Emerging Therapies in Management of Congenital Adrenal Hyperplasia
Investigational treatments for congenital adrenal hyperplasia are focused on new ways to manage symptoms without the need for supraphysiologic doses of glucocorticoids.
For individuals with congenital adrenal hyperplasia (CAH), passing puberty and attaining full adult height represent significant benchmarks in a life affected by a genetic disorder that 60 to 70 years ago was almost always fatal for newborns. With the introduction of corticosteroids in the 1950s, clinicians had a tool that compensated for the deficiencies of cortisol and aldosterone in the classic form of 21-hydroxylase (210H) deficiency CAH.1-4
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While effective, therapeutic regimens of glucocorticoids (GCs) are complex. Although physiologic doses are adequate to treat the inherent cortisol deficiency of CAH, supraphysiologic doses are typically required to regulate excess adrenal androgen production. Long-term exposure to high-dose GCs results in a myriad of adverse effects including obesity, hypertension, osteoporosis, and metabolic dysfunction.1-4
Little has changed in the approach to CAH management in the past 60 years, but the pace of research into safer, more effective therapies is accelerating. Researchers are studying novel approaches to physiologic cortisol replacement and non-glucocorticoid agents that specifically target the derangement in the hypothalamic-pituitary-adrenal axis responsible for the androgen excess of CAH.4 Following is an overview of the most promising therapeutic strategies.
Mimicking Nature
Novel ways to replace GCs include a range of intermediate- and long-acting glucocorticoid formulations as well as newer modified-release versions of hydrocortisone, all mechanisms focused on overcoming the challenge to mimic the circadian rhythm of cortisol production.4,9,10
A dual-release oral hydrocortisone preparation has an immediate-release coating covering an extended-release core and is administered once a day (Plenadren; Takeda Pharmaceuticals).4 While the therapy successfully induces a physiologic cortisol profile early in the day, “the overnight cortisol-free interval falls short of addressing the overnight ACTH-driven androgen excess that occurs in CAH and data in patients with CAH are lacking,” according to reviews of evolving therapies. 4,9
Another modified-release hydrocortisone formulation appears more promising for treatment of 21OH deficient CAH as it is designed to address the morning surge of ACTH and adrenal androgens. Chronocort (Diurnal) is also multilayered, with an inert core that is coated with HC followed by a layer of pH-sensitive delayed release coating.4,9 In trials dosing consisted of a 20 mg dose at 11 pm followed by a smaller, 10 mg dose at 7 am. In a phase 3 randomized parallel arm study in adults with classic CAH, the twice daily treatment improved morning and afternoon levels of 17-hydroxyprogesterone (17-OH) and androstenedione and decreased hormonal fluctuations thought the day at study week 24.4,9,10 Biomarker reduction with Chronocort was more effective than with immediate release HC dosed 3 times a day.4,9,10 Clinical improvements were also reported. Chronocort is approved in European Union countries for those with CAH aged 12 years and older while long-term safety studies continue, and additional US studies are planned.4,11
Another avenue with potential to provide GC replacement more closely resembling the circadian rhythm is continuous subcutaneous hydrocortisone infusion via programmable pump.4,9,10 The delivery is particularly promising for individuals with atypical hydrocortisone bioavailability.9,10 In a small phase 2 study the approach improved androgen biomarker and plasma ACTH levels, health-related quality of life, and fatigue vs baseline oral GC therapy of a similar daily dose. There were no improvements observed in important comorbidities, however, and practical considerations may limit effective use.4,9,10
HPA Axis Suppression
There are also treatment strategies in development that block the HPA axis, directly addressing ACTH-driven androgen excess and separating control of that process from GC treatment of cortisol deficiency. Agents currently in early- to mid-stage development include a monoclonal antibody to ACTH, a melanocortin type 2 receptor antagonist, and 2 small molecules that antagonize CRF1 action.4,9
CRF1 receptor blockade may act directly to reduce pituitary ACTH secretion, reducing androgen production and permitting physiologic GC administration to reestablish and maintain cortisol levels.4,9 Investigators have synthesized and tested 2 orally active selective small molecule CRF1 receptor antagonists of which 1 has recently been evaluated in a phase 3 clinical trial (crinecerfont; Neurocrine Bioscences).6 The phase 3 data highlight the promise of the mechanism of action.6
