As a class of signaling molecules, hormones regulate key aspects of physiology and behaviour across a multitude of organs. It is thus not surprising that dysregulation of hormone function is associated with a range of pathologies.

ACTH-dependent Cushing’s disease (CD) and congenital adrenal hyperplasia (CAH) are examples of conditions associated with the dysregulation of the Adrenocorticotropic hormone (ACTH). ACTH is secreted from the pituitary gland under the control of the corticotropin-releasing hormone (CRH) from the hypothalamus. ACTH acts through its receptor, the melanocortin receptor 2 (MC2R) on the adrenal cortex to stimulate the production of glucocorticoids (GCs). Under homeostatic setting, ACTH mediates the basal and stress-induced function of the hypothalamus-pituitary-adrenal (HPA) axis which is a crucial endocrine system that regulates several physiological processes such as metabolism, nervous and immune systems. This pathway is under both diurnal regulation and negative feedback regulation.

Despite different etiologies, both CAH and ACTH-dependent CD are characterized by excess ACTH production. In ACTH-dependent CD, patients suffer from pituitary adenomas or tumours in other tissue that secrete high levels of ACTH, leading to overproduction of GCs causing a range of symptoms including obesity, glucose intolerance, hypertension, acne and alopecia. Excess ACTH can also originate from non-pituitary tumors causing ectopic Cushing’s syndrome.

In CAH, patients are born with mutations in key enzymes of the steroidogenesis pathways leading to loss of GC production and adrenal insufficiency. Loss of GC secretion from the adrenal glands results in the loss of the negative feedback loop that suppresses CRH and ACTH production leading to high ACTH secretion, which under the diurnal control can be higher for several hours in the morning. Excess ACTH continuously stimulates the MC2 receptors on the adrenal cortex which results in the hyperplasia of the gland and furthermore, the accumulated GC precursor is converted to adrenal androgens. Exposure to adrenal androgens is a key driver of the CAH condition which results in precocious puberty, shortened height and fertility problems. To address these issues the goal of the GC therapy in CAH patients is not only replacement but also to establish the negative feedback loop to lower ACTH levels and suppress adrenal androgens. To achieve the latter, supraphysiological doses of GC are required which result in patients becoming Cushingoid.

Given its central role, treatment strategies targeting ACTH have garnered a lot of interest for these conditions. Initial strategies have focused on inhibiting ACTH release, either by targeting somatostatin receptors (e.g., pasireotide) on pituitary adenomas in Cushing’s or inhibiting the corticotropin-releasing hormone receptor (e.g., crinecerfont) in CAH. Despite these treatments representing advances in how these patients are treated, not all patients respond, and new treatment options are needed.

Another treatment strategy for these indications, and the one currently being pursued at OMass, is to target the MC2 receptor to inhibit the activity of ACTH directly. We expect this strategy to lead to improved outcomes as you can more completely and directly block the action of ACTH on MC2. In addition, human genetics provides support that blocking MC2 significantly decreases the production of cortisol without significant side effects, as demonstrated in patients with familial glucocorticoid deficiency that have loss of function mutations on the MC2 receptor.

Recently, Crinetics’ MC2 receptor antagonist, atumelnant, demonstrated reductions in androgens in CAH patients and urinary free cortisol in Cushing’s patients in two separate phase 2 studies, highlighting the potential for this approach in these indications.

Although this early data is exciting, the high ACTH levels in both CAH and ACTH-dependent CD implies that maximum efficacy can only be achieved through insurmountable antagonism. Whilst a high affinity surmountable antagonist is expected to reduce the effect of ACTH, the full efficacy potential is limited as at high agonist concentration the antagonist is outcompeted. For many diseases this may not be materially important since the levels of drive on the system may not reach high enough concentrations. However, this is not the case for CAH and ACTH-dependent CD; where in both cases the levels of ACTH can reach very high concentrations (in CAH as a result of the morning ACTH surge and in CD due to pulsatile ACTH secretion) and such dynamic increases in the agonist levels can lead to loss of surmountable antagonist effects.

At OMass, we have been able to model this in cells and preclinical species and demonstrate that only an insurmountable antagonist can provide full suppression of the receptor activity when the agonist concentrations are increased. To achieve this pharmacological feature, we have optimized the kinetics of binding and generated antagonists with long residency time on the receptor. This way, the antagonist in effect becomes non-competitive with the agonist and its inhibitory effect becomes independent of the agonist concentration.

As our MC2 program completes pre-clinical studies and passes through clinical testing, we are hoping that these improvements are able to translate into benefit for patients.