IRC-274 is an investigational therapy that could alleviate some of the symptoms of Cushing’s disease. Originally under development by the French pharmaceutical company Ipsen, it appears the treatment is no longer being developed because Ipsen has not published any data about the therapy since 2016.

How did IRC-274 work?

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 glands, triggering the production and release of another hormone called cortisol. Increased levels of ACTH in Cushing’s disease patients result in 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. Because IRC-274 is highly specific to the MC2R receptor it should not affect other processes in the body.

Scientists hoped that IRC-274 would return cortisol levels to normal and reduce the symptoms of Cushing’s disease.

IRC-274 in clinical trials

There were no clinical trials that tested IRC-274 in humans. Researchers  investigated it only in pre-clinical studies in human cells grown in the laboratory and on 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, the company presented the results of an experiment where researchers gave IRC-274 to rats that they implanted with a pump that constantly released ACTH. The increased ACTH caused an increase in cortisol. Introducing IRC-274 to the rats effectively blocked ACTH from triggering cortisol production. This was the first demonstration that IRC-274 could 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. For the study, they implanted an ACTH-producing tumor in mice to mimic Cushing’s disease. This caused an increase in circulating cortisol levels, similar to what happens in patients with Cushing’s disease. Treatment with IRC-274 resulted in a significant decrease of cortisol in the blood, demonstrating that IRC-274 was capable of blocking ACTH in vivo (in the body).

 

Last updated: April 22, 2020

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