Crenessity (crinecerfont) / Neurocrine, Sanofi - LARVOL DELTA

Crinecerfont: CRF1R Antagonist Approved for Treatment of Congenital Adrenal Hyperplasia. (PubMed, Ann Pharmacother) - "Crinecerfont is the first approved adjunctive therapy for classic CAH that effectively decreases supraphysiological glucocorticoids levels and associated symptoms."

Journal • Review • Congenital Adrenal Hyperplasia • Endocrine Disorders • Pediatrics • CYP1A2 • CYP21A2

What is the need for adrenalectomy in patients with congenital adrenal hyperplasia in the era of CRF1/ACTH inhibitors? (PubMed, Front Endocrinol (Lausanne)) - "Now with the newly approved crinecerfont (a corticotropin-releasing factor type 1 receptor (CRF1) antagonist, approved by FDA in US December 2024), and the coming phase 3 study of atumelnant (a MC2R antagonist), the commenced phase 2 study of Lu AG13909 (an anti-ACTH monoclonal antibody) as well as the preclinical studies with OMass MC2R antagonist compounds, there may be new options to decrease the size of the adrenal tumors/hyperplasia. However, the cost of these new drugs may be very high so they may not become widely available, and adrenalectomy may prove to be more cost effective. This review will discuss the current use of adrenalectomy in patients with CAH and how the introduction of the new drugs may change it."

Journal • Review • Adrenal Cortex Carcinoma • Congenital Adrenal Hyperplasia • Endocrine Disorders • Genito-urinary Cancer • Oncology • Solid Tumor

Pharmacokinetics, Safety and Tolerability of Crinecerfont in Participants With Congenital Adrenal Hyperplasia Who Are Less Than 2 Years Old (clinicaltrials.gov) - P2 | N=6 | Recruiting | Sponsor: Neurocrine Biosciences | Not yet recruiting ➔ Recruiting

Enrollment open • Congenital Adrenal Hyperplasia • Endocrine Disorders • Pediatrics

Correction: CRF1 and ACTH inhibitors are a promising approach to treat obesity and leptin and insulin resistance. (PubMed, Front Endocrinol (Lausanne)) - "[This corrects the article DOI: 10.3389/fendo.2025.1647028.]."

Journal • Genetic Disorders • Obesity • LEP

CRF1 and ACTH inhibitors are a promising approach to treat obesity and leptin and insulin resistance. (PubMed, Front Endocrinol (Lausanne)) - "CRF1 and ACTH blockers (such as crinecerfont and atumelnant, respectively) may replace leptin action on the adrenal axis by reducing adrenal cortisol excess in individuals with obesity...Individuals with obesity and high levels of adipose insulin resistance may benefit from CRF1/ACTH inhibitors, reducing ACTH secretion or its action. A reduction in their adipose resistance index may lead to diminished lean organ steatosis and reduced appetite due to a decrease in orexigenic signals, mainly free cortisol and insulin."

Journal • Review • Genetic Disorders • Obesity • LEP

Pharmacokinetics, Safety and Tolerability of Crinecerfont in Participants With Congenital Adrenal Hyperplasia Who Are Less Than 2 Years Old (clinicaltrials.gov) - P2 | N=6 | Not yet recruiting | Sponsor: Neurocrine Biosciences

New P2 trial • Congenital Adrenal Hyperplasia • Endocrine Disorders • Pediatrics

Crinecerfont Shows Favorable Trends in Improving Clinical Outcomes in Children and Adolescents With Classic Congenital Adrenal Hyperplasia: 1-Year Results From the CAHtalyst™ Pediatric Study (ENDO 2025) - P3 | "Children and adolescents with CAH who received up to 1 year of crinecerfont showed improvements in BMI and insulin resistance. Hirsutism in female participants improved with crinecerfont, despite substantial reductions in GC dose. Given the known adverse effects of androgen excess and GC exposure, these results represent a promising therapeutic advancement in CAH."

