Block and Replace-a New Therapeutic Concept in Congenital Adrenal Hyperplasia?

Patients with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency require life-long cortisol replacement. If left untreated, patients with the most severe form die of salt-wasting crisis in the first few weeks of life. Owing to the introduction of adrenal replacement therapy 70 years ago and newborn screening programs available today in almost all Western countries, virtually all patients survive. Seven decades later, however, therapy still looks the same, namely hydrocortisone given thrice daily in the vast majority of patients. The treatment challenge in CAH is 2-fold: to replace the missing hormone and to control the adrenocorticotropin (ACTH)-driven excess of adrenal androgens, particularly overnight to prevent the early morning rise of adrenal androgens. To achieve the latter, supraphysiological doses of glucocorticoids need to be given, and in some cases, administered in a reverse circadian treatment regimen with the maximum dose given at bedtime. Adults are often treated with longer-acting synthetic glucocorticoids taken 1 to 2 times daily to encourage compliance and control hyperandrogenemia.

We now know that patients suffer from multiple glucocorticoid-associated morbidities starting early on: Patients turn obese at a young age and suffer from multiple cardiovascular and metabolic health issues later in life (1). They still do not reach their target height but are 10 cm shorter than expected, often experience poor quality of life, have impaired fecundity and fertility, and have increased mortality (1). These unacceptable outcomes are linked to current glucocorticoid replacement, which is both unphysiologic in rhythm and too high in dose.

In attempting to tackle the challenge, 2 novel therapeutic concepts are emerging. Data on a modified-release hydrocortisone preparation mimicking the normal circadian cortisol rhythm have just been published. The phase 3 study has demonstrated normalization of overnight 17-hydroxyprogesterone (17OHP) and androgen secretion (2). The preparation is given twice daily, on awakening and before bedtime. The study, however, failed its primary end point as modified-release hydrocortisone was not superior in controlling 17OHP over 24 hours compared to conventional glucocorticoid replacement, but showed superior hormonal control only in the morning. Patients on average still needed supraphysiological glucocorticoid doses for optimal hormonal control with 30 mg hydrocortisone per day on average. The first results of an ongoing safety extension study, however, suggest that downtitration of the dose over time is possible while maintaining hormonal control. Effects on metabolism or long-term outcome markers of cardiovascular and bone health could not (yet) be shown because of the study’s short duration (6 months). The formulation has been licensed in Europe and is expected to be launched in fall 2021.

Another concept to mitigate glucocorticoid-associated adverse outcomes is corticotropin-releasing factor type 1 (CRF1) receptor antagonists (3, 4) that block ACTH secretion as ACTH is the major driver of adrenal androgen excess. Sarafoglou et al (3) present the results of 2 phase 2 studies employing the second-generation CRF1 receptor antagonist tildacerfont. Tildacerfont is a small molecule that selectively and with high affinity binds to CRF1 receptors in the pituitary gland. Tildacerfont treatment aims to reduce the ACTH drive on the adrenal, thereby allowing reduction from supraphysiologic glucocorticoid dosing to a mere replacement dose. Currently recommended doses for glucocorticoid treatment in CAH are 10 to 15 mg/m2 in pediatric patients and a 15- to 25-mg/d hydrocortisone dose equivalent in adulthood (5). A mere replacement dose would be 6 to 10 mg/m2 hydrocortisone dose equivalent translating into 10 to 20 mg/d in adults. Real-world data from current cohort studies in adults with CAH, however, show that doses used in practice range from 14 to 20/m2, well accounting for the high frequency of glucocorticoid-associated morbidities (6, 7).

Tildacerfont in the presented phase 2 studies has been well tolerated, and a once-daily application in the evening reduced ACTH in the majority of patients, as well as subsequent glucocorticoid and androgen precursors. The first phase 2 study, a dose-escalation study with once or twice daily dosing, showed no clear dose response, thus lower doses already were efficacious in blocking ACTH synthesis. The second phase 2 study showed that a once-daily regimen is efficacious in reducing or maintaining hormone biomarkers toward normal over 12 weeks.

With regard to these developments, who are the patients who might particularly benefit from a potential new block and replace therapeutic concept? Certainly not all patients, but specific subgroups of patients in particular treatment situations requiring high glucocorticoid doses. This includes patients with testicular adrenal rest tissue seeking fertility. These patients currently need to be overtreated with adrenal suppressive doses to induce adrenal rest tissue shrinkage and induce spermatogenesis. Similarly, women seeking fertility often need supraphysiological doses to suppress progesterone interfering with endometrial build-up and ovulation. Treatment in growing children and adolescents is particularly challenging because they may require higher glucocorticoid doses for control of hyperandrogenemia at the expense of hampering growth. Lastly, all patients showing metabolic and cardiovascular comorbidities such as hypertension, obesity, impaired glucose tolerance, or low bone mineral density.

A potential disadvantage of the drug is that it needs to be taken with a moderate fat meal for optimal absorption, ideally late in the evening to develop the maximum effect of ACTH suppression overnight. This may be counterproductive in an obese patient with a metabolic risk profile.

The following larger, next-phase studies will need to confirm efficacy and safety and demonstrate the extent of a potential glucocorticoid-sparing effect. A combination of block and replace with a novel circadian-modified hydrocortisone preparation is conceivable in the future.

Data clearly show that more of the same therapy as in the last decades is not enough for optimal patient care in CAH. Undoubtedly, the new emerging therapies open up new horizons of a needed change toward an individualized and more physiologic treatment for optimized long-term patient outcome in CAH.