Kyriakie Sarafoglou, MD, discusses crinecerfont FDA approval for congenital adrenal hyperplasia

Kyriakie Sarafoglou, MD | Image credit: Provided by Kyriakie Sarafoglou

The FDA approval of crinecerfont (Crenessity; Neurocrine Biosciences) on December 13, 2024, marked a significant milestone in the management of classic congenital adrenal hyperplasia (CAH), particularly in pediatric patients aged 4 years and older. CAH is a rare genetic condition characterized by a deficiency in cortisol production and overproduction of adrenal androgens, leading to complex hormonal imbalances. Traditional management has relied on high doses of glucocorticoids to suppress androgen production and replace deficient cortisol, a treatment approach associated with significant long-term side effects, including growth suppression, obesity, and osteoporosis.¹

Crenessity offers a novel therapeutic mechanism, targeting corticotropin-releasing factor type 1 (CRF1) receptors to reduce excessive ACTH and androgen production. Clinical trials demonstrated its potential to lower glucocorticoid doses while maintaining hormonal control, improving outcomes, and minimizing side effects. The CAHtalyst Pediatric Study (NCT04806451), published in The New England Journal of Medicine, revealed significant reductions in androstenedione and 17-OHP levels, as well as promising trends in body mass index, insulin resistance, and hirsutism.^1,2

To explore the implications of this approval, Kyriakie Sarafoglou, MD, lead investigator of the CAHtalyst Pediatric Study and professor at the University of Minnesota, shares insights into crinecerfont’s impact on the treatment landscape, key clinical data, and the vital role of general providers in managing pediatric CAH.¹

Contemporary Pediatrics:

How important was the approval of crinecerfont (Crenessity; Neurocrine Biosciences) in children 4 years and older with CAH?

Kyriakie Sarafoglou, MD:

Classic CAH is typically identified at or soon after birth and is a lifelong condition that in children requires treatment with hydrocortisone, typically at supraphysiologic doses, to address both cortisol deficiency and to reduce overproduction of adrenocorticotropic hormone (ACTH) and adrenal androgen.

Making treatment more challenging is that hydrocortisone, a short-acting glucocorticoid, exposes children to alternating periods of excess cortisol followed by excess androgens between doses and in the early morning hours when hydrocortisone washes out. As a result, managing CAH is a constant balancing act between reducing excess androgens while avoiding excess glucocorticoid doses. Excess androgen during childhood can cause growth acceleration, rapid bone age advancement, virilization, early puberty, and short stature. On the other hand, excess glucocorticoids can lead to many short and long-term co-morbidities including obesity, reduced growth, hypertension, insulin resistance, and osteoporosis. This is why outcomes remain suboptimal with glucocorticoid therapy alone.

As an adjunct therapy, crinecerfont offers a new treatment approach for managing classic CAH through a non-glucocorticoid mechanism. The clinical data from the pediatric trial demonstrated that crinecerfont reduced excess ACTH and downstream adrenal androgen production, which allowed for the reduction of glucocorticoid dosing.

Contemporary Pediatrics:

How do you think this approval will change the treatment landscape for CAH in this population, and what are the biggest benefits of the approval?

Sarafoglou:

Crinecerfont‘s mechanism of action consists of blocking corticotropin-releasing factor type 1(CRF₁) from binding to the receptor CRF, which reduces ACTH and androgen overproduction in CAH and allows for a lower total daily glucocorticoid dose. Using crinecerfont as an adjunct therapy could also lead to more physiologic circadian cortisol profiles and lower androgen throughout the day, especially in the early morning.

The biggest change in the treatment landscape that the approval of crinecerfont brings will be that pediatric endocrinologists will no longer have to depend solely on increasing a child’s glucocorticoid dose to reduce high androgen levels.

Contemporary Pediatrics:

What key data points stood out to you during the clinical program?

