Erik Swain , 2025-04-18 14:44:00
April 18, 2025
12 min read
The treatment strategy for congenital adrenal hyperplasia is burdensome and had not changed in more than 70 years until the approval of a new drug in late 2024.
Congenital adrenal hyperplasia (CAH) is caused by a genetic mutation that hampers production of cortisol and mineralocorticoids in the adrenal gland, and it can lead to a life-threatening adrenal crisis if not treated. Patients with classic CAH have been treated with glucocorticoids since their discovery in the 1950s. But glucocorticoids are known to cause a number of adverse events, leading endocrinologists to search for alternative or adjunctive therapies for years.
“This therapy has been available since the Nobel-awarded isolation of cortisol by Edward Kendall, PhD, Philip Hench, MD, and Tadeus Reichstein, PhD, in the mid-’50s. Glucocorticoid replacement is life-preserving in patients with adrenal insufficiency of all causes, including CAH,” Adina F. Turcu, MD, MS, the Roger Grekin M.D. Collegiate Professor of Metabolism, Endocrinology and Diabetes and associate professor of internal medicine at University of Michigan, told Healio | Endocrine Today. “However, in CAH, glucocorticoid therapy has also been used to suppress androgen overproduction, driven by adrenocorticotropic hormone (ACTH). For this goal, the currently available formulations of glucocorticoids required administration in doses and at times of the day that are not physiological. Consequently, these therapies have been associated with considerable side effects, including hyperglycemia, hypertension, bone loss, sleep disruptions, etc.”
The FDA in December approved crinecerfont (Crenessity, Neurocrine Biosciences) as an adjunct to glucocorticoid replacement to control androgens for patients with CAH.
The approval of crinecerfont means “we can reduce the glucocorticoid dose to something physiologic and remove those late-day, evening and bedtime doses that cause a lot of the adverse events in adults after decades of treatment, and yet still maintain control,” Richard J. Auchus, MD, PhD, professor of pharmacology and internal medicine in the division of metabolism, endocrinology and diabetes at the University of Michigan, told Healio | Endocrine Today. “The hope is that it will create improvements in children in their adult height and in adults their retention of fertility, and avoiding these long-term metabolic and musculoskeletal complications and cognitive complications that the CAH patients show now with the current regimen.”
Primary adrenal insufficiency
CAH comes in two main forms: classic, for which lifelong treatment is necessary to prevent adrenal crisis, and nonclassic, which often does not have obvious symptoms and is never diagnosed in more than 90% of patients.
“CAH is a form of primary adrenal insufficiency in which cortisol production is decreased or completely absent,” Kyriakie Sarafoglou, MD, professor of pediatrics and experimental and clinical pharmacology and director of the Center for Congenital Adrenal Hyperplasia and Noah’s Ark and Weiss Family CAH Research Fund and Endowment at University of Minnesota Masonic Children’s Hospital, told Healio | Endocrine Today. “The most frequent form of CAH, accounting for 90% of all cases, is due to 21-hydroxylase enzyme deficiency and caused by pathogenic variants of the CYP21A2 gene. Unlike other forms of primary adrenal insufficiency, in CAH there is also an excess production of adrenal androgens. [Classic CAH] is further subdivided into salt-wasting, where no enzyme activity is present, and in simple-virilizing form, where 1% to 2% enzyme activity is present and that is enough to maintain normal sodium levels.”
Other forms of classic CAH include 17-hydroxylase deficiency, 3-beta-hydroxysteroid dehydrogenase deficiency and 11-hydroxylase deficiency.
Nonclassic CAH is more common but is rarely diagnosed because the patient is not cortisol-deficient. If it is noticed at all, it might not be detected until later in life when a patient has fertility problems, hirsutism, excessive acne, shorter-than-expected height or other consequences of excess androgen.
