Table 1.

Novel treatment strategies for congenital adrenal hyperplasia that are available for clinical use or currently undergoing clinical evaluation.

Treatment	Administration	Advantages	Disadvantages
CRF1 receptor antagonists
Crinecerfont*	Oral, twice daily.	•Oral administration. • Effectively reduced ACTH and adrenal androgen • Possibly leads to reduced glucocorticoid requirements. • Favourable safety profile	• Lack of long-term efficacy and safety data. • Need for concomitant glucocorticoid replacement.
Tildacerfont*	Oral, once daily.	• Oral administration. • Effectively reduces ACTH and adrenal androgen levels. • Possibly leads to reduced glucocorticoid requirements. • Favourable safety profile. • Associated with testicular adrenal rest tissue reduction.	• Lack of long-term efficacy and safety data. • Need for concomitant glucocorticoid replacement. • Drug–drug interactions (including increased bioavailability of dexamethasone).
Glucocorticoid replacement
Modified-release hydrocortisone  Plenadren®	Oral, once daily.	• Oral administration. • Once daily dosing. • Favourable safety profile.	• Reduced bioavailability • Does not replace overnight cortisol levels.
Modified-release hydrocortisone (Efmody®; development name Chronocort)	• Oral, twice daily. • Recommended starting dose: 10–15 mg/m2/day (adolescents ≥ 12 years who have not completed growth); 15–25 mg/day (adults and adolescents who have completed growth). • The starting dose should be split into ⅔–¾ given in the evening at bedtime and the rest given in the morning upon awakening.	• Oral administration. • Mimics the natural cortisol rhythm. • Effectively controls androgen excess. • Associated with clinical benefit (restoration of menses, partner pregnancies, improvement of sperm count in a man with testicular adrenal rest tissue). • Favourable safety profile.	• Cannot be used for sick day dosing (patients should be provided with immediate-release glucocorticoid formulations, for example, hydrocortisone or cortisone acetate). • Not recommended in patients with increased gastrointestinal motility due to the risk of impaired absorption.
Hydrocortisone pump	Continuous s.c. infusion.	• Mimics the natural cortisol rhythm. • Effectively controls androgen excess. • Associated with clinical benefit (quality of life, restoration of menses, testicular adrenal rest tissue reduction) • Relies on technology that is already available (insulin pump).	• Evidence derived from one small-scale study. • Requires continuous device wear and high engagement by the patient and health professionals. • Possibility of malfunction. • Available hydrocortisone formulations are not designed for s.c. use. • Possible injection site and systemic reactions.
Alkindi® hydrocortisone granules (development name Infacort)	Oral, two to four times daily	• Oral administration. • Paediatric appropriate dosing available as 0.5, 1.0, 2.0, and 5 mg. • Taste masking. • Favourable safety profile.	• Does not replace overnight cortisol levels.
Acecort® hydrocortisone tablets	Oral, two to four times daily	• Oral administration. • Dosing available at 1.0, 5.0, and 10 mg. • Colour-coded	• Does not replace overnight cortisol levels.
CYP17A1 inhibitor
Abiraterone acetate*	Oral, once daily.	• Oral administration. • Effectively controls androgen excess. • Favourable safety profile.	• Need for concomitant glucocorticoid replacement. • Inhibits gonadal sex steroid biosynthesis and could be used only in patients who do not desire fertility. • Potential adverse foetal outcomes. • Potential concern for expansion of testicular adrenal rest tissue in men. • Concerns around liver toxicity. • Needs to be taken on an empty stomach (at least 1 h before and 2 h after any food). • Drug–drug interactions.
Androgen receptor antagonist
Flutamide*	Oral, three times daily.	• Oral administration. • Associated with normal linear growth and reduced glucocorticoid requirements in a small-scale study.	• Need for concomitant glucocorticoid ± aromatase inhibitor treatment. • Concerns around liver toxicity. • Contraception is recommended in women of reproductive age.

*Currently used in patients with 21OHD-CAH only as part of clinical trials.