Neurocrine Biosciences (United States)

Continuous glucose monitoring (CGM) technology is becoming increasingly available to people with diabetes using insulin therapy; however, availability for people with type 2 diabetes (T2D) not on insulin remains limited. For people with T2D, there is strong evidence of glycemic benefit with CGM use for those treated with insulin, and CGM is accepted as standard of care. This review explores the impact of CGM use on glycemic and patient-reported outcomes in noninsulin treated populations with T2D, reporting outcomes from 10 identified randomized controlled trials and 15 nonrandomized studies. We report evidence that supports the use of this technology in people with T2D not using insulin.

ABSTRACTDespite significant investment, no effective disease‐modifying therapies for Alzheimer's disease (AD) have been developed to date. As understanding of the underlying causes of AD evolves, numerous animal models have been generated to study the disease. However, persistent therapeutic failures raise questions about the reasons for these shortcomings, including whether they stem from poor target selection and/or limitations in replicating key aspects of AD pathophysiology in animal models. In this study, a machine learning‐based workflow previously reported in the literature was modified and used to identify shared dysregulation in phenotype‐defining pathways across both animal models and human datasets—termed translatable pathways. This approach provided a framework for assessing the translational relevance of three widely used AD models: APP/PS1, 3×Tg, and 5×FAD, from hippocampal microarray data. The analysis suggested no translatable pathways in the APP/PS1 and 3×Tg preclinical models, whereas key pathways were identified in the 5×FAD (SREBP control of lipid synthesis and cytotoxic T‐lymphocyte pathways) model. Additionally, applying the workflow to publicly available microarray data from ibuprofen‐treated mice accurately predicted the clinical failure of ibuprofen for treating AD in human trials. This study highlights the importance of evaluating the translatability of animal models to human disease and provides a suitable framework for improving the selection of preclinical models in Alzheimer's research.

Disclosure: O. Lekarev: Consultant for Neurocrine Biosciences and Eton Pharmaceuticals; medical and scientific advisory board for CARES Foundation. A. Erkin-Cakmak: None. M.G. Vogiatzi: Research support and consulting for Neurocrine, Spruce, Crinetics and Adrenas. E.A. Imel: Received clinical trial research funds and consulted for Neurocrine Biosciences; received clinical trial research funds from Spruce. M. Clemente: None. R. Coutant: None. G.B. Rosales: Full-time employee of Neurocrine Biosciences, Inc. E. Roberts: Full-time employee of Neurocrine Biosciences, Inc. G.S. Jeha: Full-time employee of Neurocrine Biosciences, Inc. R.H. Farber: Full-time employee of Neurocrine Biosciences, Inc. J.L. Chan: Full-time employee of Neurocrine Biosciences, Inc..Background: Crinecerfont, a corticotropin releasing factor type 1 receptor (CRF1) antagonist, is a first-in-class medication that is FDA-approved for adjunctive treatment to glucocorticoid (GC) replacement to control androgens in patients with classic congenital adrenal hyperplasia (CAH). In two phase 3 trials, crinecerfont significantly reduced excess adrenal androgens, enabling subsequent reductions in GC doses in pediatric and adult patients with CAH. Objective: To analyze changes in androstenedione (A4) levels and GC doses while maintaining or improving A4 in subgroups of participants from the CAHtalyst™ Pediatric study (NCT04806451) of crinecerfont. Methods: Children and adolescents with CAH were randomized 2:1 to double-blind treatment with crinecerfont (25, 50, or 100 mg BID based on weight) or placebo for 28 weeks. 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). Least squares (LS) mean changes from BL in A4 (before morning GC dose) at Week 4 and in GC dose at Week 28 were analyzed in the overall population and in subgroups defined by: region (US, outside US); sex (male, female); race (white, non-white); age (<12, 12-17 years); weight at BL (<55, ≥55 kg); body mass index (BMI) at BL (<85th, ≥85th percentile); pubertal stage at BL (Tanner stages 1-2, stages 3-5); A4 at BL (≤ULN [upper limit of normal], >ULN); and GC dose at BL (<16, ≥16 mg/m2/d HCe, for GC change only). Results: The study included 103 participants (crinecerfont, n=69; placebo, n=34). The mean age (±SD) was 12.1±3.5 years and 51% (n=53) were male. Mean A4 at BL was 431±461 ng/dL; mean GC dose was 16.4±3.9 mg/m2/d HCe. At Week 4, A4 was significantly reduced with crinecerfont but increased with placebo (-197 vs. +71 ng/dL; LS mean difference [LSMD]: -268 ng/dL; P=0.0002 [primary endpoint]). LSMDs of the point estimates for A4 change at Week 4 favored crinecerfont over placebo in all subgroups. At Week 28, GC dose was significantly reduced with crinecerfont (while maintaining or improving A4) but increased with placebo (-18.0% vs. +5.6%; LSMD: -23.5%; P<0.0001 [key secondary endpoint]). LSMDs of the point estimates for percent change in GC dose at Week 28 favored crinecerfont over placebo in all subgroups. For both A4 and GC, subgroup analyses were consistent with the primary and key secondary endpoint results in the overall population. Conclusion: 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.Presentation: Saturday, July 12, 2025

