By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The Food and Drug Administration has approved a new oral treatment for adults with Cushing’s disease (CD) who cannot undergo pituitary surgery or still have the disease after undergoing surgery. Currently, only pasireotide, an injectable somatostatin analog, is approved for this indication. Osilodrostat inhibits the enzyme 11 beta-hydroxylase (CYP11B1), a key enzyme in the biosynthesis of cortisol in the adrenal gland.1 It is the first drug with this mechanism of action and the first oral drug approved for this use. It received orphan drug designation and will be distributed as Isturisa.
Osilodrostat should be prescribed to adult patients with CD for whom pituitary surgery is not an option or has not been curative.1
The recommended initial dose is 2 mg orally twice daily, with or without food.1 For patients with moderate hepatic impairment, the dose is 1 mg twice daily. Asian patients should start with 1 mg twice daily.2 Cut the dose in half with concomitant administration of a strong CYP3A4 inhibitor. A dose increase may be needed in the presence of strong CYP3A4 and CYP2B6 inducers. The dose is titrated by 1 to 2 mg twice daily, no more than every two weeks, based on rate of cortisol change, tolerability, and improvement in signs and symptoms of the disease. In clinical trials, the maintenance dosage varied between 2 mg and 7 mg twice daily. The maximum recommended maintenance dose is 30 mg twice daily. Before treatment initiation, hypokalemia and hypomagnesemia should be corrected, and an electrocardiogram should be obtained at baseline and repeated within one week after treatment initiation. After the maintenance dose has been established, cortisol levels should be monitored every one to two months or as indicated. The dose should be decreased or temporarily discontinued if urine free cortisol levels fall below target range, or if there is a rapid decrease in levels or symptoms of hypocortisolism. Osilodrostat is available as 1 mg, 5 mg, and 10 mg tablets.
Osilodrostat is the first CYP11B1 inhibitor approved for CD.
Osilodrostat can cause hypocortisolism and is associated with dose-dependent QT interval prolongation.1 Blockade of CYP11B1 may lead to increases in aldosterone precursors and androgens with associated side effects of increased levels, such as hypokalemia, edema, hypertension, hirsutism, and acne (in females). The most common (≥ 30%) adverse reactions include adrenal insufficiency (43%), fatigue (39%), nausea (37%), and headache (31%).1
Osilodrostat has demonstrated potent activity in vitro human adrenocortical cell cultures.3 Its safety and efficacy were assessed in a 48-week study comprised of four study periods, including a 12-week open label titration period, a 12-week open label maintenance period, an eight-week double-blind, randomized, placebo-controlled withdrawal period, and a 14- to 24-week open label treatment period.1 The primary efficacy endpoint was based on the randomized withdrawal phase. Most CD subjects had undergone surgery and had persistence or recurrence of disease (mean of three 24-hour urine-free cortisol [mUFC] > 1.5 time upper limit of normal [ULN]). The median mUFC was 476 nmole/24 hr, or approximately 3.5 × ULN. The primary endpoint was the percentage of complete responders at the end of the randomized withdrawal phase. Response was mUFC < ULN at the end of the maintenance period. After 24 weeks, 71 responders were randomized to osilodrostat (n = 36) or placebo (n = 35) for eight weeks. At the end of eight weeks, response was 86% for osilodrostat and 29% for placebo. It is unclear if osilodrostat improved cardiovascular and metabolic parameters (e.g., blood pressure, body weight, waist circumference, HbA1c). Currently, there are no direct comparisons to pasireotide. However, in a Phase III study of pasireotide, subjects received two doses (0.6 mg twice daily or 0.9 mg twice daily), with response rates of 15% and 26% at six months, respectively.4,5 There was a high frequency of hyperglycemia in pasireotide-treated subjects (40%), with 46% requiring glucose-lowering medications.
CD is caused by a pituitary tumor, resulting in excess secretion of adrenocorticotropin and subsequent excess production of cortisol by the adrenal cortex.6-8 It is a rare disease that is more common in women and leads to significant morbidities, mortality, and health-related quality of life issues. Treatment of choice is pituitary surgery, with complete remission rate of 60-90%.7,9 In patients who are not cured or are not candidates for surgery, treatment options include pasireotide, which may be useful for milder disease with UFC < 2 × ULN.9 However, the drug frequently causes hyperglycemia. Ketoconazole also has shown effectiveness, but can cause hepatotoxicity.9 Osilodrostat offers a new option, with an estimated response rate slightly over 50%. It is expected to be available in the second or third quarter of 2020. The cost was unavailable at the time of this review.
- Recordati Rare Diseases, Inc. Isturisa Prescribing Information, March 2020.
- Duggan S. Drugs 2020;80:495-500.
- Creemers SG, et al. J Clin Endocrinol Metab 2019;104:3437-3449.
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- Novartis. Signifor Prescribing Information, January 2020.
- Food and Drug Administration. FDA approves new treatment for adults with Cushing’s disease, March 6, 2020.
- Wen YH, et al. J Clin Med 2019;8. doi: 10.3390/jcm8111961.
- Lau D, et al. Neurosurg Focus 2015;38:E11.
- Nieman LK, et al. J Clin Endocrinol Metab 2015;100:2807-2831.