Emerging treatment for CAH

Abstract

Purpose of review:

Although the basic treatment of congenital adrenal hyperplasia (CAH) is well established, there are active clinical research projects to more closely mimic the normal diurnal rhythm of cortisol secretion and to reduce total glucocorticoid doses to minimize adverse metabolic effects.

Recent findings:

We review clinical studies on CAH treatment published in the last 18 months or currently underway according to ClinicalTrials.gov listings. These can be grouped into several broad themes: [a] alternative dosing forms of hydrocortisone with altered pharmacokinetics or easier dose titration; [b] corticotropin-releasing hormone receptor antagonists that reduce ACTH secretion and thereby reduce adrenal androgen secretion; [c] androgen biosynthesis inhibitors; [d] a first clinical trial of a gene therapy vector.

Summary:

Alternative dosing forms of hydrocortisone are, or will shortly be, marketed, but cost may be a barrier to utilization, at least in the US market. Trials of corticotropin releasing hormone receptor antagonists and androgen biosynthesis inhibitors are currently underway. The author believes that trials of gene therapy for CAH are premature.

Introduction.

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders affecting cortisol biosynthesis. Reduced activity of an enzyme required for cortisol production leads to chronic overstimulation of the adrenal cortex and accumulation of precursors proximal to the blocked enzymatic step. The most common form of CAH, accounting for >90% of cases in most populations, is caused by steroid 21-hydroxylase deficiency due to mutations in CYP21A2, so we will use the term ‘CAH’ to denote 21-hydroxylase deficiency here. Patients with severe or “classic” CAH cannot synthesize cortisol adequately and require glucocorticoid replacement; most of these are “salt-wasting” patients who cannot synthesize aldosterone and thus also require fludrocortisone. CAH treatment is the subject of a 2018 Endocrine Society Clinical Practice Guideline (1). The genetics, pathophysiology and treatment options for CAH have been recently reviewed (2**, 3*). Here, we summarize clinical trials that have been recently completed or are currently underway that attempt to improve glucocorticoid treatment of CAH.

The goals for glucocorticoid treatment for classic CAH include both hormonal replacement and reducing adrenal androgen production. There have been limited trials comparing the efficacy and safety of different glucocorticoid replacement regimens for CAH in children and adults and a recent meta-analysis was unable to draw any firm conclusions (4*). Recent reports from international (5*) and German-Austrian (6*) patient registries confirm that the vast majority of patients with CAH are indeed being treated with hydrocortisone (i.e., the physiologic glucocorticoid, cortisol), at median doses of ~14 mg/M²/d through most of childhood and adolescence. These are supraphysiologic doses (physiologic cortisol secretion is ~6-8 mg/M²/d), which carry an increased risk of comorbidities. Compared to the US population, patients with CAH have higher prevalence of obesity, hypertension, insulin resistance, fasting hyperglycemia, and decreased high-density lipoprotein (HDL) during childhood and obesity, hypertension, and insulin resistance during adulthood (7*).

Alternative hydrocortisone preparations.

One problem with hydrocortisone is that, depending on the locale, the smallest available dosage is often a 5 or 10 mg tablet, presenting challenges for dose titration, especially in small children. This may be addressed with custom-compounded suspensions or encapsulated powder, but high quality compounding pharmacies are not available in all locales, and compounding errors have been reported (summarized in ref (3)). Alkindi® (Eton Pharmaceuticals) is a new dosage form consisting of encapsulated microtablets (sprinkles); the capsules can be opened and the sprinkles given with a small amount of liquid or other excipient. One small, open label, single arm, study in 17 children with CAH suggests that this medication is safe and effective (8*), and it is now marketed in Europe and the US. Unfortunately, it is extremely expensive in the US; the American retail price for 50 capsules each containing 5 mg of Alkindi Sprinkle granules is $3,656.40, whereas the price for 50 x 5 mg hydrocortisone tablets is $16.28 (https://www.drugs.com/price-guide, accessed 30 December 2021).