Background: Mismatch negativity (MMN) is a component of the auditory event-related potential (ERP) that is elicited during a passive oddball paradigm where task-irrelevant infrequent deviants are presented in a stream of more frequent standard stimuli. MMN is believed to index a pre-attentive stage of auditory information processing closely linked to N-methyl-D-aspartate receptors (NMDAR). Ketamine is thought to act primarily as an NMDAR antagonist, has been used in clinical trials to model the symptoms of schizophrenia and is increasingly used in the clinic to treat depression. Various studies have reported that ketamine reduces MMN amplitude which, in turn, might reflect reduced function of NMDAR-mediated neurotransmission. Nonetheless, there is growing evidence showing MMN amplitude either having high variability or, paradoxically, moving in the opposite direction after ketamine in different individuals. Methods: In here, we analyzed results from three independent ERP studies to test the hypothesis of a cross-over interaction (″disordinal″ drug effect) between the duration-deviant MMN at baseline (without ketamine) and the direction and magnitude of the ketamine effect. To rule out regression to the mean (RTM), a statistical phenomenon that may also partially explain this cross-over interaction, we separately estimated RTM using a drug-free test-retest study. Results: Our results are the first to statistically demonstrate the existence of a disordinal drug response to ketamine, where the direction and magnitude of ketamine-induced changes in MMN amplitude can be predicted by baseline MMN amplitude. Conclusions: These new insights may contribute to novel precision medicine approaches to treatment of CNS disorders.

Abstract Disclosure: N. Nokoff: Consultant for Neurocrine Biosciences, Inc.; expert panel member for World Athletics. K.B. Krishna: None. L. Antonio: Sandoz, Merck, Advisory board member for Simple Pharma. R.H. Farber: Full-time employee of Neurocrine Biosciences, Inc. J.L. Chan: Full-time employee of Neurocrine Biosciences, Inc. J. Sturgeon: Full-time employee of Neurocrine Biosciences, Inc. G.B. Rosales: Full-time employee of Neurocrine Biosciences, Inc. G.S. Jeha: Full-time employee of Neurocrine Biosciences, Inc. V.H. Lin: Full-time employee of Neurocrine Biosciences, Inc. A.N. Dauber: Consultant and grant recipient for BioMarin and Pfizer; consultant for Novo Nordisk and QED Therapeutics. Background: Crinecerfont, a corticotropin releasing factor type 1 receptor (CRF1) antagonist, is a first-in-class medication that is FDA-approved for adjunctive treatment to glucocorticoid (GC) replacement to control androgens in patients with classic congenital adrenal hyperplasia (CAH). In two phase 3 trials, crinecerfont significantly reduced excess adrenal androgens, enabling reductions in GC doses in pediatric and adult patients with CAH. Objective: To evaluate changes in GC regimens in patients with CAH treated with crinecerfont. Methods: Individuals with CAH were randomized to crinecerfont (25, 50, or 100 mg BID in CAHtalyst™ Pediatric [NCT04806451]; 100 mg BID in CAHtalyst Adult [NCT04490915]) or placebo. 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. Changes in dosing frequency and GC regimens (switching from with PRED or DEX to without PRED or DEX) were evaluated with nominal P-values. Fludrocortisone was continued as needed. Results: 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). Percent changes in GC dose at Week 28 while maintaining/improving A4 showed a decrease with crinecerfont but not placebo (least squares mean difference [LSMD]: -23.5%; P&amp;lt;0.0001 [key secondary endpoint]). In participants taking only HC at BL, reduction in dosing frequency by ≥1 dose/d at Week 28 was more common with crinecerfont (16.1% vs 3.6%; P=0.1087). In CAHtalyst Adult (N=182), mean GC dose at BL was 17.6 mg/m2/d (32.3 mg/d) and 58.2% were taking only HC; 29.1% were taking PRED±HC and 12.6% were taking DEX (±another GC). At Week 24, the percent reduction in GC dose while maintaining/improving A4 was greater with crinecerfont than placebo (LSMD: -17.0%; P&amp;lt;0.0001 [primary endpoint]). In participants taking only HC at BL, reduction in dosing frequency was more common with crinecerfont than placebo (36.5% vs 12.5%; P=0.0253). Switching from a DEX-containing regimen at BL to a DEX-free regimen at Week 24 was more common with crinecerfont (87.5% vs 40.0%; P=0.0740), as was switching from PRED±HC to HC only (32.4% vs 10.5%; P=0.0418). Conclusion: 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 chronic treatment with synthetic GCs. Presentation: Monday, July 14, 2025