“It may come into clinical attention in boys with early development of secondary sex characteristics or early pubertal development,” Ayca Erkin-Cakmak, MD, MPH, assistant professor of pediatrics in the division of pediatric endocrinology at the University of California, San Francisco, told Healio | Endocrine Today. “For females, it might come to attention due to early periods, hirsutism and excessive weight gain. You have to recognize the symptoms and treat them. Later in life, they may experience fertility challenges due to irregular periods and anovulation. And then you introduce treatment to help them with fertility. For boys, you have to introduce treatment if they have early pubertal development to mediate these clinical findings and support their growth properly.”
Consequences of CAH
Because classic CAH is life-threatening if undetected, many countries, including the United States, conduct newborn screening.
“Focusing on 21-hydroxylase deficiency, because of the overproduction of androgens, girls are born with various degrees of genital masculinization,” Auchus said in an interview. “Both boys and girls can have an adrenal crisis after the maternal cortisol runs out about a week later. Newborn screening is mainly done to prevent sudden death from an adrenal crisis in the first week or 2 of life. If they survive that, they have poor feeding, are prone to infections, they have prolonged illness when they get infections and still can get an adrenal crisis from that. The androgen excess causes rapid skeletal maturation and growth, so they are tall children but short adults.”
The consequences of failing to diagnose classic CAH can be grave, Erkin-Cakmak said.
“If not recognized, due to lack of cortisol, glucocorticoids or mineralocorticoids, or both of the hormone deficiencies, that can result in electrolyte imbalances such as hyponatremia, hyperkalemia, hypoglycemia, metabolic acidosis and hypotension, which is a clinical picture called adrenal crisis, which is life-threatening,” Erkin-Cakmak said. “Patients with classic CAH are at risk for adrenal crisis throughout their lives, in the setting of acute illness, inadequate treatment or lack of diagnosis as a newborn.”
Challenges of glucocorticoids
Glucocorticoids have long been the standard treatment for classic CAH. Although glucocorticoids are effective for preventing adrenal crisis, the medications often present other challenges for patients.
“You use cortisone, or now hydrocortisone, which is cortisol, treatment to both replace the cortisol deficiency, which is not that hard, but also to lower the undesired steroids, primarily the androgens, which is a bit harder,” Auchus told Healio | Endocrine Today. “The reason is that cortisol production is such that circulating concentrations are normally 10 µg/dL. If you convert that to androgens, that’s 10,000 ng/dL of androgens — a huge amount. You have to lower that in a child 100 to 1,000 times to about 10 ng/dL to 100 ng/dL. It takes a lot of glucocorticoid to do that. So, instead of just a circadian rhythm-type replacement dose of cortisol that we used to treat autoimmune Addison’s disease, for example, we have to use multiple daily doses, and doses that are well above the daily cortisol production rate, which averages about 7 mg/m2 per day. Patients with CAH are usually getting 15 mg/L2 to 17 mg/L2 per day as they are growing up, which is about twice or more of a physiologic dose. They also receive late-day and late-night supraphysiologic doses, which cause a lot of glucocorticoid-related consequences in adults after years and years.”
These consequences can be felt later in life, as patients with lifelong glucocorticoid treatment have elevated risk for developing obesity, heart disease, mood disorders, osteoporosis and other conditions, Erkin-Cakmak said.
“The higher-than-physiologic dose of glucocorticoids causes side effects such as obesity, short stature and metabolic abnormalities,” Erkin-Cakmak said. “One of the biggest challenges for the management of classic CAH has been balancing the excess androgens with the impact of the high glucocorticoid therapy.”
For some patients, “fludrocortisone might be used depending on the enzyme deficiency,” Erkin-Cakmak said. “Our treatment goals are to replace the missing glucocorticoid, cortisol and mineralocorticoid for normal bodily function, but also to reduce the excess ACTH and androgen levels. An excess of androgens results in advanced bone age, virilization, precocious puberty and behavioral challenges.”
Adults with classic CAH can be treated with long-acting steroids such as dexamethasone, prednisone and methylprednisolone, but they are generally not used in children because they negatively affect growth, Sarafoglou said. “Short-acting hydrocortisone given at least three times per day is recommended to replace deficient cortisol in active and growing children,” she said.
