Neurocrine Biosciences, Inc. and Diurnal Ltd. presented information from its neuroendocrinology pipeline at the Endocrine Society Annual Meeting, ENDO 2024, including primary data just published in The New England Journal of Medicine from its CAHtalyst? Phase 3 registrational studies of crinecerfont in pediatric and adult patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. In addition, Neurocrine Biosciences presented CAHtalog?

Registry data regarding the negative impact of high glucocorticoid (GC) doses and natural history in pediatric and adult CAH patients, as well as disease- and GC-related comorbidities data in CAH patients. CAHtalystTM Phase 3 Pediatric and Adult Data: In an oral presentation on June 1, Richard Auchus, M.D., Principal Investigator, Professor of Pharmacology and Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes at the University of Michigan, presented CAHtalyst Phase 3 Adult data demonstrating that the study met its primary and important key secondary endpoints, with 63% of crinecerfont-treated participants achieving reduction in GC dosing to physiologic range (= 11mg/m2/day) while maintaining androstenedione control at Week 24 as compared with just 18% with placebo control participants. The data were published in an online edition of The New England Journal of Medicine and will appear in a future print issue of the journal.

In a poster presentation on June 2, Kyriakie Sarafoglou, M.D., Professor, Department of Pediatrics and Department of Experimental and Clinical Pharmacology, Divisions of Endocrinology and Genetics & Metabolism, at the University of Minnesota, presented CAHtalyst Phase 3 Pediatric data demonstrating that the study met its primary and key secondary endpoints and was well tolerated, showing 29.9% of crinecerfont participants achieved a reduction in GC dosing to a physiologic range (=11mg/m2/day) at Week 28 while maintaining androgen control versus 0% of placebo participants (Poster #SUN-441). The data were published in an online edition of The New England Journal of Medicine and will appear in a future print issue of the journal. CAHtalogTM Registry?Negative Impacts of Supraphysiologic Dosing in Patients with CAH: A real-world study explored the effects of high GC doses in pediatric and adult patients enrolled in the CAHtalog registry, highlighting the fluctuations in GC dose and androstenedione over time and the relationship between higher GC dose and negative clinical outcomes in patients with CAH (Poster #SUN-685).

The findings included: Among 44 pediatric patients, 12 (27.3%) received a high GC dose (>15 mg/m2/day), that was associated with: Premature adiposity rebound starting at ~2 years of age (usual age is ~6 years); Early growth acceleration attributed to advanced bone age, followed by blunted pubertal growth. In 69 patients (45 pediatric, 34 adult and 10 in both groups) with available comorbidity-related data, hypertensive diseases and metabolic complications were significantly more prevalent with high versus low GC doses::In pediatric patients, short stature was more common with high versus low GC dose. In 40 patients (27 pediatric, 14 adult and 1 in both groups) with = 3 matched GC-androstenedione records, 92% had = 1 transition in health state over the median 7-year observation period:Higher GC dose with androstenedione < upper limit of normal (ULN) was the most common health state observed at the first recorded datapoint (48%), with only 3% maintaining that health state throughout the observation period; Although 22% of patients presented with lower GC and androstenedione; Limitations included absence of temporal context, variation in observational period and number of records per patient and blood draw timing.

CAHtalogTM Registry?Natural History of CAH: The results of a longitudinal study were presented using medical records from the CAHtalog registry and provided insight into the natural history of classic CAH, including the height and weight trends that carry across pediatric and adult patient groups (Poster# SUN-417). Data were analyzed from 42 pediatric patients (55% female) and 32 adult patients (72% female) enrolled in the registry. Median duration of observation was 9 years in pediatric patients and 13 years in adults.

The findings included: Pediatric patients had early growth acceleration followed by blunted pubertal growth. This trend was more pronounced in females, with mean height-for-age generally exceeding the 90th percentile at ages 4?10 years but dropping below 50th percentile at ages 13?17 years. Mean bone age-to-chronological age ratios were highest in females aged 5 years and males aged 7 years.

The mean body mass index (BMI)-for-age consistently exceeded the 85th percentile (i.e., overweight or obese) in males aged = 5 years and females aged = 6 years. Across adult age groups in both sexes, median BMI met the threshold for overweight (= 25 kg/m2) or obesity (=30 kg/m2). 83% of female patients (all ages) and 100% of male patients had a BMI = 25 kg/m2; 74% of female patients and 33% of males had a BMI = 30 kg/m2.

Obesity, hypertension, fatigue, acne, and hyperlipidemia were common, particularly among adults. Among adults, the comorbidity of obesity (68%) was more prevalent than in the general population (42%). Analyses of these real-world data highlight the limitations of current conventional GC therapies, which usually require supraphysiologic doses to manage adrenal androgen excess.

High rates of comorbidities related to GC treatment and androgen excess indicate the challenges with current GC treatments in maintaining androgen control without causing adverse effects. Claims-Based Cohort Analysis?Disease- and GC-Related Comorbidities in CAH: A retrospective cohort study was conducted analyzing insurance claims from 2020-2022 within the Merative MarketScan commercial and Medicaid databases (Poster #SUN-437). The frequency of comorbidities related to adrenal androgen excess and/or supraphysiologic GC dosing was captured using International Classification of Diseases, 10th Revision (ICD-10) codes.

Matching between the CAH and general population (GenPop) cohorts was based on age, sex, payer type, region and enrollment duration with a 1:5 ratio (CAH:GenPop). Compared with GenPop, CAH patients had significantly greater rates of multiple chronic conditions related to both excess adrenal androgens and supraphysiologic GC doses, including short stature, anxiety disorders, and diabetes. Top significant comorbidities in adults with CAH versus GenPop: Anxiety disorders?34% versus 26%; Fatigue?27% versus 18%; Depression?26% versus 19%; Obesity?23% versus 13%; Hirsutism/excess hair (female only)?11% versus 1%.

Top significant comorbidities in pediatric patients with CAH versus GenPop:Obesity?14% versus 5%; Fatigue?13% versus 6%; Anxiety disorders?12% versus 8%; Hirsutism/excess hair (female only)?11% versus 1%; Acne?10% versus 6%.