Clinical • Clinical data • Congenital Adrenal Hyperplasia • Dyslipidemia • Endocrine Disorders • Pediatrics

Crinecerfont Improves Reproductive Hormones in Classic Congenital Adrenal Hyperplasia: 1-Year Results from the Phase 3 CAHtalyst™ Adult Study (ENDO 2025) - P3 | "Background: Gonadal dysfunction with classic congenital adrenal hyperplasia (CAH) is due to testicular adrenal rest tumors and/or poor hormonal control (males) and to high adrenal androgens and progesterone (P4) (females). Crinecerfont has previously been shown to substantially reduce ACTH, adrenal androgens, and androgen precursors in phase 2 and/or phase 3 studies with pediatric and adult patients with CAH. These analyses from the CAHtalyst Adult study indicate that normalization of reproductive hormones could also be achieved with crinecerfont, even in the context of substantial GC dose reductions. CRF1 antagonism may be a promising therapeutic approach for improving reproductive hormones in adults with CAH."

Clinical • P3 data • Congenital Adrenal Hyperplasia • Endocrine Disorders • Oncology • Pediatrics

Crinecerfont Allows for More Physiologic Glucocorticoid Treatment With Reduction of Androstenedione to a Normal Range in Adults With Classic Congenital Adrenal Hyperplasia: Post Hoc Analyses of the CAHtalyst™ Adult Study (ENDO 2025) - P3 | "GC doses were kept stable for the first 4 weeks to measure the impact on androgens, followed by a planned GC down-titration over 8 weeks to achieve a target dose of 8-10 mg/m2/d in hydrocortisone equivalents (HCe). In CAHtalyst Adult, 63% of participants taking crinecerfont achieved a physiologic GC dose (≤11 mg/m2/d HCe) at Wk24 while maintaining/improving A4. Post hoc analyses showed 82% achieved a physiologic GC dose with crinecerfont regardless of A4 level; of these, 53% had normal A4. In contrast, 37% achieved a physiologic GC dose with placebo, and 49% had elevated A4 despite supraphysiologic GC dosing."

Clinical • Retrospective data • Congenital Adrenal Hyperplasia • Endocrine Disorders • Pediatrics

Crinecerfont Maintains Serum Androstenedione Levels with Reduced Glucocorticoid Doses in Adults with Classic Congenital Adrenal Hyperplasia: 1-Year Results from the CAHtalyst™ Adult Study (ENDO 2025) - P3 | "In both periods, GC doses were kept stable for 4 weeks to measure the impact on androgens and then reduced to a target of 8-10 mg/m2/d in hydrocortisone equivalents. In adults with CAH, substantial reductions in A4 and in GC doses were observed with crinecerfont in the DBPC period. By the end of OL treatment, A4 was maintained or improved even in the context of lower, more physiologic GC doses. Thus, crinecerfont not only reduces androgen excess; by enabling GC doses to be lowered, crinecerfont can also reduce the adverse effects of chronic supraphysiologic GC exposure."

Clinical • Congenital Adrenal Hyperplasia • Endocrine Disorders • Pediatrics

Crinecerfont Enables Reduction of Glucocorticoid Doses While Maintaining or Improving Androstenedione in Pediatric Patients with Classic Congenital Adrenal Hyperplasia: Subgroup Analyses From the Phase 3 CAHtalyst™ Pediatric Study (ENDO 2025) - P3 | "GC doses were kept stable for the first 4 weeks to evaluate the impact on androgens and then reduced to a target of 8-10 mg/m2/d in hydrocortisone equivalents (HCe) by Week 28 while maintaining or improving A4 relative to Day 1 baseline (BL). Crinecerfont was effective in enabling GC dose reductions while maintaining or improving A4 in pediatric patients with CAH across all subgroups analyzed. These results demonstrate that pediatric patients with CAH can derive the androgen-lowering and GC-lowering benefits of crinecerfont treatment regardless of region, sex, race, age, weight/BMI, pubertal stage, or pretreatment A4 level or GC dose."