In addition, “in patients with salt-wasting CAH, fludrocortisone, a mineralocorticoid, is used to maintain normal sodium and potassium levels,” Sarafoglou said.
Approval of crinecerfont
When a lifesaving treatment comes with burdensome adverse events, figuring out ways to reduce them becomes tremendously important. That led to research focusing on how to reduce production of ACTH and downstream androgens and get glucocorticoid doses down to a physiologic level.
The first fruits of that research were borne in December, when the FDA approved crinecerfont, which suppresses ACTH and reduces overproduction of androgens, as an adjunct to glucocorticoid therapy.
The approval was based on the phase 3 CAHtalyst and CAHtalyst Pediatric trials.
In CAHtalyst, presented by Auchus at ENDO 2024 and simultaneously published in The New England Journal of Medicine, at week 24, the change in the glucocorticoid dose (with androstenedione control) was –27.3% in the crinecerfont group compared with –10.3% in the placebo group (least-squares mean difference, –17 percentage points; P < .001). Researchers achieved a physiologic glucocorticoid dose (less than 11 mg/m2 per day) for 63% of participants in the crinecerfont group compared with 18% of those in the placebo group (P < .001).
In CAHtalyst Pediatric, presented by Sarafoglou at ENDO 2024 and simultaneously published in NEJM, at 28 weeks, children assigned crinecerfont had an 18% decrease in glucocorticoid dose compared with a 5.6% increase for those assigned placebo (P < .001). The observed mean glucocorticoid dose at 28 weeks was 12.8 mg/m2 per day for the crinecerfont group compared with 17 mg/m2 for the placebo group. Of the crinecerfont group, 30% achieved a physiologic glucocorticoid dose of less than 11 mg/m2 per day with maintenance of androstenedione control at 28 weeks compared with no participants in the placebo group.
“Crinecerfont is an oral corticotropin-releasing factor type 1 receptor antagonist, and it is the first FDA-approved non-glucocorticoid therapy now available for CAH,” Turcu told Healio | Endocrine Today. “By suppressing ACTH, crinecerfont mitigates the androgen excess in patients with 21-hydroylase deficiency. This obviates the need to use supraphysiological doses of glucocorticoids and, hence, reduces the risk of glucocorticoid-related adverse effects.”
This means that crinecerfont “could be used as adjunct therapy starting early in life for patients who are either exposed to androgen excess or glucocorticoid excess or both, to prevent the associated comorbidities that begin in childhood and continue into adulthood,” Sarafoglou told Healio | Endocrine Today. “Lower androgen levels may allow for physiologic (or close to physiologic) levels across the three daily hydrocortisone doses and potentially mitigate the negative consequences of long-term glucocorticoid overexposure that also begins once treatment for CAH begins. Starting [crinecerfont] before symptoms develop could potentially allow for better growth outcomes, normal pubertal development and less comorbidities.”
More alternatives in pipeline
A second alternative for patients with CAH may emerge in the coming years. In January, Crinetics Pharmaceuticals announced that top-line results from an open-label, phase 2 TouCAHn study of atumelnant, a novel, once-daily oral ACTH receptor antagonist in development for treatment of classic CAH and ACTH-dependent Cushing’s syndrome, were positive.
At 12 weeks, among patients with classic CAH caused by 21-hydroxylase deficiency, serum androstenedione levels declined by –619 ng/dL in those assigned a 40 mg dose (P = .0003), by –774 ng/dL in those assigned a 80 mg dose (P < .0001) and by –954 ng/dL in those assigned a 120 mg dose (P < .0001), according to a press release from the company.
