Millendo’s ATR-101 Reduces Cortisol Levels in Dogs with Cushing’s Disease, Study Shows

Millendo Therapeutics‘ experimental small molecule ATR-101 shows promise as a treatment for Cushing’s disease in dogs, suggesting its potential in humans with the syndrome, according to a new study.

It also suggests that dogs with naturally occurring Cushing’s could be used as a model for human disease. The disease is much more common in canines than it is in humans.

The study, “ATR-101, a selective ACAT1 inhibitor, decreases ACTH-stimulated cortisol concentrations in dogs with naturally occurring Cushing’s syndrome,” was published in BMC Endocrine Disorders.

The pituitary gland produces a hormone known as adrenocorticotropic hormone (ACTH), which stimulates the adrenal glands to produce cortisol, a type of steroid. But when the adrenal glands produce too much cortisol, it may lead to the development of Cushing’s disease.

Cushing’s in humans is similar to the disease in dogs regarding its cause of origin, clinical symptoms, and biological processes leading to the disease.

The treatment of Cushing’s disease in both species is not ideal, indicating a need for improved therapies.

ATR-101 is an inhibitor of ACAT1, an enzyme that’s  responsible for creating a reservoir of molecules used for producing steroids. Cortisol is a steroid, so blocking ACAT1 would lead to a decrease in the levels of cortisol.

The experimental therapy is currently in clinical development for the treatment of adrenocortical carcinoma, congenital adrenal hyperplasia, and Cushing’s disease in humans.

Prior research conducted in healthy dogs has shown that ATR-101 leads to a rapid decrease in ACTH-stimulated cortisol levels, leading researchers to conduct a study to evaluate the effects of ATR-101 in dogs with Cushing’s disease.

ATR-101 activity was assessed in 10 dogs with naturally-occurring Cushing’s syndrome. Seven of the 10 had pituitary-dependent disease — meaning that high cortisol levels were caused by excess ACTH production by the pituitary gland — and three dogs had adrenal-dependent disease.

Clinical, biochemical, hormonal, and pharmacokinetic (how the therapy is processed in the body) data were obtained weekly.

ATR-101 induced a significant decrease in cortisol concentrations in the responders (nine out of 10 dogs). The mean reduction of cortisol levels was 50% at the study’s completion.

ATR-101 was found to be well-tolerated, and there were no serious drug-related adverse events.

“ATR-101 is well-tolerated and reduces post-ACTH-stimulated cortisol concentrations in dogs with naturally occurring CS [Cushing’s syndrome],” the investigators wrote.

One of the limitations that hampers drug development of Cushing’s disease in humans is the rarity of the disease. The approximate incidence of the disease is only two cases per million per year.

However, canine Cushing’s is much more common than its human counterpart, estimated at one or two cases per 1,000 dogs per year with similar causes and biology, providing a convenient model to study drug development.

“This [study] should establish a valuable precedent in using the dogs with naturally occurring [Cushing’s disease] for the development of human therapeutics, hopefully resulting in benefits for both species,” the researchers concluded.