MICA: Clinical validation of a non-invasive diagnostic test for adrenal insufficiency using comparative pharmacodynamic equivalence

The adrenal glands sit above the kidneys and are part of the body's endocrine system. They produce a number of different hormones; those involved in metabolism (cortisol), salt and water balance (aldosterone) and androgens (sex steroids e.g. testosterone). Adrenal insufficiency (AI) describes the inability of the body to produce adequate levels of cortisol. Cortisol helps to control blood pressure and blood sugar levels and is released as part of the body's stress response. Without treatment (replacement cortisol) AI can lead to serious illness and death through low blood pressure causing circulatory collapse (adrenal crisis). There are numerous causes of AI, both in adults and children. In high-income countries destruction of the adrenal gland by the immune system, brain tumours and the prescription of steroid medication for inflammatory conditions (e.g. arthritis, asthma, cancers) are the commonest but globally major causes are TB and AIDS. AI is usually permanent but, especially in those patients taking steroid medication, it may not be and repeated testing may be required. The Short Synacthen Test (SST) is the most popular diagnostic test for adrenal insufficiency worldwide. Synacthen is a drug structurally very similar to the brain hormone, ACTH, which stimulates the adrenal glands to produce cortisol. In the SST blood tests are taken before Synacthen is given and 30-60 minutes after in order to measure the rise in cortisol produced from the adrenal gland. If the cortisol rise is inadequate the patient is diagnosed with AI and requires replacement cortisol (hydrocortisone). Over recent years requests for SSTs have risen in line with the increasing prescription of steroid medication and heightened awareness of the adrenal insufficiency steroids can cause. The SST requires intravenous cannulation and blood sampling. It is thus invasive, resource-intensive (requiring a day care hospital admission and trained personnel to deliver the test) and unpleasant for the patient, especially children; leading to a rise in both the cost and the threshold for requesting the test.

We have developed a non-invasive, needle-free, alternative to the SST, with the drug, tetracosactide (Synacthen), given nasally via a spray and the resultant cortisol response measured on saliva samples. The new drug is a combination of tetracosactide with chitosan, a nasal drug enhancer, which helps the tetracosactide be absorbed from the nose into the bloodstream. To date we have completed five clinical trials testing different doses and formulations (mixtures) and found our new drug, Nasacthin, to be reliably absorbed and well tolerated in healthy adult men and children. We have sought advice from the MHRA (UK medicines regulator) as to what studies to do next in order to be granted a licence to be able to use Nasacthin in clinical practice inorder to diagnose AI in patients. They have recommended we perform studies in healthy men, women and children to verify the Nasacthin Test does not produce a lower cortisol response compared to the SST and then to test it in a patient population to ensure confidence that it diagnoses AI as accurately as the SST.

Our non-invasive test would negate the need for needles and reduce (indeed in some cases avoid entirely) additional hospital visits for patients, thus reducing costs for the healthcare provider and importantly improving the overall patient experience. The novel test has utility in the inpatient, outpatient and community settings; rural and hard to reach communities globally; in both adults and children; and will provide a vital research tool for future studies on the response of the adrenal gland to steroids in many diverse patient cohorts, including children.

Cortisol is an essential stress hormone and failure of production, adrenal insufficiency (AI), is associated with significant mortality due to adrenal crisis. The common causes in the Western world are iatrogenic adrenal suppression from steroid use, pituitary gland pathologies & autoimmunity; and globally TB & AIDS. The Short Synacthen Test (SST) is the diagnostic test of choice for AI. It is invasive (cannulation/blood sampling) & resource-intensive (skilled personnel/daycare admission), resulting in raised thresholds for investigation & delayed diagnosis. Globally there is an unmet need for a non-invasive cost-effective test. We are developing an innovative needle-free SST, using Synacthen (tetracosactide) mixed with the nasal drug enhancer chitosan. This novel nasal formulation, Nasacthin, combined with saliva used to measure the glucocorticoid response (salivary cortisol & cortisone), renders the test non-invasive. PK studies (60 healthy volunteers) have demonstrated reproducible plasma & salivary results. In 2018 we gained MHRA Scientific Advice on the clinical regulatory pathway to Market Authorisation (MA) for the Nasacthin formulation. Further MHRA advice (2021) agreed our design for the clinical studies required for MA which are: 1) demonstrating comparative pharmacodynamic (PD) non-inferiority of Nasacthin to 250mcg IV Synacthen in healthy adults & children; and 2) a PD study demonstrating adrenal function testing with Nasacthin is able to correctly diagnose patients with AI by calculation of positive percent agreement with the IV SST. These studies will facilitate commercialisation by providing the clinical data for the regulatory approval of Nasacthin, giving industry sufficient confidence to develop the full data package for MA. The route to market will be through a licence deal to a pharmaceutical company bringing patient benefit through a streamlined clinical care pathway, yielding timely diagnosis and a better tolerated test, especially in children.