“Atumelnant blocks one step further down” from crinecerfont, Auchus told Healio | Endocrine Today. “It blocks ACTH action on the adrenal. The phase 2 results, some of which we presented at ENDO, look promising. Whether or not this strategy is equivalent, preferable or not as good, time will tell. But I would definitely say that the results are promising and this is certainly another avenue to pursue with a different mechanism of action. I think it’s great that there are now different drugs with different targets and mechanisms of action that endocrinologists have at their disposal.”
Because ACTH acts through the melanocortin type 2 receptor primarily expressed in the adrenal gland, atumelnant has potential to be a treatment for all types of ACTH-dependent Cushing’s syndrome, Maria Fleseriu, MD, FACE, professor of medicine and neurological surgery and director of the Pituitary Center at Oregon Health & Science University and a Healio | Endocrine Today Co-editor, said in an interview.
“In its first study in Cushing’s syndrome, a phase 1b/2a trial including five patients with ACTH-dependent Cushing’s syndrome performed at NIH, once-daily oral atumelnant for 10 days induced a very rapid lowering of both serum and 24-hour urine cortisol, with subsequent adrenal insufficiency and need for glucocorticoid replacement,” Fleseriu said. “Treatment also led to some improvement, or even resolution, in a few patients with some signs and symptoms of hypercortisolism. Though short term, the observed expected ACTH increase did not induce loss of efficacy for cortisol decrease. Atumelnant was generally well tolerated and further clinical trials in Cushing’s syndrome are planned. This drug seems very potent, at least short term, as long-term data are not available yet, and could be beneficial in patients where a rapid cortisol control is desired, even preoperatively in some cases.”
Crinetics announces positive topline results from phase 2 trial of atumelnant in congenital adrenal hyperplasia (CAH). https://crinetics.com/crinetics-announces-positive-topline-results-from-phase-2-trial-of-atumelnant-in-congenital-adrenal-hyperplasia-cah. Published Jan. 10, 2025. Accessed March 4, 2025.
Sarafoglou K, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa2404655.
Study of Lu AG13909 in participants with congenital adrenal hyperplasia. https://clinicaltrials.gov/study/NCT05669950. Updated July 5, 2024. Accessed March 5, 2025.
Another drug in development, Lu AG13909 (H. Lundbeck), a monoclonal antibody targeting ACTH, is being evaluated in two phase 2 trials, one for treatment of CAH and one for treatment of Cushing’s disease.
“By binding to ACTH with high affinity, Lu AG13909 could reduce elevated ACTH levels and, thus, reduce cortisol,” Fleseriu said. “A new area of research with novel drugs approved and/or studied for CAH has opened new avenues for medical treatment of Cushing’s syndrome.”
Looking for a ‘home run’
Despite the first major activity in the CAH treatment pipeline in decades, there remain a number of areas ripe for future research. One is whether a genetics-based therapy is feasible for this population.
“What crinecerfont and atumelnant are doing is lowering the unwanted steroids and allowing physiologic cortisol replacement. But they don’t restore cortisol production,” Auchus said. “[Gene-based therapies] would restore cortisol production. That would be the home run, so these people don’t have to take any medicines.”
The first gene therapy to be tested in humans with CAH was BBP-631 (Adrenas Therapeutics/BridgeBio Pharma), an investigational adeno-associated virus 5 vector-based therapy. However, Adrenas Therapeutics and BridgeBio Pharma announced in September that development would cease because while the therapy increased cortisol levels in patients enrolled in the phase 1/2 Adventure trial, the results were not substantial enough to continue investing in the agent.
“In theory, [gene therapy] is very promising,” Turcu said. “Practically speaking, it has been tested primarily in rodents and monkeys; we don’t have sufficient data on its feasibility, effectiveness and safety in humans. It’s a little too early to hope too much that it can replace medical therapy in the near future.”
Better tools for monitoring the disease are also needed, Sarafoglou said.
“Obtaining single hormonal measurements two to three times a year does not provide information about disease control over the course of the day, during the preceding 3 to 6 months, or even during the preceding few days,” Sarafoglou said. “Currently, there has been a surge in the development of novel drugs for the treatment of CAH. To assess the effectiveness and long-term outcomes linked to treatment, we need a better monitoring system that ideally could be used for multiple measurements of adrenal steroids in the home environment and during clinic visits. That is my wish.”