<b>Conclusion:</b> Valbenazine was safe and effective in elderly adults who received up to 48 weeks of treatment. Long-term treatment led to substantial and sustained TD improvements per clinician assessment (AIMS, CGI-TD) and patient report (PGIC), with no impact on psychiatric stability.

Abstract Disclosure: P.C. White: Consulting Fee; Self; Neurocrine Biosciences, Inc.. Research Investigator; Self; Neurocrine Biosciences, Inc. G.P. Sen: Employee; Self; Neurocrine Biosciences, Inc. F. Tang: Employee; Self; Cytel. J. Chen: Employee; Self; PicnicHealth. K. Lin-Su: Advisory Board Member; Self; CARES Foundation. D. Matos: Employee; Self; CARES Foundation. H. Cheng: Employee; Self; Neurocrine Biosciences, Inc. E. Roberts: Employee; Self; Neurocrine Biosciences, Inc. J.L. Chan: Employee; Self; Neurocrine Biosciences, Inc. G.S. Jeha: Employee; Self; Neurocrine Biosciences, Inc.. Introduction: Patients with congenital adrenal hyperplasia (CAH) are exposed to excess androgens and glucocorticoids (GC), which can affect growth and lead to obesity and other metabolic complications. CAHtalog is an active US-based CAH registry developed in partnership with CARES Foundation on the PicnicHealth platform to abstract retrospective and prospective medical record data. This study reports auxological and comorbidity data for pediatric and adult patients in the CAHtalog registry. Methods: All available medical records for consented adult and pediatric patients were collected. Data were abstracted and structured into a de-identified dataset. CAHtalog data available as of October 2023 were included for analysis. Auxological data were compared to the 2000 CDC growth data. Changes in body mass index (BMI) since the first documented measurements were evaluated. Comorbidities were defined based on diagnosis codes (ICD-9/10), laboratory measurements, vital signs, and/or clinical notes. Results: Data from 32 adult (mean age: 35.8±12.7 years; 72% female) and 35 pediatric patients (mean age: 12.7±5.5 years; 51% female) were available. From the first through last medical record with relevant ages (≥18 or &amp;lt;18 years), median follow-up durations were 13 years (adult) and 11 years (pediatric). Pediatric patients had early growth acceleration (that was more pronounced in females) with 95% confidence intervals for height-for-age of 66-99th percentile for females (2-10 years) and 42-87th percentile for males (2-13 years), followed by blunted pubertal growth. The mean peak bone age to chronological age ratio was 1.2±0.2 at age 7 years. The mean BMI-for-age consistently exceeded the 90th percentile in children aged ≥6 years, particularly for females. In adults, obesity (BMI ≥30) was highly prevalent in both females (74%) and males (33%) at all ages (61% overall), exceeding NHANES 2017-2018 general population prevalence (42%). Hypertension (53%), fatigue (47%), acne (36%), hyperlipidemia (33%), and insomnia/sleep disturbances (28%) were common comorbidities. Conclusion: Our CAH data reveal a persistent abnormal growth pattern, characterized by accelerated growth in early childhood and a deceleration in adolescents; early obesity was noted and sustained into adulthood. The anomalous growth trajectory and high rate of comorbidities reiterate the importance of early intervention and targeted disease management in this population. Presentation: 6/2/2024

Secondary pharmacology screening of investigational small-molecule drugs for potentially adverse off-target activities has become standard practice in pharmaceutical research and development, and regulatory agencies are increasingly requesting data on activity against targets with recognized adverse effect relationships. However, the screening strategies and target panels used by pharmaceutical companies may vary substantially. To help identify commonalities and differences, as well as to highlight opportunities for further optimization of secondary pharmacology assessment, we conducted a broad-ranging survey across 18 companies under the auspices of the DruSafe leadership group of the International Consortium for Innovation and Quality in Pharmaceutical Development. Based on our analysis of this survey and discussions and additional research within the group, we present here an overview of the current state of the art in secondary pharmacology screening. We discuss best practices, including additional safety-associated targets not covered by most current screening panels, and present approaches for interpreting and reporting off-target activities. We also provide an assessment of the safety impact of secondary pharmacology screening, and a perspective on opportunities and challenges in this rapidly developing field.