Corticotropin-releasing factor; Children; Classic congenital adrenal hyperplasiaFactor alliberador de corticotropina; Nens; Hiperplàsia suprarenal congènita clàssicaFactor liberador de corticotropina; Niños; Hiperplasia suprarrenal congénita clásic

Clemente, Maria

Felner, Eric

Kim, Mimi

Lodish, Maya

Martinerie, Laetitia

Nokoff, Natalie

Sarafoglou, Kyriakie

Journal of the Endocrine Society

English

Scientia, Dipòsit d’Informació Digital del Departament de Salut

1West China Hospital of Sichuan University, Chengdu, China;2Mayo Clinic, Rochester, MN; 3Mayo Clinic College of Medical,Rochester, MNINK4a in T cell, a cell cycle enzyme that associ-ated with chronological aging and cell senescence, is associ-ated with hypercortisolism and hypercortisolism-relatedcomorbidities. Design, Setting, and Participants: Inthis single-center cross-sectional study, we prospectivelyrecruited consecutive patients with hypercortisolism be-tween July 1, 2020 and August 24 2022. Patients were in-cluded if they were diagnosed with Cushing syndrome(CS) or mild autonomous cortisol secretion (MACS). Age-(± 2 years) and sex-matched referent subjects withoutknown adrenal disorders were included if abdominal im-aging was available. Participants on exogenous glucocorti-coids within 3 months prior were excluded. Exposure:Presence of hypercortisolism (MACS and CS). MainOutcomes and Measures: Primary outcomes includedp16INK4a, advanced glycation end products (AGE) readerresult, Frailty Index score, frailty (defined as frailty in-dex>0.31), and physical performances in patients andmatched referents at index date. Secondary outcomesincluded correlation between biological age markers, hor-monal workup and the risk of comorbidities. p16INK4aexpression analysis was adjusted for age, sex, smoking,and alcohol use for all analyses except for associationswith CVDand frailty.Results:Of 85 patients (87%women,mean age 53 years), 51 (60%) had MACS (34 had matchedreferents), 34 (40%) had overt CS (16 had matched refer-ents). Patients with CS demonstrated a median 1.9-foldhigher p16INK4a expression (P<.001), and patients withMACS showed a median of 1.70-fold p16INK4a expression(P=.013), when compared to referent subjects. Age- and sex-adjusted p16INK4a expression was associated with frailtyindex score (r=0.23, P=.035), time-up-and-go test (r=0.28,P=.048), gait speed (r=-0.36, P=.035), but not with AGEreader result, 6-minute walk test, or hand grip measure-ment. The p16INK4a expression was associated with historyof cardiovascular disease (age-adjusted odds ratio (aOR)=3.70, 95% confidence interval (CI), 1.20-11.43) and frailty(aOR=2.27, 95%CI, 1.04-4.98). Conclusion and rele-vance: We demonstrated evidence of cell senescence inboth patients with CS and patients with MACS. Furtherstudies need to determine the impact of surgical, cortisol-lowering, and senolytic medical therapies in MACS on cellsenescence and associated aging-related comorbidities.Abstract citation ID: bvae163.127Adrenal (ExcludingMineralocorticoids)7317CAHtalyst Pediatric: Results From The Randomized,Double-Blind, Placebo-Controlled Period Of A Phase3 Trial Of Crinecerfont, A Corticotropin-ReleasingFactor Type 1 Receptor Antagonist, In Children AndAdolescents With Classic Congenital AdrenalHyperplasiaK. Sarafoglou1, M. S. Kim2,3, M. Lodish4, E. I. Felner5,6,L. Martinerie7, N. J. Nokoff8, M. Clemente9,10, P. Y. Fechner11,M. G. Vogiatzi12,13, P. W. Speiser14,15, J. Sturgeon16, E. Roberts16,G. S. Jeha17, J. L. Chan16, and