Given the normal diurnal rhythm of cortisol secretion—highest in the morning, lowest in the middle of the night--another major drawback to hydrocortisone treatment is its short serum half-life (90 minutes). This results in inadequate suppression of adrenal androgen precursors when its biological effect wears off. There is some evidence that 4 times a day administration may yield the best results (9*), but consistent adherence is difficult to achieve. Neither retrospective studies (10*) nor randomized crossover studies (11**) show an advantage for giving more hydrocortisone in either the morning (circadian pattern) or the evening (reverse circadian pattern). Sustained-release hydrocortisone preparations have been developed as an alternative to longer-acting synthetic corticosteroids such as prednisone/prednisolone or dexamethasone. One such formulation, Plenadren® (Shire Services BVBA, Belgium), is approved in Europe for treatment of adrenal insufficiency in adults. When given once daily to patients with primary adrenal insufficiency, it significantly improves body weight and immune function, compared to conventional hydrocortisone replacement at the same daily dose (12). However, data on its use in CAH patients are lacking. Recent small nonrandomized studies in adults with primary adrenal insufficiency suggest a small benefit in fatigueability (13*), and benefits in sleep quality (14*), blood pressure, BMI, ACTH, HbA1c, cholesterol, and quality of life (15*, 16*),

Another modified-release preparation (Chronocort®, Diurnal, UK) has been studied in CAH patients. It exerts a delayed (4 hours following intake) and sustained action. If taken at 2300 (11 PM), the delayed release mimics the overnight rise and following morning peak of cortisol. A second dose is given in the morning (7 AM) ensuring cortisol supply during the day. A phase III trial including 122 patients with classic CAH revealed superior hormonal control during the early morning and early afternoon compared to patients receiving standard glucocorticoid (17**). The study failed its primary endpoint--change in 24-hour standard deviation score of the CYP21A2 substrate, 17-hydroxyprogesterone—but the percentage of patients with controlled morning serum 17OHP (< 1200 ng/dL) after 6 months of treatment was higher (91%) with the modified release preparation than with standard therapy (71%). Therefore, a definitive trial (NCT05063994) is planned in 150 participants with CAH over 16 years of age, using this latter measure as its primary endpoint.

Continuous subcutaneous delivery of HC using an insulin pump can closely mimic physiologic cortisol secretion patterns (18) and thus dampen the morning surge in ACTH and adrenal androgens (19*). Drawbacks of this approach include cost, the cumbersome nature of the devices, and frequent kinking or dislodging of the infusion sets.

The synthetic corticosteroids, prednisone and prednisolone, have longer half-lives than hydrocortisone. Indeed, prednisolone has the same blood profile as Plenadren (20*), but it is readily available as an inexpensive generic. Because they are not the “physiologic” glucocorticoid, prednisone and prednisolone are not favored for treating CAH (1), especially in children. They have a bad reputation regarding growth suppression (21), but that may be because they are employed in a biased manner in patients who are difficult to control on moderate doses of hydrocortisone. In adults, prednisolone has the same metabolic adverse effects profile as hydrocortisone (22), but there is a paucity of direct comparisons between these agents (4).

Adjunctive therapy to lower androgen levels.

Alternatively, medications that lower androgen production and/or action can be added to lower-dose glucocorticoid therapy as is used to treat primary adrenal insufficiency. The combination of testolactone (an aromatase inhibitor) and flutamide (an androgen receptor antagonist) with 8 mg/m²/d HC normalized growth and bone maturation in a 2-year randomized trial of 28 children (23). A long-term study of this combination is ongoing to determine the efficacy of this regimen on improving adult height (NCT00001521).

Abiraterone acetate is a potent CYP17A1 inhibitor used to treat prostate cancer (24). When added to HC 20 mg/d, 6 days of treatment with 100-250 mg/d of abiraterone acetate normalized androstenedione in 6 adult women (25) with parallel reductions in testosterone, androgen metabolites, and 11-oxo-androgens (26*). Abiraterone acetate therapy can cause DOC accumulation and consequent hypertension and/or hypokalemia in patients with prostate cancer via CYP21A2-mediated 21-hydroxylation of intra-adrenal progesterone (26*), however, this conversion cannot occur in patients with classic CAH. Abiraterone acetate is likely to be most useful in prepubertal children with classic CAH to suppress androgens and estrogens until the anticipated age of puberty, and a phase I trial testing this approach is underway (NCT02574910). Abiraterone acetate monotherapy might cause DOC accumulation in patients with NC CAH if not combined with glucocorticoid therapy or a mineralocorticoid receptor antagonist. Moreover, its use in pubertal girls would require concomitant estrogen treatment, for example with oral contraceptive pills. Third-generation anti-androgens such as enzalutamide, apalutamide, and darolutamide have not been tested in CAH patients but also might be useful treatments in women of reproductive age willing to use contraception.

