The steroidogenesis inhibitor levoketoconazole was effective in reducing and normalizing morning urinary free cortisol concentrations and biomarkers of cardiovascular risk among a large cohort of adults with endogenous Cushing’s syndrome, as well as improving clinical signs of the disease and quality of life measures, according to findings published in The Lancet Diabetes & Endocrinology.
“The findings show that levoketoconazole [Recorlev, Strongbridge Biopharma] was safe and effective in a representative population of patients with endogenous Cushing’s syndrome,” Maria Fleseriu, MD, FACE, professor of neurological surgery and professor of medicine in the division of endocrinology, diabetes and clinical nutrition in the School of Medicine at Oregon Health & Science University and director of the OHSU Northwest Pituitary Center, told Endocrine Today. “Despite the availability of approved treatments, current medications either have limited indications or do not address the various manifestations of Cushing’s syndrome, creating a substantial unmet need for this rare endocrine disorder. These data are encouraging and provide further support for the potential utility of levoketoconazole as a viable treatment option in Cushing’s syndrome.”
Currently, the azole antifungal ketoconazole, a racemic mixture of two enantiomers, is approved only in Europe and is used off-label for Cushing’s syndrome in the U.S., Fleseriu said. Ketoconazole has been associated with risk for hepatotoxicity in observational studies, for which weekly monitoring is recommended by the FDA.
“It is important to be clear that levoketoconazole is not ketoconazole,” Fleseriu said. “Levoketoconazole is the pure 2S,4R enantiomer of ketoconazole, and based on recent data, may be a more potent inhibitor of cortisol secretion compared with ketoconazole. Additionally, rigorous studies of ketoconazole in Cushing’s syndrome have never been conducted, so there is still a lot we don’t know about ketoconazole, though it is currently used as an off-label treatment and comes with a black box warning in the U.S.”
Fleseriu and colleagues analyzed data from 94 adults with endogenous Cushing’s syndrome and a mean 24-hour urinary free cortisol (UFC) of at least 1.5 times the upper limit of normal, recruited from 60 sites in 19 countries, as part of the phase 3, open-label, nonrandomized SONICS study (mean baseline UFC, 671.4 nmol per 24 hours). Participants received oral levoketoconazole during a 2- to 21-week incremental dose-titration phase, starting at 150 mg twice daily (maximum, 600 mg twice daily), followed by a 6-month maintenance phase. Primary outcome was the proportion of patients with UFC normalization at the end of the maintenance phase without dose increase during the maintenance phase. Prespecified adverse events of special interest were potential liver toxicity, corrected QT prolongation and adrenal insufficiency.
The steroidogenesis inhibitor levoketoconazole was effective in reducing and normalizing morning urinary free cortisol concentrations and biomarkers of cardiovascular risk among a large cohort of adults with endogenous Cushing’s syndrome, as well as improving clinical signs of the disease and quality of life measures.
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Of the 77 participants who advanced to the maintenance phase, 62 (81%) had UFC normalization by the end of dose titration. At the end of the 6-month maintenance phase, 29 participants (31%) were responders; the least-squares mean estimate of the proportion of responders was 0.3 (95% CI, 0.21-0.4).
“The study met its primary endpoints, with urinary free cortisol confirmed normal among 30% of the intent-to-treat population, without a proceeding dose increase following 6 months of maintenance therapy,” Fleseriu said. “Furthermore, the response rate was higher in patients with lower morning UFC concentrations at baseline. Additional analyses of UFC demonstrated that at month 6, median UFC reduction exceeded 80% among participants with the highest mean UFC at baseline, which averaged five times the upper limit of normal.”
Researchers also observed reductions from baseline for several key predefined secondary endpoints, including LDL and total cholesterol, glucose and body weight, that accompanied the marked improvement in UFC, Fleseriu said.
Therapy well tolerated
The most common adverse events reported during the study were nausea (32%) and headache (28%), with adverse events leading to study discontinuation for 13% of patients. Four patients experienced serious adverse events that were considered related to the study drug: abnormal liver function test results (n = 1), QT interval prolongation (n = 2) and adrenal insufficiency (n = 1).
Fleseriu said the findings from SONICS indicate that levoketoconazole was overall well tolerated with comparatively lower liver toxicity vs. off-label ketoconazole, therefore potentially requiring a less restrictive monitoring schedule.
“While I wasn’t necessarily surprised by this data, I was very pleased to see that the robust effect of levoketoconazole in normalizing or decreasing UFC levels in most patients was complemented by significant improvements in multiple markers for CV risk, such as fasting glucose, weight and LDL cholesterol and a decrease in testosterone and hirsutism in women,” Fleseriu said. “These benefits on CV risk markers are important to clinicians, health care providers and payers alike, as they represent a potential for levoketoconazole to affect Cushing’s syndrome CV comorbidities that are associated with excess mortality, substantial morbidity and high cost of care.”
In commentary accompanying the study, Ashley B. Grossman, MD, FRCP, FMedSci, a senior research fellow of Green Templeton College at the University of Oxford, U.K., noted that new formulations of drugs, if approved, do not mean that more traditional drugs, such as racemic ketoconazole, are less effective.
“Indeed, there is some evidence that with traditional ketoconazole abnormal liver function might improve with drug continuation,” Grossman wrote. “Thus, in 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. 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.” – by Regina Schaffer
Disclosures: Fleseriu reports she has received research support paid to her institution as principal investigator from Milendo, Novartis and Strongbridge and has received consultant fees from Novartis and Strongbridge. Grossman reports she has received funding from Novartis.