R. Farber161University of MinnesotaMedical School and College of Pharmacy,Minneapolis, MN; 2Children’s Hospital of Los Angeles, LosAngeles, CA; 3Keck School of Medicine of USC, Los Angeles, CA;4University of California San Francisco, Berkeley, CA; 5EmoryUniversity School of Medicine, Atlanta, GA; 6Children’sHealthcare of Atlanta (CHOA), Atlanta, GA; 7HôpitalUniversitaire Robert Debré, AP-HP, Université Paris Cité, Paris,France; 8University of Colorado Anschutz Medical Campus,Aurora, CO; 9University Hospital Vall d’Hebrón, Barcelona, Spain;10Instituto de Salud Carlos III, Barcelona, Spain; 11SeattleChildren’s Hospital, University of Washington School of Medicine,Seattle, WA; 12Children’s Hospital of Philadelphia, Philadelphia,PA; 13Perelman School of Medicine, University of Pennsylvania,Philadelphia, PA; 14Cohen Children’s Medical Center of NY, NewHyde Park, NY; 15Donald and Barbara Zucker School of Medicineat Hofstra/Northwell, Hempstead, NY; 16Neurocrine Biosciences,Inc., San Diego, CA; 17Neurocrine Biosciences, Inc., Tiburon, CADisclosure: K. Sarafoglou: Consulting Fee; Self;Neurocrine Biosciences, Inc., Crinetics Pharmaceuticals,Eton Pharmaceuticals, Spruce Biosciences. ResearchInvestigator; Self; Neurocrine Biosciences, Inc., AdrenasTherapeutics, Spruce Biosciences. M.S. Kim: AdvisoryBoard Member; Self; Spruce Biosciences. ResearchInvestigator; Self; Neurocrine Biosciences, Inc., Diurnal,A68 | Journal of the Endocrine Society | https://doi.org/10.1210/jendso/bvae163J Endocrine Soc, Volume 8, Issue Supplement_1, October–November 2024 A68Downloaded from https://academic.oup.com/jes/article/8/Supplement_1/bvae163.127/7813354 by Jose Baselga user on 24 December 2024Spruce Biosciences. M. Lodish: None. E.I. Felner: None.L. Martinerie: None. N.J. Nokoff: Advisory BoardMember; Self; World Athletics. Consulting Fee; Self; IonisPharmaceuticals Inc., Neurocrine Biosciences, Inc.M. Clemente: Consulting Fee; Self; AstraZeneca,Boehringer Ingelheim, Eli Lilly & Company, NovoNordisk. Research Investigator; Self; Eli Lilly &Company, Novo Nordisk. P.Y. Fechner: Consulting Fee;Self; Neurocrine Biosciences, Inc., Eton Pharmaceuticals.Research Investigator; Self; Neurocrine Biosciences, Inc.,Diurnal, Spruce Biosciences. M.G. Vogiatzi: ConsultingFee; Self; Adrenas Therapeutics, Eton Pharmaceuticals.Research Investigator; Self; Neurocrine Biosciences, Inc.,Spruce Biosciences. P.W. Speiser: Advisory BoardMember; Self; Adrenas Therapeutics, Chan Zuckerberg’sRare as One Initiative. Consulting Fee; Self; RocheDiagnostics. Research Investigator; Self; NeurocrineBiosciences, Inc.. Speaker; Self; Medscape, Wolters KluterPublishing. J. Sturgeon: Employee; Self; NeurocrineBiosciences, Inc. E. Roberts: Employee; Self; NeurocrineBiosciences, Inc. G.S. Jeha: Employee; Self; NeurocrineBiosciences, Inc. J.L. Chan: Employee; Self; NeurocrineBiosciences, Inc. R. Farber: Employee; Self; NeurocrineBiosciences, Inc..Introduction: Classic congenital adrenal hyperplasia(CAH) due to 21-hydroxylase deficiency (21OHD), a geneticdisorder characterized by cortisol deficiency and excess ad-renal androgens, typically requires management withsupraphysiological glucocorticoid (GC) doses. Crinecerfontis a novel oral CRF1 antagonist that reduced elevatedACTH and adrenal androgens in patients with 21OHD in14-day, open-label Phase 2 studies. This