Clinical • P3 data • Congenital Adrenal Hyperplasia • Endocrine Disorders • Pediatrics

Crinecerfont Enables Reduction of Glucocorticoid Doses While Maintaining or Improving Androstenedione in Adults with Classic Congenital Adrenal Hyperplasia: Subgroup Analyses From the Phase 3 CAHtalyst™ Adult Study (ENDO 2025) - P3 | "GC doses were kept stable for 4 weeks to evaluate the impact on androgens, followed by a planned GC down-titration over 8 weeks to a target of 8-10 mg/m2/d in hydrocortisone (HC) equivalents...Changes from BL in A4 at Week 4 and in GC dose at Week 24 were analyzed in the overall population and in subgroups categorized by: region (US, outside US), sex (male, female), body mass index (ULN; evaluated for A4 change only). In 182 randomized participants (crinecerfont, n=122; placebo, n=60), mean A4 at BL was 620±729 ng/dL; mean GC dose was 17.6±4.9 mg/m2/d (32.3±9.3 mg/d)... Crinecerfont was effective in enabling GC dose reductions while maintaining or improving A4 in adults with CAH across all subgroups analyzed. These results demonstrate that adults with CAH can derive the androgen-lowering and GC-lowering benefits of crinecerfont treatment regardless of sex, race, BMI, or pre-treatment A4 levels, GC dose, or GC regimen."

Clinical • P3 data • Congenital Adrenal Hyperplasia • Endocrine Disorders • Pediatrics

Crinecerfont Improves Clinical Outcomes in Adults With Classic Congenital Adrenal Hyperplasia: 1-Year Results From the CAHtalyst™ Adult Study (ENDO 2025) - P3 | "Adults with CAH who received up to 1 year of crinecerfont continued to show improvements in BMI and insulin resistance, as expected with lower GC doses. Moreover, despite substantial GC dose reductions, hirsutism in female participants improved with crinecerfont. Given the known adverse effects of ACTH/androgen excess and chronic supraphysiologic GC exposure, these results represent a promising therapeutic advancement in CAH."

Clinical • Clinical data • Congenital Adrenal Hyperplasia • Dyslipidemia • Endocrine Disorders

Crinecerfont Shows Favorable Trends in Improving Weight-Related Outcomes in Pediatric Patients With Classic Congenital Adrenal Hyperplasia: 1-Year Results from the CAHtalyst™ Pediatric Study (ENDO 2025) - P3 | "Children and adolescents with CAH who received up to 1 year of crinecerfont showed reductions in BMI SDS. Moreover, one-third of participants who were overweight or obese at baseline achieved a ≥0.15 reduction in BMI SDS with crinecerfont, and 13% achieved normal BMI. These analyses indicate that the GC dose reductions enabled by crinecerfont can allow for improvements in the weight-related effects associated with chronic supraphysiologic GC exposure."

Clinical • Congenital Adrenal Hyperplasia • Endocrine Disorders • Genetic Disorders • Obesity • Pediatrics

Crinecerfont Maintains Adrenocorticotropic Hormone and 17-Hydroxyprogesterone Levels with Reduced Glucocorticoid Doses in Adults with Classic Congenital Adrenal Hyperplasia: 1-Year Results from the CAHtalyst™ Adult Study (ENDO 2025) - P3 | "In both periods, GC doses were kept stable for 4 weeks to measure the impact on androgens and then reduced to a target of 8-10 mg/m2/d in hydrocortisone equivalents. Mean ACTH and 17-OHP were maintained near or below BL in adults with CAH who received up to 1 year of crinecerfont, allowing for substantial reductions in GC dose. Crinecerfont is a non-GC approach for managing excess ACTH and adrenal androgens, enabling GC doses to be lowered and thereby reducing androgens and the adverse effects of chronic supraphysiologic GC exposure."