In this trial that enrolled participants with poorly controlled 21OH-deficiency CAH, the primary endpoint was the percent change from baseline to week 24 in daily GC dose while maintaining androstenedione control. The investigational drug met that pivotal endpoint and was superior to placebo. Crinecerfont also “markedly lowered” levels of the key markers of disease control, androstenedione and 17-OH vs placebo after an initial 4-week stable-dose period.6 The researchers also found that improved androgen control allowed reduction in daily GC dose to a physiologic range, without loss of androstenedione control. Specifically, 62.7% of participants treated with the study drug achieved a physiologic glucocorticoid dose while maintaining androstenedione control compared with 17.5% of those treated with placebo.6
Tildacerfont, the second investigational CRF1 antagonist failed in phase 2 trials to reduce androstenedione levels from baseline at week 12. In a separate ongoing phase 2 trial, tildacerfont is being assessed for reduction of GC use in adults with CAH who have close to normal levels of androstenedione.12
A high affinity long-acting humanized neutralizing monoclonal antibody to ACTH (ALD1613; Alder BioPharmaceuticals) is currently in preclinical studies and has shown substantial and durable reductions in plasma glucocorticoid levels.4 Another adrenal androgen-reducing strategy involves blocking adrenal steroidogenesis via 17-OH inhibition. There is 1 agent in ongoing phase 2 trials while phase 2 studies with a second agent were stopped.4
Other Evolving Therapies
Cell-based therapy. Investigation of cell-based therapies is capitalizing on methods of cellular reprogramming to induce generation of pluripotent stem cells. Lineage conversion work has been successful in generating human-induced steroidogenic cells in preclinical testing.4,9
Gene-based therapy. Progress in adeno-associated virus vector-based therapies has extended gene therapy potential to include CAH. The hope for gene-based treatments is to restore HPA-axis regulated glucocorticoid and mineralocorticoid production by replacing the faulty CYP21A2 gene and restoring 21OH levels. There is currently an ongoing phase 1-2first-in-human open-label, dose escalation trial evaluating the safety and efficacy of the approach for adults with classic CAH.4
Surgery. Surgical adrenalectomy was originally proposed in the 1990s specifically for children who had double null mutations. Although there are published reports of successful outcomes, including reduced mean daily GC dose equivalency of more than 30% and positive fertility results, the surgery currently is not recommended. It may be considered, however, as a last therapeutic resort in select patients unresponsive to medical management, particularly in cases of infertility.2,4
Conclusion
The persistent challenge to precisely titrate available GC preparations in order to both replace 21OH deficiency and sufficiently reduce adrenal androgen excess places individuals with CAH at risk for a wide range of poor health outcomes, across the lifespan. There are several approaches to glucocorticoid replacement therapy, glucocorticoid-sparing adjuvant therapy, and both cell- and gene-based strategies that have the potential to greatly improve patient outcomes.
References
1. Auer MK, Nordenström A, Lajic S, Reisch N. Congenital adrenal hyperplasia. Lancet. 2022;401(10374): 1-18. doi:10.1016/S0140-6736(22)01330-7
2. Speiser PW, Arlt W, Auchus RJ, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(11):4043-4088. doi:10.1210/jc.2018-01865
3. Claahsen-van der Grinten HL, Speiser PW, Ahmed SF, et al. Congenital adrenal hyperplasia—current insights in pathophysiology, diagnostics, and management. Endocr Rev. 2022;43(1):91-159. doi:10.1210/endrev/bnab016
4. Mallappa A, Merke DP. Management challenges and therapeutic advances in congenital adrenal hyperplasia. Nat Rev Endocrinol. 2022;18(6):337-352. doi: 10.1038/s41574-022-00655-w
5. Merke DP, Auchus RJ. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. N Engl J Med. 2020;383(13):1248-1261. doi:10.1056/NEJMra1909786
6. Auchus RJ, Hamidi O, Pivonello R, et al for the CAHtalyst Adult Trial Phase 3 trial of crinecerfont in adult congenital hyperplasia. N Engl J Med. Published online June 1, 2024. doi: 10.1056/NEJMoa2404656
7. Auchus RJ, Witchel SF, Leight KR, et al. Guidelines for the Development of Comprehensive Care Centers for Congenital Adrenal Hyperplasia: Guidance from the CARES Foundation Initiative. Int J Pediatr Endocrinol. 2010;2010:275213. doi:10.1155/2010/275213
8. Turcu AF, Auchus RJ. Novel treatment strategies in congenital adrenal hyperplasia. Curr Opin Endocrinol Diabetes Obes. 2016;23(3):225-232. doi:10.1097/MED.0000000000000256
9. Schröder MAM, Claahsen ‑ van der Grinten HL. Novel treatments for congenital adrenal hyperplasia. Rev Endocr Metab Disor. 2022; 23:631–645. doi:10.1007/s11154-022-09717-w
10. Charoensri S, Auchus RJ. A contemporary approach to the diagnosis and management of adrenal insufficiency. Endocrinol Metab (Seoul). 2024; 39(1): 73–82. doi: 10.3803/EnM.2024.1894
11. Diurnal receives special protocol assessment agreement for Chronocort from the FDA. News release. Diurnal. July 12, 2021. Accessed June 24, 2024. https://www.diurnal.com/Investor/news/diurnal-receives-special-protocol-assessment-agreement-for-chronocort-r-from
12. Spruce Biosciences reports full year 2023 financial results and provides corporate updates. News release. Spruce Biosciences. March 13, 2024. Accessed June 24, 2024. https://investors.sprucebio.com/news-releases/news-release-details/spruce-biosciences-reports-full-year-2023-financial-results-and
