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Neuroendocrine and Pituitary
Tumor Clinical Center (NEPTCC) Bulletin

Winter 2020/2021 | Volume 26, Issue 1

Journal Club: Review of Levoketoconazole and Osilodrostat in the Treatment of Cushing’s Syndrome

-ALLISON KIMBALL, MD

Dr. Allison Kimball

Cushing’s syndrome is a serious condition characterized by cortisol excess and associated with increased mortality, primarily related to cardiovascular disease (1, 2). The most common source of cortisol overproduction is a pituitary adenoma (Cushing’s disease). Medical treatment is indicated for persistent or recurrent hypercortisolism following surgery, estimated to occur in one third of patients (3), or when surgery or radiation are contraindicated. Although several medications with different mechanisms of action are available, Cushing’s syndrome is difficult to treat. Additional effective and well-tolerated medications are needed.

Results from phase 3 trials studying the efficacy and safety of two new pharmacologic treatments for Cushing’s syndrome, levoketoconazole and osilodrostat, were recently published (4, 5), and a review of these studies follows.

SONICS (levoketoconazole)

Ketoconazole (a racemic mixture of the enantiomers 2S,4R-ketoconazole and 2R,4S-ketoconazole) inhibits several enzymes involved in adrenal steroidogenesis, leading to decreased cortisol production. It is not FDA-approved for the treatment of Cushing’s syndrome in the US, although it is used off-label for this purpose. Important considerations are drug-drug interactions and side effects, and there is a black box warning for rare liver toxicity, which advises monitoring of liver function tests. While efficacy of ketoconazole has been established by retrospective and observational data, it has never been studied in a prospective clinical trial. The 2S,4R enantiomer of ketoconazole, levoketoconazole, is about twice as potent in vitro in inhibiting enzymes such as 17α-hydroxylase and 11β-hydroxylase, which makes it a promising pharmacologic treatment option (6).

SONICS was a multicenter, open-label, single-arm study of oral levoketoconazole in 94 adults with Cushing’s syndrome who had mean 24-hour urinary free cortisol (UFC) >1.5 times the upper limit of normal (ULN) (4). Participants were treated with the starting dose of levoketoconazole 150 mg twice daily followed by titration over 2-21 weeks (in 150 mg increments until mean UFC normalization) before entering a 6-month maintenance phase. The primary outcome was the proportion of participants with mean UFC ≤ ULN at the end of the maintenance phase without requiring a dose increase during maintenance (complete response).

At baseline, mean age was 43.7 years and mean UFC was 4.9 times the ULN. Eighty-five percent of participants had pituitary Cushing’s disease. Seventy-seven of 94 participants entered, and 61 completed, the maintenance phase. Mean UFC decreased quickly in the dose-titration phase and remained controlled from months 2-6 (Figure 1A). Twenty-nine of 94 participants (31%) experienced complete response (Figure 1B); the response rate was higher in participants with lower baseline mean UFC concentration. Improvements were seen in cardiovascular biomarkers, including HbA1c, fasting glucose, total and LDL cholesterol, and weight. Also improved were quality of life and subjective signs and symptoms related to Cushing’s syndrome. In general, levoketoconazole was well-tolerated and safe; the most common adverse events were headache and nausea.

The results suggest that levoketoconazole may be an effective treatment for Cushing’s syndrome. Important limitations of this study include its open-label design and absence of a control group. Because there are no prospective studies assessing ketoconazole in Cushing’s syndrome, comparison of levoketoconazole to ketoconazole is not possible.

 

Figure 1

Figure 1. A) Mean UFC from baseline to the end of the maintenance phase. Dotted line represents the ULN for UFC (138 nmol/24 h [50 μg/24 h]). Error bars represent ± 1 SE. B) Change in individual mean UFC from baseline to the end of maintenance phase. Each vertical set of datapoints is for one subject. Abbreviations: mUFC=mean urinary free cortisol, ULN=upper limit of normal. Reproduced with permission from Fleseriu et al., Lancet Diabetes Endocrinol, 2019 (4).