Clinical • Congenital Adrenal Hyperplasia • Endocrine Disorders • Pediatrics

Crinecerfont Allows for More Physiologic Glucocorticoid Dosing Regimens in Patients With Classic Congenital Adrenal Hyperplasia: Results from the Phase 3 CAHtalyst™ Adult and CAHtalystTM Pediatric Studies (ENDO 2025) - P3 | "In both studies, GC was kept stable for the first 4 weeks to measure the impact on androgens and then reduced to a target of 8-10 mg/m2/d in hydrocortisone (HC) equivalents at the end of double-blind treatment (Week 28 [pediatric]; Week 24 [adult]) while maintaining or improving androstenedione (A4) relative to baseline (BL). Long-acting, synthetic GCs (dexamethasone [DEX], (methyl)prednis(ol)one [PRED]) and timing (bedtime dose) were to be decreased first...Fludrocortisone was continued as needed. In CAHtalyst Pediatric (N=103), mean GC dose at BL was 16.4 mg/m2/d; 92.2% were taking only HC (no DEX or PRED)... Patients with CAH who received crinecerfont for ~6 months had greater mean decreases in GC doses while maintaining or improving A4 compared to placebo. HC dosing frequency was more likely to decrease with crinecerfont, as was switching to DEX- and PRED-free regimens. These changes reduce the CAH treatment burden and may decrease the risk of adverse effects of..."

Clinical • P3 data • Congenital Adrenal Hyperplasia • Endocrine Disorders • Pediatrics

Crinecerfont Reduces Plasma Adrenocorticotropic Hormone and Serum 17-Hydroxyprogesterone Levels in Children and Adolescents with Classic Congenital Adrenal Hyperplasia: 1-Year Results from the CAHtalystTM Pediatric Study (ENDO 2025) - P3 | "In both periods, GC doses were kept stable for the first 4 weeks to measure the impact on androgens and then reduced to a target of 8-10 mg/m2/d in hydrocortisone equivalents while maintaining or improving androstenedione (A4) relative to Day 1 baseline (BL). In children/adolescents with CAH who received up to 1 year of crinecerfont, ACTH and 17-OHP were reduced to below BL levels, even after reductions in GC dose. These decreases were consistent with the significant A4 reduction reported in the DBPC period. Crinecerfont, a novel oral CRF1 antagonist, is a non-GC approach to manage excess ACTH and adrenal androgens in CAH, enabling GC doses to be lowered and thus achieving the dual goals of reducing androgen excess and the risks associated with long-term supraphysiologic GC exposure."

Clinical • Congenital Adrenal Hyperplasia • Endocrine Disorders • Pediatrics

Crinecerfont Maintains Reductions in Serum Androstenedione Levels and Glucocorticoid Doses in Children and Adolescents with Classic Congenital Adrenal Hyperplasia: 1-Year Results from the CAHtalystTM Pediatric Study (ENDO 2025) - P3 | "In children and adolescents with CAH, reductions in excess A4 and GC doses observed with crinecerfont during the DBPC period were maintained during the OL period. By the end of OL treatment, mean A4 was maintained below BL levels despite a significant reduction in GC dosing to lower, more physiologic doses. Thus, not only can crinecerfont reduce androgen excess, but by enabling GC doses to be lowered, crinecerfont may also reduce the adverse effects of chronic exposure to supraphysiologic GCs over a lifetime of treatment."

Clinical • Congenital Adrenal Hyperplasia • Endocrine Disorders • Pediatrics

Crinecerfont Allows for More Physiologic Glucocorticoid Treatment With Reduction of Androstenedione to a Normal Range in Pediatric Patients With Classic Congenital Adrenal Hyperplasia: Post Hoc Analysis of the CAHtalyst™ Pediatric Study (ENDO 2025) - P3 | "GC doses were kept stable for the first 4 weeks to measure the impact on androgens and then reduced (if possible based on A4) to a target dose of 8-10 mg/m2/d in hydrocortisone equivalents (HCe) by Week 28 while maintaining or improving A4 relative to baseline (BL). In the 28-week CAHtalyst Pediatric study, 30% of participants receiving crinecerfont achieved a physiologic GC dose (≤11 mg/m2/d HCe) while maintaining or improving A4. Post hoc analyses showed 36% achieved a physiologic GC dose with crinecerfont regardless of A4 level; of these, 50% had normal A4. In contrast, no participants achieved a physiologic GC dose with placebo, and 68% had elevated A4 despite supraphysiologic GC dosing."

