IRC-274 is an investigational therapy that may alleviate some symptoms of Cushing’s disease. It is being developed by the French pharmaceutical company Ipsen.

How IRC-274 works

Cushing’s disease is caused by a tumor in the pituitary gland. This tumor stimulates the production of excess adrenocorticotropic hormone (ACTH). ACTH binds to the melanocortin-2 receptor (MC2R) in the adrenal gland, triggering the production and release of another hormone called cortisol. Increased levels of ACTH in Cushing’s disease patients result in a prolonged production of high levels of cortisol, causing the symptoms of the condition.

IRC-274 is an ACTH antagonist. It is a peptide or small part of a protein, that can inhibit ACTH from binding to MC2R. This prevents ACTH from activating the receptor, and reduces cortisol production by the adrenal glands.

It is hoped that IRC-274 will return cortisol levels to normal and reduce the symptoms of Cushing’s disease. IRC-274 is highly specific to the MC2R receptor, and should not affect other processes in the body.

IRC-274 in clinical trials

It has not been tested in clinical trials in humans. It is currently in pre-clinical study and has been tested in human cells, as well as both rat and mouse models, of Cushing’s disease.

At the 96th Annual Meeting of the Endocrine Society (ENDO 2014), Ipsen presented data demonstrating that IRC-274 successfully blocks the ACTH-activated signaling pathways that would lead to cortisol production in human cell lines. This confirmed the mechanism of action of IRC-274.

At the same conference, Ipsen presented the results of an experiment where it was given to rats implanted with a pump that constantly released ACTH. The increased ACTH caused an increase in cortisol. However, introducing IRC-274 to the rats effectively blocked ACTH from triggering cortisol production. This was the first demonstration that it can successfully lower cortisol levels in a living organism.

Researchers from Ipsen presented the results of an additional study in mice at the ENDO 2016 conference. An ACTH-producing tumor was implanted in mice to mimic Cushing’s disease. This caused an increase in circulating cortisol levels, similar to what is seen in patients with Cushing’s disease. Treatment with IRC-274 resulted in a significant decrease of cortisol in the blood, demonstrating that IRC-274 is capable of blocking ACTH in vivo (in the body).

These results support IRC-274’s potential to help Cushing’s disease patients, but clinical trials are required to fully evaluate its safety and possible clinical benefit. The company has not disclosed any such plans yet.

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