New Drugs and Therapeutics Update
CRENESSITY (crinecerfont) capsules and oral solution
On December 13, 2024, the FDA approved CRENESSITYTM (crinecerfont) as adjunctive treatment to glucocorticoid replacement to control androgen levels in adult and pediatric patients 4 years of age and older with classic congenital adrenal hyperplasia (CAH). In individuals with classic 21-hydroxylase deficiency (21-OHD) CAH, loss of normal feedback by cortisol to the hypothalamus and pituitary gland leads to excessive adrenocorticotropin hormone (ACTH) synthesis, thus exacerbating adrenal androgen production. CRENESSITY is an oral corticotropin-releasing factor type 1 (CRF1) receptor antagonist that results in reduced ACTH levels and decreased adrenal androgen production (2) thus allowing treatment with lower glucocorticoid doses and helping to prevent adverse effects associated with chronic exposure to supraphysiologic glucocorticoid doses.
The approval was based on results from two randomized, double-blinded, placebo-controlled phase 3 trials in patients with classic CAH due to 21-OHD. The pediatric trial included 103 children ages 4 to 17 years who were on stable but supraphysiologic glucocorticoid doses (mean baseline glucocorticoid daily dose of 17 mg/m2/day) randomized 2:1 to CRENESSITY TM or placebo. At week 4, following a stable glucocorticoid treatment regimen, participants in the CRENESSITY TM group demonstrated a significant reduction in androstenedione levels (primary outcome) compared to an increase in the placebo group (least-squares mean difference of –268 ng per deciliter). At week 28, participants in the CRENESSITY TM group experienced a significant percent decrease from baseline in glucocorticoid daily dose compared to an increase in the placebo group (least-squares mean difference of -24%).
Dosage forms and strengths: CRENESSITY TM is available as capsules (25 mg, 50 mg, 100 mg) and an oral solution (50 mg/mL). Dosing for children ages 4 years and older is weight based: 10 to <20 kg prescribe 25 mg twice daily; 20 to <55 kg prescribe 50 mg twice daily; ≥55 kg prescribe 100 mg twice daily, with a meal. Patients should continue their glucocorticoid upon initiation of and during treatment with CRENESSITY TM, with decreasing dose adjustments as indicated. Use glucocorticoid stress doses in case of increased cortisol need (e.g., acute intercurrent illness, serious trauma, surgical procedures). CRENESSITY TM requires dose adjustment when using CYP3A4 inducers.
Adverse reactions: CRENESSITY TM has a warning for acute adrenal insufficiency or adrenal crisis with inadequate concomitant glucocorticoid therapy, including during situations associated with increased cortisol need. The most common adverse reactions (occurring in at least 4% and greater than placebo) in pediatric patients included headache, abdominal pain, fatigue, nasal congestion, and epistaxis. In the pediatric clinical trial, 6% (4 of 67) of CRENESSITY TM -treated patients reported suicidal ideation without method, intent, or plan on the Columbia-Suicide Severity Rating Scale compared to 0% (0 of 31) in the placebo arm. Neutrophil counts less than 2 x 103 cells/mcL occurred in 37% (25 of 68) of CRENESSITY TM -treated patients compared to16% (5 of 32) in the placebo group.
Reference:
(1) CRENESSITY TM Prescribing Information. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=BasicSearch.process
(2) https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-congenital-adrenal-hyperplasia
(3) 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
Prepared by Preneet Cheema Brar, MD, MS and Daniel Mak, MD.