Sarafoglou:

The phase 3 CAHtalyst global registration studies, including the CAHtalyst Pediatric study and CAHtalyst Adult study, were part of the largest-ever clinical trial program of classic CAH.²

• The CAHtalyst Pediatric study met its primary endpoint, demonstrating a significant change in baseline androstenedione levels to Week 4 following an initial glucocorticoid (GC)-stable period. Androstenedione levels, measured prior to morning glucocorticoid dose, were reduced by half in children taking crinecerfont at 4 weeks. Following the initial GC-stable period, the crinecerfont group had a substantial least-squares mean decrease from baseline at Week 4 in androstenedione (-197 ng/dL) compared with an increase for placebo (+71 ng/dL) (LSMD: -268 ng/dL [95% CI: -403, -132] P < 0.001).²
• The study also met the key secondary endpoint with a substantial decrease by more than half in 17-OHP at Week 4 in the crinecerfont group (-5865 ng/dL) versus slightly increased levels in the placebo group (+556 ng/dL) (LSMD: -6421 ng/dL [95% CI: -8387, -4454] P < 0.001).²
• Children taking crinecerfont were able to safely reduce their GC doses while maintaining androstenedione control (protocol-specified target of ≤120% of baseline²
• or ≤ ULN), a key secondary endpoint. Participants in the crinecerfont group reduced their total average daily dose from 16.5 to 12.8 mg/m2/day for a mean percent change from baseline of -18% versus +6% for placebo at Week 28 while maintaining or improving baseline androstenedione (LSMD: -24% [95% CI: -29.9, -17.2] P < 0.001).²
• Importantly, 30% of crinecerfont treated participants achieved a physiological GC dose (≤11 mg/m²/day hydrocortisone equivalents) at Week 28 while maintaining androstenedione control, compared with zero participants in the placebo group.²
• At Week 28, favorable trends were seen for exploratory endpoints in participants in the crinecerfont group that reflect the clinical impact of supraphysiological GC dosing and androgen excess²:

1. Reduction in body mass index standard deviation scores (0.09 reduction with crinecerfont vs 0.04 increase with placebo).
2. Improved insulin resistance (0.63 reduction with crinecerfont versus 0.27 increase with placebo).
3. Reduced hirsutism (excessive hair growth) among females (7.0 mm reduction with crinecerfont versus 2.3 mm increase with placebo).

• Regarding safety, crinecerfont was well tolerated with few treatment-related adverse events. Most side effects were temporary and mild to moderate in severity. In the pediatric population, there were no cases of adrenal crisis among patients taking crinecerfont or placebo. As crinecerfont is an adjunct therapy patients prescribed crinecerfont should continue taking GCs for cortisol replacement.²

Contemporary Pediatrics:

How can the general providers play a role when it comes to treating/managing pediatric patients with CAH?

Sarafoglou:

CAH is a complex genetic condition that must be managed within the context of the child’s holistic health. General providers play a key role in the coordination and care of children with CAH and can work closely with endocrinologists and other specialists to help manage CAH throughout childhood.

Contemporary Pediatrics:

Is there anything else regarding the FDA approval of crinecerfont you would like to include?

Sarafoglou:

Pediatric endocrinologists will have the option of using crinecerfont to ameliorate excess adrenal androgen and glucocorticoids associated with current treatment. Starting crinecerfont at 4 years of age has the potential of reducing the development or the degree of adverse clinical outcomes associated with both of these states.

References:

1. Ebert, M. FDA approves Crenessity for treatment of classic congenital adrenal hyperplasia. Contemporary Pediatrics. December 13, 2024. Accessed January 14, 2024. https://www.contemporarypediatrics.com/view/fda-approves-crenessity-for-treatment-of-classic-congenital-adrenal-hyperplasia

2. Sarafoglou K, Kim MS, Lodish M, et al. Phase 3 trial of crinecerfont in pediatric congenital adrenal hyperplasia. N Engl J Med. 2024;391(6):493-503. doi:10.1056/NEJMoa2404655