Clinical • Retrospective data • Congenital Adrenal Hyperplasia • Endocrine Disorders • Pediatrics

Crinecerfont Shows Favorable Trends in Improving Weight-Related Outcomes in Adults With Classic Congenital Adrenal Hyperplasia: 1-Year Results From the CAHtalyst™ Adult Study (ENDO 2025) - P3 | "Adults with CAH who received up to 1 year of crinecerfont showed reductions in BMI and weight. Among participants who were overweight or obese at BL, 30.8% achieved a >5% reduction in weight at Month 12. These analyses indicate that the substantial GC dose reductions enabled by crinecerfont can allow for improvements in the weight-related effects associated with chronic supraphysiologic GC exposure."

Clinical • Congenital Adrenal Hyperplasia • Endocrine Disorders • Genetic Disorders • Obesity

Evaluation of Potential Drug-Drug Interactions with Crinecerfont (ENDO 2025) - "Study 3 (N=25) evaluated the PK of an oral contraceptive (ethinylestradiol/levonorgestrel 30/150 µg) with (Test) or without (Reference) crinecerfont 100 mg. Given the safety profile of crinecerfont, the increase in crinecerfont exposure with ketoconazole was not considered clinically relevant, and no dose adjustments are necessary when administering crinecerfont with CYP3A4 inhibitors. Decreased crinecerfont exposure with rifampin might reduce the efficacy of crinecerfont. Thus, if taken with a strong CYP3A4 inducer, the morning and evening doses of crinecerfont should be increased 2-fold."

Congenital Adrenal Hyperplasia • Endocrine Disorders

SI03-17. Advancing Care in Classic Congenital Adrenal Hyperplasia (CAH): Study Insights from CAHtalyst™ Pediatric and Adult: Androgen and GC Dose Reductions (ENDO 2025) - "Join a presentation from the lead authors of CAHtalyst™ Adult and Pediatric to learn about CRENESSITY (crinecerfont), the first and only CRF1 antagonist for classic CAH...This program is sponsored by, and the speaker is presenting on behalf of, Neurocrine Biosciences. It is being presented consistent with FDA guidelines and is not approved for continuing education credit."

Clinical • Congenital Adrenal Hyperplasia • Endocrine Disorders • Immunology • Pediatrics

Successful Treatment Of Congenital Adrenal Hyperplasia 11 Beta Hydroxylase Deficiency With Crenessity. (ENDO 2025) - "The combination of Crenessity and Cortef normalized the steroid profile for the first time in 3 years of treatment in the case of CAH 11 beta-hydroxylase deficiency. There were no complications, and the child tolerated therapy well."

Late-breaking abstract • Congenital Adrenal Hyperplasia • Endocrine Disorders • Fatigue • CYP21A2

Efficacy of Crinecerfont in Reducing Androgen Levels in Congenital Adrenal Hyperplasia: A Meta-Analysis of Randomized Trials (ENDO 2025) - "Reductions were greater in adults (MD: -273.68 ng/dL, 95% CI: [-365.63; -181.73]) than in pediatrics (MD: -155.13 ng/dL, 95% CI: [-244.93; -65.34]).ConclusionsCrinecerfont effectively reduces 17OHP and androstenedione levels in both pediatric and adult CAH populations, offering a promising therapeutic strategy to minimize reliance on high-dose glucocorticoids. Further trials are warranted to confirm long-term efficacy and safety."

Retrospective data • Congenital Adrenal Hyperplasia • Endocrine Disorders • Pediatrics

Game Changers: Blockbuster Small-Molecule Drugs Approved by the FDA in 2024. (PubMed, Pharmaceuticals (Basel)) - "Notably, eight of these drugs (including Rezdiffra®, Voydeya®, Iqirvo®, Voranigo®, Livdelzi®, Miplyffa®, Revuforj®, and Crenessity®) are classified as "first-in-class" and have received breakthrough therapy designation. These agents not only exhibit distinct mechanisms of action but also offer substantial improvements in efficacy for patients compared to prior therapeutic options. This article offers a comprehensive analysis of the mechanisms of action, clinical trials, drug design, and synthetic methodologies related to representative drugs, aiming to provide crucial insights for future pharmaceutical development."

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