Agents that reduce the ACTH-mediated drive for androgen production are possible approaches. The binding of corticotropin-releasing hormone to its type 1 receptor (CRHR1) is a major input to corticotropes, raising intracellular cyclic AMP and stimulating ACTH secretion. The CRHR1 antagonists tildacerfont and crinecerfont (NBI-74788) have been tested in small phase 2 trials in adults with CAH.

Tildacerfont was evaluated in separate 2 week and 12 week studies. In both studies, it had no significant effect in subjects who were already in adequate hormonal control (androstenedione levels less than twice the upper limit of normal). Eleven less well controlled subjects had reductions from baseline in ACTH (−59.4% to −28.4%) and relatively modest reductions in 17-hydroxyprogesterone (−38.3% to 0.3%), and androstenedione (−24.2% to −18.1%), with no clear dose response. In Study 2, in which all subjects received 400 mg of tildecerfont daily, the 5 participants with inadequate baseline hormonal control had ~80% reductions in ACTH, 17-OHP and androstenedione levels, but again there was no effect on subjects in good baseline control (27*) .

A 2 week trial of crinecerfont, a similar agent, enrolled 18 participants. Median percent reductions were more than 60% for ACTH (−66%), 17OHP (−64%), and androstenedione (−64%) with crinecerfont 100 mg twice a day (28*).

Additional Phase 2b or Phase 3 trials are underway to assess the long-term benefits of these agents in CAH patients. They have study designs, consisting of a 12-28 week randomized, double-masked, placebo-controlled period, followed by a 24-58 week open-label extension period (total treatment duration 52-78 weeks). They include trials of crinecerfont in 81 children (NCT04806451) and 165 adults (NCT04490915), and studies of tildacerfont in 90 adults (NCT04544410) and 70 poorly-controlled adults (NCT04457336). In general, the endpoints involve reductions in androstenedione levels and glucocorticoid doses, with secondary outcomes including reduction in adverse effects of glucocorticoid overtreatment including weight, fat mass, and HOMA-IR (homeostatic model assessment of insulin resistance). These approaches will not eliminate the need for glucocorticoid replacement, albeit perhaps in lower doses. By suppressing ACTH secretion, CRHR1 antagonists make it difficult to monitor adequacy of glucocorticoid replacement with 17-OHP or androstendione levels, making the patient’s state of well-being (e.g., lack of fatigue or orthostatic signs) a more reliable measure.

Unilateral or bilateral adrenalectomy has been suggested as an approach to long-term management of classic CAH to limit adrenal androgens. A meta-analysis of 48 CAH cases, 34 (71%) described symptomatic improvement after bilateral adrenalectomy but with 34 cases reporting short-term and 13 cases long-term adverse outcomes, including an increased risk of adrenal crisis (29). Consequently, this approach has fallen out of favor (1). The adrenolytic drug nevanimibe was tested in a dose-escalation study of 14-day treatment periods interrupted with 14-day placebo periods, up to 1000 mg twice daily (30*). The median 17OHP was consistently lower in treatment periods and rose during placebo periods, consistent with a reversible effect on steroidogenesis, but only 20% met the primary endpoint (17OHP ≤2x upper limit of normal). A study using longer treatment periods in order to achieve greater and more sustained reductions in adrenal-derived androgens was initiated (NCT03669549) but terminated after an interim analysis (https://clinicaltrials.gov/ct2/show/NCT03669549, accessed 22 Dec 2020). Thus current data do not support the approach of “medical adrenalectomy”.

Gene-based therapies.

