51成人动漫

BOSTON -- Investigational crinecerfont reduced the need for glucocorticoids in adults and kids with congenital adrenal hyperplasia (CAH), two phase III trials found.

In of 182 patients, those on crinecerfont had a 27.3% reduction in glucocorticoid dose compared with a 10.3% reduction with placebo over 24 weeks (least-squares mean difference -17.0 percentage points, P<0.00), reported Richard Auchus, MD, PhD, of University of Michigan Medical School in Ann Arbor, and colleagues.

The of 103 patients reported a similar outcome, as those treated with crinecerfont had an 18% reduction in mean glucocorticoid versus a 5.6% increase with placebo by week 28 (least-squares mean difference -23.5 percentage points, P<0.001), according to Kyriakie Sarafoglou, MD, of the University of Minnesota Medical School in Minneapolis, and colleagues.

Both trials were presented at ENDO 2024, the annual meeting of The Endocrine Society, and simultaneously published in the New England Journal of Medicine.

"We've been overtreating these people with glucocorticoids for a long time and despite that many of them still have elevated androgens, and they definitely have complications from long term treatment -- obesity, diabetes, bone loss, etc. You generally have to make people toxic on glucocorticoids to control them." Auchus told 51成人动漫. "We're trying to find a way to treat them with a more physiologic dose of glucocorticoids and yet maintain control of the androgens."

"You don't have to give people high doses of glucocorticoids and non-physiologic regimens anymore, [if] the drug gets approved," he said.

"We're trying to do what's called a block and replace," Auchus explained. "We [typically] block the androgen production with high doses of glucocorticoids. You don't [need to do] that anymore. You can block that with a different drug and then just replace the cortisol deficiency like you would in someone with Addison's disease."

This rare genetic disorder is caused by a 21-hydroxylase deficiency leading to androgen excess. No nonglucocorticoid treatments are approved for this disorder. recommend managing with supraphysiologic doses of glucocorticoids, higher than those needed to treat adrenal insufficiency alone.

Oral crinecerfont acts as a selective corticotropin-releasing factor type 1 (CRF₁) receptor antagonist to reduce and control excess adrenal androgens. Antagonism of CRF₁ receptors in the pituitary has been shown to decrease adrenocorticotropic hormone levels, which then decreases the production of adrenal androgens.

Trial Details

In the CAHtalyst trials, 122 adults were randomized to the crinecerfont group and 60 to the placebo group. Glucocorticoid treatment was maintained at a stable level for 4 weeks to evaluate androstenedione values, then followed by glucocorticoid dose reduction and optimization over 20 weeks. This was done with the goal of achieving the lowest glucocorticoid dose that maintained androstenedione control -- 120% of the baseline value or within the reference range. Patients could stress dose, like during illness or injury, as needed throughout the trial.

At baseline, the average glucocorticoid dose was 17.6 mg/m² per day of a hydrocortisone equivalent and average androstenedione level was 620 ng/dL. Only those receiving a daily glucocorticoid dose of more than 13 mg/m² of body-surface area of a hydrocortisone equivalent were included in the analysis. The average age was 31, half were male, and 90% were white.

As for the pediatric trial, 69 participants between ages 2 to 17 were assigned to the crinecerfont group and 34 to the placebo group. For inclusion, they had to be receiving a total glucocorticoid dose of more than 12.0 mg/m² per day in hydrocortisone dose equivalents. At baseline, the mean glucocorticoid dose was 16.4 mg/m² per day and the mean androstenedione level was 431 ng/dL. Glucocorticoid doses were maintained at a stable level from baseline through week 4 and was then adjusted in one to four steps to a target of 8.0 to 10.0 mg/m² per day in hydrocortisone dose equivalents through week 28.

Adults in the crinecerfont group took a twice daily oral dose of 100 mg with morning and evening meals. Crinecerfont in kids was dosed according to body weight -- 25 mg for a body weight of 10 to <20 kg, 50 mg for a body weight of 20 to <55 kg, or 100 mg for a body weight of ≥55 kg.

At week 4, androstenedione level significantly dropped in the crinecerfont groups:

• Pediatric patients on crinecerfont: -197 ng/dL
• Pediatric patients on placebo: +71 ng/dL
• Adults on crinecerfont: -299 ng/dL
• Adults on placebo: +45.5 ng/dL

A physiologic glucocorticoid dose with androstenedione control was reported in 63% of crinecerfont-treated adults and in 18% in the placebo group. And 30% of crinecerfont-treated pediatric patients achieved a physiologic glucocorticoid dose (≤11.0 mg/m² per day in hydrocortisone dose equivalents) with maintenance of androstenedione control versus none on placebo.

Most adverse events (AEs) in adults and pediatric patients were mild to moderate. Two crinecerfont-treated pediatric patients and four adults withdrew due to AEs. The most common AEs were fatigue and headache in adults and headache, pyrexia, and vomiting in kids.

Auchus said a 6-month, open-label phase was performed with data to come, where placebo participants were switched to crinecerfont. Future studies of crinecerfont will look at long-term management of these patients and assessment of secondary outcomes like cardiovascular risk and bone health changes.

He said his hope is that this drug will make management of CAH easier for both patients and healthcare providers.

"People who specialize in CH [congenital hyperplasia] see a lot of CH patients because a lot of endocrinologists aren't comfortable taking care of this disease because it's hard," he said." It'll be fulfilling to manage this disease because we'll be able to keep people healthy. People will have fewer blood tests, better compliance, and won't need to drive 300 miles to see somebody who's specializes in this. I hope it will actually make life easier for everybody, both doctor and patient."