Experimental Treatments for Cushing’s Disease

Cushing’s disease is a condition characterized by excess production of the hormone cortisol. The disease usually is the result of a tumor in the pituitary gland that leads to the production of too much adrenocorticotropic hormone, or ACTH. ACTH stimulates the production of cortisol, leading to symptoms such as weight gain, high blood pressure, memory problems, and difficulty concentrating.

Doctors usually treat Cushing’s disease by surgically removing the tumor. However, in some patients, they cannot completely remove the tumor, and many patients require medication in addition to surgery.

Signifor, by Novartis, is the first medication that the U.S. Food and Drug Administration (FDA) approved to reduce cortisol levels in adults with Cushing’s disease who cannot have surgery or have failed surgery.

There also are other medications that patients can take to reduce their cortisol levels, such as Metopirone (metyrapone) and Nizoral (ketoconazole). 

Research is ongoing to develop new Cushing’s disease treatments. Here’s a rundown of some:

Epidermal growth factor receptor (EGFR) inhibitors

Epidermal growth factor receptor (EGFR) is a protein known to be involved in tumor growth. Recent studies have demonstrated that many patients with Cushing’s disease have a mutation in a gene that provides instructions for making an enzyme called USP8. USP8 removes a label from EGFR that cells use to mark proteins for recycling. The mutations make USP8 more active, so it removes more labels from EGFR. This means that less EGFR is recycled and EGFR signaling is increased encouraging tumor growth.

EGFRs also play a role in the production of cortisol. In people with a mutation in the USP8 gene, the constant activity of EGFRs triggers the overproduction of cortisol.

Blocking EGFR may, therefore, help reduce the high cortisol associated with Cushing’s disease and reduce the risk of tumor development

Examples of EGFR inhibitors include Iressa (gefitinib) by AstraZeneca and Tarceva (erlotinib) by Astellas and Genentech, which the FDA has approved to treat other conditions, but not yet for Cushing’s disease.

Melanocortin-2 receptor antagonists

Researchers also are investigating peptides, or small parts of a protein, as a Cushing’s disease treatment.

Peptides can prevent the activation of the melanocortin-2 receptor or MC2R. Normally ACTH binds to MC2R to activate it, triggering cortisol production. Researchers are developing compounds to prevent this interaction, which would decrease cortisol production.

Recorlev (levoketoconazole, COR-003)

Recorlev is a cortisol inhibitor that Strongbridge Biopharma (formerly Cortendo) is developing as a Cushing’s disease treatment. Both the FDA and the European Medicines Agency (EMA) have granted recorlev orphan drug status.

A Phase 3 clinical trial called SONICS (NCT01838551) tested the treatment in Cushing’s disease with promising results. A follow-up Phase 3 clinical trial (NCT03277690) is recruiting an estimated 54 participants (some who have participated in previous clinical trials for this treatment) to test the effectiveness  and safety compared to patients who have never taken Recorlev.

Retinoic acid

Research has shown that retinoic acid can reduce ACTH production and  normalize cortisol levels. A trial in Brazil showed that isotretinoin, a oral synthetic retinoic acid, significantly reduced cortisol levels in the urine. It even led to some patients having normal cortisol levels again.

A clinical trial (EudraCT: 2008-006379-65) in Italy also is evaluating retinoic acid as a Cushing’s disease treatment. The study began in 2008 and is ongoing.

Seliciclib (R-Roscovitine)

Seliciclib is an inhibitor of two proteins — cyclin E and cyclin-dependent kinase, or CDK — that play a role in ACTH production. By reducing ACTH, the treatment aims to decrease cortisol production and alleviate symptoms of Cushing’s disease. 

Researchers have completed a number of Phase 1 and 2 clinical trials of seliciclib in various cancers. An additional Phase 2 clinical trial (NCT03774446) is currently recruiting participants at the Cedars-Sinai Medical Center to test the safety and efficacy of seliciclib in treating Cushing’s disease.


Last updated: April 21, 2020


Cushing’s Disease News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.