Turcu said one priority will be individualizing treatment for patients, and that includes learning more about the long-term effects of new and established therapies.
“All of these studies only looked at traditional biomarkers, primarily nonactive biomarkers like 17-hydroxyprogesterone and androstenedione,” Turcu said. “Androstenedione is a precursor to active androgens. We usually don’t target therapy based on 17-hydroxyprogesterone. So now the real clinical question comes in: Will these therapies be effective in suppressing the bioactive androgens? Here, we also speak of some novel biomarkers, the adrenal-specific 11-oxyandrogens, like 11-ketotestosterone, which are elevated in patients with CAH. Will these therapies be effective in suppressing bioactive androgens, and then ultimately clinical findings? These questions haven’t been addressed by the recent studies, which relatively short in duration.”
As more therapies come to the market, patients with CAH will have more opportunities to find a regimen that works for them.
“It is an exciting time for patients with CAH, as glucocorticoids have been the sole treatment for us over decades for this rare disease,” Erkin-Cakmak said. “Having adjunctive therapy options will create more opportunities and more tailored treatment plans for our patients.”
- References:
- A trial of Lu AG13909 in adult participants with Cushing’s disease (BalanCeD). https://clinicaltrials.gov/study/NCT06471829. Updated Dec. 27, 2024. Accessed March 5, 2025.
- Auchus RJ, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa2404656.
- BridgeBio Pharma reports topline results from phase 1/2 trial of investigational gene therapy for congenital adrenal hyperplasia (CAH). https://bridgebio.com/news/bridgebio-pharma-reports-topline-results-from-phase-1-2-trial-of-investigational-gene-therapy-for-congenital-adrenal-hyperplasia-cah. Published Sept. 10, 2024. Accessed March 5, 2025.
- Crinetics announces positive topline results from phase 2 trial of atumelnant in congenital adrenal hyperplasia (CAH). https://crinetics.com/crinetics-announces-positive-topline-results-from-phase-2-trial-of-atumelnant-in-congenital-adrenal-hyperplasia-cah. Published Jan. 10, 2025. Accessed March 4, 2025.
- Elenius H, et al. J Endocr Soc. 2024;doi:10.1210/jendso/bvae163.114.
- Sarafoglou K, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa2404655.
- Study of Lu AG13909 in participants with congenital adrenal hyperplasia. https://clinicaltrials.gov/study/NCT05669950. Updated July 5, 2024. Accessed March 5, 2025.
- For more information:
- Richard J. Auchus, MD, PhD, can be reached at rauchus@med.umich.edu.
- Ayca Erkin-Cakmak, MD, MPH, can be reached at ayca.erkin-cakmak@ucsf.edu.
- Maria Fleseriu, MD, FACE, can be reached at fleseriu@ohsu.edu; Bluesky: @mariafleseriu.bsky.social.
- Kyriakie Sarafoglou, MD, can be reached at saraf010@umn.edu.
- Adina F. Turcu, MD, MS, can be reached on X at @adina_turcu.
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Sources/Disclosures
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Source:
Healio Interviews
Disclosures:
Auchus reports consulting for and receiving research support from Crinetics, H. Lundbeck, Neurocrine Biosciences and Neurocrine UK and receiving research support from Adrenas Therapeutics (a BridgeBio company) and Spruce Biosciences. Erkin-Cakmak and Turcu report no relevant financial disclosures. Fleseriu reports receiving institutional research grants from Crinetics and Sparrow and occasional consultant fees from Crinetics, Recordati Rare Diseases, Sparrow and Xeris Pharmaceuticals. Sarafoglou reports consulting for and receiving research support from Adrenas Therapeutics (a BridgeBio company), Crinetics, Neurocrine Biosciences and Spruce Biosciences; she does not receive personal income from those activities.