 

LINC 3 (osilodrostat)

LINC 3 (5) was the first phase 3 study of a pharmacologic treatment in patients with Cushing’s disease that included a double-blind, placebo-controlled withdrawal period. Participants received osilodrostat, which reversibly inhibits the enzyme 11-ß-hydroxylase that catalyzes the last step of cortisol synthesis.

In LINC 3, 137 adults aged 18-75 with recurrent or persistent Cushing’s disease and mean 24-hour UFC >1.5 times the ULN were studied. Open-label oral osilodrostat was started at 2 mg twice daily and then adjusted every 2 weeks until week 12 (up to 30 mg twice daily) to normalize mean UFC (period 1). Osilodrostat was continued at the therapeutic dose from weeks 13-24 (period 2). At week 26, patients with mean UFC ≤ ULN at week 24 who did not require uptitration after week 12 were randomly assigned to continue osilodrostat or switch to placebo for 8 weeks (period 3). All participants received open-label osilodrostat from weeks 35-48 (period 4). The primary endpoint was complete response rate, defined as the proportion of participants who maintained mean UFC ≤ ULN at the end of the 8-week withdrawal period.

At baseline, median age was 40 years and mean UFC was 7.3 times the ULN. Seventy-two of 137 participants (53%) achieved complete response at week 24 and were therefore eligible for the randomized withdrawal phase; 36 participants continued osilodrostat and 35 were assigned to placebo. More participants who continued osilodrostat maintained a complete response at week 48 (86% versus 29% in placebo group; Figure 2). As in SONICS, cardiovascular-related metabolic parameters were assessed, and osilodrostat treatment was associated with improvements in fasting glucose, weight, total cholesterol, and systolic and diastolic blood pressure. Clinically meaningful improvements in depression and quality of life were also observed. The most common adverse events were nausea, headache, fatigue, and adrenal insufficiency. Although inhibition of 11-ßhydroxylase leads to the accumulation of precursors, most related side effects were mild. Both men and women experienced an increase in testosterone and 11% of women experienced androgenic side effects (acne, hirsutism), but this did not result in study discontinuation by any subject. Despite the expected increase in mineralocorticoids, hypertension and low serum potassium were not frequently reported among participants taking osilodrostat.

 

Figure 2

Figure 2. Changes in mean UFC during the withdrawal phase, by treatment group (A) and from baseline to week 24 (B). Each vertical set of datapoints is for one subject. For panel B, data are arranged from highest to lowest baseline mean UFC. Abbreviations: UFC=urinary free cortisol, RR=response rate, ULN=upper limit of normal. Reproduced with permission from Pivonello et al., Lancet Diabetes Endocrinol, 2020 (5).

 

In conclusion, the results demonstrate that osilodrostat is effective in lowering mean UFC and improving clinical parameters associated with hypercortisolism. The double-blind, placebo-controlled withdrawal period was a strength of this study, although the short duration may explain why nearly a third of participants still had normal UFC after withdrawal of osilodrostat. Follow-up studies of osilodrostat to assess long-term efficacy and safety are warranted.

Summary

Levoketoconazole and osilodrostat are promising pharmacologic therapies for Cushing’s syndrome that result in rapid and sustained reductions in UFC. Both have acceptable safety and tolerability profiles. Levels of adrenocorticotropic hormone (ACTH) rose in patients with Cushing’s disease in both studies, as is expected with adrenal-blocking medications. Neither study was long enough to determine the risk of tumor enlargement. Levoketoconazole is not currently available in the United States. In March 2020, osilodrostat was FDA-approved for adults with Cushing’s disease for whom pituitary surgery cannot be performed or has not been curative.


References:

1. Pivonello R et al. Endocr Rev. 2015; 36: 385–486.

2. Pivonello R et al. Lancet Diabetes Endocrinol. 2016; 4:611–29.

3. Nieman LK et al. J Clin Endocrinol Metab. 2015; 100:807–31.

4. Fleseriu M et al. Lancet Diabetes Endocrinol. 2019; 7:855–65.

5. Pivonello R et al. Lancet Diabetes Endocrinol. 2020; 8:748–61.

6. Auchus RJ et al. Endocr Rev. 2018; 39 (2 suppl): SUN-410 (abstr).