ESPE Yearbook of Paediatric Endocrinology

Nat Rev Endocrinol. 2022; 18(6): 337-352. PMID: 35411073https://pubmed.ncbi.nlm.nih.gov/35411073/

Brief Summary: This review summarizes the current knowledge and understanding of the therapeutic challenges and the novel advances in the management of classical congenital adrenal hyperplasia (CAH).

This review describes the present and novel therapeutic options for 21OHD CAH. Several novel approaches to address the lack of normal cortisol circadian rhythm and hyperandrogenism in CAH are plausible future targets for intervention. Among those are: i) Modified release hydrocortisone (Chronocort); ii) Adrenal steroidogenesis inhibitors (abiraterone, nevanimibe); iii) HPA axis suppressors (CRF1R antagonists, ACTH antagonist - monoclonal antibody, mC2R antagonist); iii) Cell-based therapies - human induced steroidogenic cells and transplantation of bioartificial adrenal cortex; and iv) Gene-based therapies - Adeno-associated virus-based gene therapy, BBP-631 (currently ongoing phase I–II trials).

Chronocort was investigated in a multicenter phase III, randomized, parallel arm study in 122 adults with classic CAH, conducted over 24 weeks. The trial missed its primary end point as Chronocort was not superior to standard glucocorticoid therapy based on the 24-hour profile of serum 17OHP concentrations. However, compared with standard glucocorticoid therapy, Chronocort improved 17OHP and androstenedione concentrations in the morning and early afternoon, with a decrease in daily hormonal fluctuations. At 18 months extension, further benefits included: improved menstruation (n= 4) and patient or partner pregnancy (n= 5). Chronocort (brand name Efmody) received marketing approval in 2021 in the UK and Europe for patients with CAH aged 12 years and older.

Abiraterone is a potent CYP17A1 inhibitor that lowers testosterone production and is used to treat prostate cancer. Abiraterone was studied as a phase I, non-randomized, open-label, multiple-dose (6 days), sequential dose-escalation (100–250 mg once-daily) trial in six women (aged 19–46 years) with classical CAH. Abiraterone decreased serum concentrations of testosterone, and 11-oxygenated androgens and urinary androgen metabolites. A phase I–II study in prepubertal children is underway.

Potential strategies to address the drivers of excess androgen synthesis in CAH include molecules that antagonize the action of CRF1, a monoclonal antibody to ACTH and a selective MC2R antagonist. The CRF1R antagonists, crinecerfont and tildacerfont, are described in papers 8.8 and 8.9 of this chapter.

The first feasibility study of gene therapy for CAH used a replication-deficient adenovirus containing human CYP21A2in 21OHD knockout mice. An intra-adrenal injection of the vector restored adrenocortical function for up to 40 days. A subsequent study of an intravenous injection of an AAV-CYP21A2vector in CAH mice restored steroidogenesis for>15 weeks. Intramuscular injection of an AAV vector with mouse Cyp21a1in CAH mice resulted in enzyme expression for>6 months. BBP-631 (Adrenas Therapeutics, USA) is an AAV5 vector encoding human CYP21A2. Preclinical durability studies of a single intravenous injection in CAH mice and cynomolgus monkeys demonstrated adrenal tropism of the vector and dose-dependentRNA expression for 12 weeks and durable expression of vector genome copies up to 24 weeks. A phase I–II, open-label, dose-escalation trial investigating the safety and efficacy of gene therapy for adults with classic CAH is under way.

In summary, multiple hormonal imbalances complicate the management of CAH. Future research in CAH aims to tailor therapy to maximize clinical benefits and minimize long-term adverse outcomes. The multitude of new advances in glucocorticoid replacement therapy, glucocorticoid-sparing adjuvant therapies, and cell-based and gene-based therapies promises an improved outcome in patients with CAH.