Oral nonsteroidal treatment ‘new paradigm’ for adults with congenital adrenal hyperplasia
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Key takeaways:
- Crinecerfont, an oral nonsteroidal treatment, reduced mean daily glucocorticoid dose vs. placebo for people with congenital adrenal hyperplasia.
- The drug was associated with reduced adrenal androgen production.
BOSTON — Adults with congenital adrenal hyperplasia receiving an oral nonsteroidal treatment saw a marked reduction in daily glucocorticoid dose at 24 weeks with maintenance of androgen control compared with placebo, researchers reported.
The data suggest that the treatment, crinecerfont (Neurocrine Biosciences), a selective corticotropin-releasing factor type 1 receptor, could offer an alternative strategy for controlling excess adrenal androgens for people with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency while also reducing glucocorticoid doses to a more physiologic range. The data were presented at ENDO 2024 and simultaneously published in The New England Journal of Medicine.
A risky standard of care
The standard of care for CAH typically involves cortisol replacement with hydrocortisone taken three or four times daily, according to Richard J. Auchus, MD, PhD, the trial’s principal investigator and professor of pharmacology and internal medicine in the division of metabolism, endocrinology and diabetes at the University of Michigan. The burdensome regimen also comes with long-term health risks, Auchus said, including obesity, diabetes, hypertension and osteoporosis.
“It was always a delicate balance between too much and too little,” Auchus told Healio. “There are lots of blood draws; lots of angst. Yes, they are surviving into adulthood now, but they have all these complications. It is obesity, diabetes, osteoporosis — all the morbidities that can be ascribed to the glucocorticoids they are taking. But also, infertility due to the androgens and the androgen precursors. We are not succeeding in replacing their glucocorticoids in a way that avoids the complications of glucocorticoid therapy or keeping their unwanted steroids under control.”
Because of the long-term risks, adherence among patients, particularly during adolescence, is a struggle, Auchus said.
“In general, it was not very satisfying for the patients or the endocrinologists taking care of them,” Auchus said during an interview. “People are not doing well from the disease or from current treatment. And people were told this was the best we could do. Many of us have been looking for a better way to control the disease without exposing them to more glucocorticoids. Because, sure, I can control anyone with dexamethasone, but I know what it is going to do to you in 20 or 30 years.”
Reductions in glucocorticoid doses, androgen levels
For the CAHtalyst phase 3 trial, researchers analyzed data from 182 adults with classic CAH from 54 centers across the U.S., Canada, Europe and Israel. The mean age of patients was 31 years; 51% were men and 90% were white. Researchers randomly assigned participants to crinecerfont 100 mg (n = 122) or placebo twice daily (n = 60) for 24 weeks. Glucocorticoid regimens were maintained from baseline to week 4 (stable period). From week 4 through week 12 (reduction period), glucocorticoid doses were decreased according to a schedule based on the starting dose and dose strength availability to a target dose of 8 mg/m2 to 10 mg/m2 per day of a hydrocortisone equivalent.
From weeks 12 to 24 (optimization period), glucocorticoid doses were adjusted with the goal of achieving the lowest dose by week 24 while maintaining androstenedione control.
The primary efficacy endpoint was the percent change from baseline to week 24 in the daily dose of glucocorticoid while maintaining androstenedione control.
The mean glucocorticoid dose for participants at baseline was 17.6 mg/m2 of body-surface area per day of hydrocortisone equivalents; the mean androstenedione level was elevated at 620 ng/dL.
At week 24, the change in the glucocorticoid dose (with androstenedione control) was –27.3% in the crinecerfont group and –10.3% in the placebo group, for a least-squares mean difference of –17 percentage points (P < .001). Researchers reported a physiologic glucocorticoid dose for 63% of participants in the crinecerfont group and for 18% of those in the placebo group (P < .001).
At week 4, androstenedione levels fell among participants in the crinecerfont group by a mean of –299 ng/dL but increased in the placebo group by a mean of 45.5 ng/dL, for a least-squares mean difference of –345 ng/dL (P < .001).
Crinecerfont was generally well tolerated. The most common adverse events were fatigue, headache and coronavirus infection. There were few serious adverse events and none were related to the study drug, Auchus said.
As Healio previously reported, the FDA granted a breakthrough therapy designation for crinecerfont in December, after also receiving fast track and rare pediatric disease designations.
Simplifying disease management
“We are looking at a new paradigm,” Auchus told Healio. “Instead of lowering expectations and telling people, ‘This is the best we can do,’ we have to start thinking that ‘normal’ is normal. Now, we have something more in our armamentarium. It will be a sequence. Some people can be well controlled on a physiologic dose of hydrocortisone. But now, we have a nonsteroid alternative that we can go to.”
The researchers noted that a priority in the trial was a reduction in the glucocorticoid dose to a level that was as close to physiologic as possible without loss of androgen control, rather than primarily lowering adrenal androgen levels. In specific cases, the clinical treatment of adults with CAH requires intense control, such as when a patient desires pregnancy. The trial did not assess whether the glucocorticoid dose that was required for intense control was lower with crinecerfont therapy.
Auchus said the treatment, if FDA approved, will simplify disease management for patients in a way that could be life-changing.
“If you give them something that is safe and easy to manage, that reduces the number of lab tests, which makes them feel better and not gain so much weight, they can be more invested in their condition,” Auchus told Healio. “They get to take their medicine and get on with their lives. They still will have to deal with preventing adrenal crises during illness; some of those [risks] do not go away. But in the end, people will be more engaged, and endocrinologists will be able to take care of this disease without a lot of special education and nuanced testing. It will be easier for people to find care and find the control that they need.”
The 24-week placebo-controlled period of the trial was followed by 1 year of open-label crinecerfont treatment and an optional open-label extension. The optional open-label extension portion of the trial is still ongoing and researchers will continue to collect longer-term data, Auchus said.
Reference:
Auchus RJ, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa2404656.
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Auchus RJ, et al. Congenital adrenal hyperplasia: From monitoring to therapeutic advances. Presented at: ENDO annual meeting; June 1-4, 2024; Boston.
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