Currently used and investigational drugs for Cushing´s disease

ABSTRACT

Introduction: Cushing’s disease (CD) is caused by a corticotroph adenoma of the pituitary gland that secretes excess adrenocorticotropic hormone (ACTH) causing increased morbidity and mortality. Surgery is the treatment of choice, but is not always successful. Alternatives include radiotherapy, adrenal surgery, and pharmaceutical therapy. The latter is increasingly gaining momentum due to the recent development of compounds that reduce hypercortisolaemia or its symptoms, acting through different mechanisms.

Areas covered: In this article, the authors provide a complete overview of the treatment options for Cushing´s disease, including adrenal-directed, tumor-targeted, and peripheral therapies that are currently used or in development, and discuss their potential advantages and limitations.

Expert opinion: Considering the lack of long-term remission in up to half of the patients after surgery, and the delayed response to radiotherapy along with potential side effects, there is a strong need for an effective pharmaceutical treatment. Pasireotide, mifepristone, ketoconazole and metyrapone have been approved by regulatory authorities but their use remains limited due to considerable costs and side effects. Research in this field has focused recently on the improvement of pre-existing drugs and the development of safe new ones. However, few approaches aim at targeting the source of the disease, the ACTH-secreting adenoma.

KEYWORDS:

• Cushing’s disease
• ACTH
• somatostatin analogues
• dopamine agonists
• retinoic acid

Article highlights

• Cushing´s disease increases morbidity and mortality in patients if not treated.

• Surgery to remove corticotroph adenomas is the initial treatment of choice; when it is not effective further options are repeated surgery, radiotherapy, adrenalectomy, and/or medical treatment.

• Most of the investigational drugs act at adrenal level, inhibiting cortisol synthesis. However, many of them can produce adrenal insufficiency. Despite the reduction of cortisol, the accumulation of its precursors can also result in severe side effects. Moreover, treatment resistance often leads to increasing the drug dose.

• Pasiretoide is the only approved drug that targets the ACTH-secreting pitutiary adenoma, indicating that new compounds acting directly at the cause of the disease need to be developed. Results obtained with HSP90 inhibitors and retinoic acid agonists confirm the importance of the search for novel molecular pathways involved in CD.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.