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at the end of the study typically exceeded those recommended for adrenal replacement . Good adrenal control was achieved in just 28 % of visits and 93 % of patients had hypertension at one or more visits . 10 Data from this observational study and others have provided insights for the development of new pharmacotherapies that are now in clinical development aiming to ameliorate morbidity and mortality of patients with CAH . 6
Novel treatment options
Modified-release hydrocortisone
A multi-particulate formulation of hydrocortisone with a delayed release coating has been developed . This preparation allows for delayed and sustained absorption . When taken at bedtime and on rising , this replicates the overnight diurnal rise in cortisol . 11 Modified-release hydrocortisone improves 24-hour control of 17-OHP , the traditional adrenal biomarker , and the alternative adrenal androgen pathway metabolites when compared to standard glucocorticoid therapies . 8
Melanocortin type 2 receptor antagonist ACTH activity at the melanocortin type 2 receptor ( MC2R ) results in the synthesis and secretion of cortisol ( corticosterone in rats ). By blocking this receptor , the action of ACTH has been shown to be effectively blocked in vitro . In vivo studies in rats have shown good oral bioavailability and dose-dependent acute suppression of corticosterone levels and control of ACTH levels , reversing the phenotype caused by ACTH excess . 12 Currently double blind , randomised placebo-controlled phase 1 studies with an oral
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MC2R antagonist ( CRN04894 ) are underway in humans . 6 , 7
Corticotropin-releasing factor type 1 receptor antagonists ACTH suppression is another promising strategy for future treatment . The primary regulator of ACTH synthesis and release is corticotrophin-releasing factor ( CRF ). This hormone is released from the hypothalamus into the hypophyseal portal system and acts directly on corticotropes via two different receptors : CRF type 1 ( CRF1 ), which is abundant in the pituitary , and the CRF type 2 ( CRF2 ), predominantly found in peripheral tissues .
Tildacerfont is a novel CRF1 receptor antagonist that binds to CRF1 receptors in the pituitary to inhibit excessive production of ACTH and , as a result , 17-OHP and other adrenal androgens . It requires daily oral dosing .
CRF1 receptor antagonism prevents the need for supraphysiologic doses of glucocorticoids while effectively reducing high androgen exposure . This approach mitigates the long-term negative consequences of life-long supraphysiological glucocorticoid treatment . 13 To date , the safety profile has been acceptable in non-clinical toxicology studies and phase 2 studies in adults with classic CAH . 13
A phase 2a study has demonstrated target engagement and reductions in ACTH , 17-OHP and A4-androstenedione , key hormones for disease control . There were no serious adverse events and adverse events ( most frequently headache in 7.1 % and upper respiratory tract infection in 7.1 %) were mild and unrelated to treatment . 13 A
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larger study ( CAHmelia program ) is currently being undertaken in Australia to further investigate the safety and efficacy of this agent ( see ‘ Online resources ’).
Conclusions
CAH due to 21-hydroxylase deficiency is a rare genetic condition resulting in several significant hormonal imbalances . Adverse outcomes result from the disease itself and chronic glucocorticoid treatment .
While progress has been made regarding pathophysiology , clinical features and genetics of the disease , current therapeutic options are still not optimal .
The development of novel treatments will help improve the management ,
The classic form is typically diagnosed at birth via newborn screening , allowing treatment to be initiated before an adrenal crisis occurs .
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quality of life and health outcomes of these patients . 14
Conflicts of Interest Dr Gabriela Finkielstain is a consultant for Spruce Biosciences , a biopharmaceutical company the develops novel therapies for rare endocrine disorders , including tildacerfont .
References on request from kate . kelso @ adg . com . au
Online resources
• For patient referrals , visit the CAHmelia Australia site : sprucebio . com / cahmelia-au
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One goal of treatment is to suppress adrenal androgen overproduction . |