Cushing’s disease is a condition resulting from excess production of the hormone cortisol. It is generally caused by a tumor in the pituitary that causes the gland to generate too much adrenocorticotropic hormone, or ACTH. ACTH stimulates the production of more cortisol, leading to symptoms such as weight gain, high blood pressure, memory problems, and difficulty concentrating.

Cushing’s disease is usually treated by surgically removing the tumor. But this may not be feasible for everyone. And it may not be possible to completely remove the tumor.

Most medication to reduce cortisol levels, such as Metopirone (metyrapone) and Nizoral (ketoconazole), can be taken only short term. Signifor, by Novartis, is one of the few approved long-term treatments to reduce cortisol levels in adults who cannot have surgery or have failed surgery.

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

Osilodrostat (LCI699)

Osilodrostat, developed by Novartis, works by inhibiting an enzyme called 11 beta-hydroxylase, or CYP11B1, which carries out the final biological step in cortisol production.

This reduces the amount of cortisol generated, alleviating Cushing’s disease symptoms. A clinical trial that Novartis conducted showed that osilodrostat led to a significant reduction in cortisol levels in the urine. The results were published in the journal Pituitary.

Novartis is recruiting participants for a Phase 3 clinical trial called LINC-4 (NCT02697734) that will assess osilodrostat’s safety and effectiveness against Cushing’s disease.

Recorlev (levoketoconazole, COR-003)

Recorlev is a cortisol inhibitor that Strongbridge Biopharma (formerly Cortendo) is developing as a Cushing’s disease treatment. Both the U.S. Food and Drug Administration and the European Medicines Agency have granted it orphan drug status.

A Phase 3 clinical trial called SONICS (NCT01838551) is testing the drug in the disease.

R-Roscovitine

R-Roscovitine is an inhibitor of two proteins — cyclin E and cyclin-dependent kinase, or CDK — that are involved in ACTH production. By reducing ACTH, the drug 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 r-roscovitine. Patients are being recruited for an additional Phase 2 clinical trial (NCT02160730).

Retinoic acid

Retinoic acid has been shown to reduce ACTH production and thus normalize cortisol levels. A trial in Brazil showed that a synthetic retinoic acid known as isotretinoin significantly reduced cortisol levels in urine. It even led to some patients having normal cortisol levels again.

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

Further randomized, placebo-controlled, double-blind clinical trials are required to fully assess retinoic acid’s safety and effectiveness in Cushing’s disease patients, researchers say.

Epidermal growth factor receptor (EGFR) inhibitors

Researchers are also looking at epidermal growth factor receptor (EGFR) inhibitors as potential therapies for Cushing’s disease.

EGFRs are involved in the production of cortisol. In people with a mutation of the USP8 gene, EGFRs are constantly active, triggering overproduction of cortisol. Blocking EGFR may help reduce the high cortisol associated with the disease.

Melanocortin-2 receptor antagonists

Researchers are also 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 the interaction, which would decrease cortisol production.

An example is the French pharmaceutical company Ipsen, which has developed a compound called IRC-274.

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