Scientists from the Universities of Oxford and Sheffield are collaborating with the US biopharmaceutical company Sparrow Pharmaceuticals on DC-MACS a Phase 2 clinical study of the drug clofutriben to treat autonomous cortisol secretion (ACS).
Clofutriben, also known as SPI-62, is produced by Sparrow and used to inhibit HSD-1, an enzyme that helps to regulate the production of cortisol in the body.
ACS is a prevalent and serious condition caused by the overproduction of cortisol from a tumour of the adrenal gland. As patients with ACS lack the outward clinical features of the similar Cushing’s syndrome, and their symptoms present as common, chronic conditions, the condition is often not diagnosed.
Most patients with ACS are diagnosed when the tumour shows up on a scan for an unrelated health condition and the patient subsequently receives endocrine tests. As that occurs infrequently, patients with ACS are potentially exposed to excess circulating cortisol for long periods of time, leading them to face major health complications and increased risk of early death.
The signs and symptoms of ACS include a wide range of mental and physical effects including diabetes, hypertension, bone fractures and weight gain, as well as mood, cognition and sleep disorders. There is currently no established drug treatment for this condition, and current practice involves monitoring for complications, but not active treatment.
The study will be led by two leading endocrinologists: Professor Jeremy Tomlinson of the University of Oxford, who first described a patient with a Cushing’s tumour, but no signs or symptoms of Cushing’s syndrome because of HSD-1 deficiency; and Professor John Newell-Price of the University of Sheffield, the current President of the Endocrine Society.
Professor Tomlinson is supported by the National Institute for Health and Care Research (NIHR) Oxford Biomedical Research Centre, for which he is the Theme Lead for Metabolic Experimental Medicine. The study will be conducted jointly in the NIHR-supported Clinical Research Facilities in both Oxford and Sheffield.
“In partnering with Sparrow for the DC-MACS trial, we hope to pioneer a completely novel intervention for this common, yet serious disease,” said Professor Tomlinson. “If successful, this trial could provide patients with ACS with a treatment that could transform their health and quality of life.”
Professor Newell-Price added: “ACS today usually goes undiagnosed. This leaves many patients at risk of morbidity from their hypercortisolism, including cardiovascular disease and bone fractures, and even a higher risk of death. Hopefully, we can not only demonstrate a new potential treatment, but also raise awareness of this dangerous disease.”
The objectives of the randomised, double-blind, placebo-controlled study are to evaluate the efficacy, safety and pharmacological effects of clofutriben, a novel, highly potent, and selective HSD-1 inhibitor, for treating ACS.
HSD-1, an intracellular enzyme, activates cortisol in target tissues in which cortisol excess is associated with morbidity including liver, adipose, muscle and brain.
This study will also evaluate endocrine markers such as insulin sensitivity, glucose disposal and levels of fat in the blood.
Forty patients across two sites – Sheffield Teaching Hospitals NHS Foundation Trust and Oxford University Hospitals NHS Foundation Trust – will take part in the study.
Sparrow Pharmaceuticals, is an emerging, clinical-stage biopharmaceutical company developing novel, targeted therapies to address unmet needs in both rheumatology and endocrinology.
Its Chief Scientific Officer, David Katz, said: “Clofutriben substantially lowers intracellular cortisol, which can bind intracellular receptors and thereby cause the morbidity associated with ACS. Clofutriben has potential to be the first targeted therapy for that common, serious, and currently under-recognised disease.”
This study is being conducted with funding from the UK Research and Innovation Medical Research Council.