Gene therapy using an Adeno-Associated Virus (AAV) has been tested in an mouse model of 21OHD which carries a deletion of the active murine gene (Cyp21a1), Intravenous injections of AAVrh10-CAG-human CYP21A2-HA vector endowed with adrenocortical tropism efficiently but only transiently restored near-normal adrenal function (31). A likely explanation lies within the biology of the gland; the adrenal cortex undergoes a self-renewal process (32). Adrenocortical self-renewal relies on the differentiation of at least two cell populations of progenitor cells, located in capsular and subcapsular compartments, which are able to differentiate and become fully mature steroidogenic cells forming the distinct histological and functional layers of the zona glomerulosa and zona fasciculata. If Cyp21--AAVs are not able to transduce adrenocortical stem/progenitor cells, newly formed steroidogenic cells will therefore be Cyp21a1-deficient and mice will revert to a CAH phenotype. In order to offer a long-term curative solution, it will be important to identify AAVs serotypes that efficiently transduce stem/progenitor cells.

It should be kept in mind that mice do not express Cyp17a1 in their adrenal glands and consequently cannot synthesize sex steroid precursors in the adrenals. Thus, mice cannot be used to model the efficacy of suppression of adrenal androgen secretion with gene therapy. Moreover, enzyme kinetics suggest that extra-adrenal expression of CYP21A2 using gene therapy is likely to produce adequate amounts of cortisol only with very high levels of precursor steroids, which means that any use of gene therapy in humans must be directed to the adrenals if it is to have utility in controlling adrenal androgen secretion in humans. Despite the limited published preclinical data, a Phase 1/2 trial (NCT04783181) of an AAV5-based agent, BBP-631 (Adrenas Therapeutics), is listed in ClinicalTrials.gov as recruiting. Twenty-five adult participants will receive a single dose of intravenous (IV) BBP-631 and be monitored for 52 weeks post-treatment, with an additional 4 years of monitoring for safety and efficacy in a separate long-term follow-up study.

The author believes that this study is premature. An early bioethical document, the 1990 NIH “Points to Consider” (33), recommends answering the following questions before undertaking a gene therapy trial:

• Describe the natural history and range of expression of the disease selected for treatment.?

• What alternative therapies exist?

• Compare the probability and magnitude of potential adverse effects on patients with the probability and magnitude of deleterious consequences from the disease if recombinant DNA transfer is not used.

The answers to these questions do not inspire confidence that CAH should be treated with gene therapy, at least with current technology. CAH, even in its most severe, classic salt wasting form, is treated readily and relatively inexpensively with glucocorticoid and fludrocortisone, although as discussed in the present article, there may be opportunities to optimize pharmacologic management. Hospitalizations for adrenal crisis are unusual after early childhood and patients generally live normal lives on treatment. In contrast, experience with gene therapy is limited, available treatments are expensive and can carry a significant risk of serious adverse effects.

Considerations involved in designing and manufacturing gene therapy vectors are beyond the scope of this article (reviewed in (34*)). There is, at present, only one systemic gene therapy commercially available: Zolgensma (onasemnogene abeparvovec-xioi, Novartis). Zolgensma is an adeno-associated virus-9 based gene therapy indicated for the treatment of pediatric patients less than 2 years of age with spinal muscular atrophy (SMA) with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene; this is a progressive, lethal disease. This agent carries a “black box warning” that acute serious liver injury and elevated aminotransferases can occur with Zolgensma, and serious adverse events are reported in 11% of treated patients (35*). Its current cost is $2.125 million per treatment (36*).

There are many other diseases with progressive courses and ultimately poor outcomes where gene therapy may represent the only realistic hope of amelioration. The author believes that clinical research on gene therapy for CAH should be deferred until greater experience is gained with late phase studies of AAV gene therapy vectors to treat diseases where no effective alternative exists.

Conclusion.

Alternative dose forms of hydrocortisone, adjunctive treatments to lower androgen levels or ACTH, and gene therapy are under active study in patients with CAH.

Key points.

• Modified-release forms of hydrocortisone may improve hormonal control in patients with congenital adrenal hyperplasia, but long-term benefits have not yet been established.

• Corticotropin-releasing hormone receptor antagonists and a sex steroid biosynthesis inhibitor may reduce secretion of adrenal androgen precursors and thus decrease glucocorticoid requirements in congenital adrenal hyperplasia patients, but long-term benefits have not yet been established.

• A Phase 1 trial of gene therapy for congenital adrenal hyperplasia is underway, but this approach offered only temporary benefit in preclinical studies, and a related adeno-associated virus vector has a high frequency of serious adverse effects.