also emphasized the improvement in cardiovascular risk factors associated with levoketoconazole. "Cardiovascular disease is believed to be responsible for most of the excess mortality and substantial morbidity in Cushing syndrome, and some studies have shown that cardiovascular risk persists even after biochemical cure," they wrote. Because Cushing syndrome is so rare, cardiovascular outcome studies are infeasible, they noted. However, "observing changes in established cardiovascular risk markers is a practical means by which various therapies can be judged as to their potential ability to prevent major adverse cardiovascular events."

Doctors using levoketoconazole should be careful to avoid drug interactions, Fleseriu and colleagues cautioned. "As with ketoconazole, the potential for drug interactions must be considered with levoketoconazole. Patients taking specific medications were excluded from this study, and careful examination of patients' medication lists for possible drug–drug interactions, as well as gastric acid inhibition, will be necessary when considering levoketoconazole."

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