Phase 3 study(CAHtalyst Pediatric: NCT04806451) evaluated whethercrinecerfont can reduce androstenedione (A4) levels andsupraphysiological GC doses in pediatric patients with21OHD. Methods: Children and adolescents (2-17 yrs)with classic 21OHD, stable GC regimens at doses >12 mg/m2/d in hydrocortisone equivalents (HCe), A4 >midpointof reference range, and 17-hydroxyprogesterone (17-OHP)>2x upper limit of normal (ULN) were randomized (2:1)to either crinecerfont (25, 50, or 100 mg BID based onweight) or placebo for 28 weeks. GC dosing was maintainedstable for 4weeks and then reduced, if possible, based onA4levels to achieve a dose of 8-10 mg/m2/d while maintainingA4 control (≤120% of baseline or ≤ULN) by week 28.Results: In the 103 randomized participants (53 male;mean [range] age: 12 [4-17] yrs), demographics and base-line characteristics were similar between treatment arms(69 crinecerfont, 34 placebo). Mean baseline GC dose was16.4 mg/m2/d HCe (92% on HC alone, 8% on a predniso[lo]ne-containing regimen). Baseline A4 (mean±SD) was 431±461 ng/dL and 17-OHP was 8682±6847 ng/dL. Over 95%completed the double-blind treatment period. At week 4(end of GC-stable period), crinecerfont led to greater reduc-tions in A4 vs placebo (least squares mean difference[LSMD]: -268 ng/dL; p=0.0002) (primary endpoint) and17-OHP (LSMD: -6421 ng/dL; p<0.0001) (key secondaryendpoint). At week 28, the crinecerfont arm had a greaterpercent reduction in GC dose while maintaining A4 control,vs placebo (LSMD: -24%; p<0.0001) (key secondary end-point). Moreover, 30% of participants on crinecerfontachieved a protocol-defined physiological GC dose (≤11mg/m2/d) while maintaining A4 control, vs 0% on placebo(nominal p=0.0009). The most commontreatment-emergent adverse events (AEs) in the crinecer-font arm were headache (25% vs 6% for placebo), pyrexia(23% vs 24%), and vomiting (15% vs 30%). There were fewserious AEs (5% overall) with none assessed as related tostudy drug. Conclusions: Crinecerfont, an oral CRF1 an-tagonist, represents a novel treatment option to improveandrogen control in pediatric patients with classic21OHD. In the largest interventional Phase 3 study con-ducted to date in these patients, crinecerfont led to a signifi-cant decrease in A4 while the GC dose was stable, enablinga significant percent reduction of supraphysiological GCdoses while maintaining A4 control by 28 weeks.Crinecerfont was well tolerated overall.Presentation: 6/2/20241) Antagonist, In AdultsWith Classic Congenital Adrenal Hyperplasia,,,1University of Michigan Medical School, Ann Arbor, MI, USA; 2UTSouthwestern Medical Center, Dallas, TX, USA; 3UniversitàFederico II di Napoli, Naples, Italy; 4Mayo Clinic, Rochester, MN,USA; 5IRCCS Ospedale San Raffaele, Milan, Italy; 6University ofPittsburgh School of Medicine, Pittsburgh, PA, USA; 7SapienzaUniversity of Rome, Roma, Italy; 8CHU d’Angers, Angers, France;9Université d’Angers, Angers, France; 10University CollegeLondon Hospital, Kent, United Kingdom; 11Medical University ofVienna, Vienna, Austria; 12Karolinska Institutet and KarolinskaUniversity Hospital, Stockholm, Sweden; 13Karolinska UniversityHospital, Stockholm, Sweden; 14National Institutes of HealthClinical Center, Bethesda, MD, USA; 15Eunice Kennedy ShriverNational Institute of Child Health and Human Development,Bethesda, MD, USA; 16LMU Munich, Munich, Germany;17Neurocrine Biosciences, Inc., San Diego, CA, USAJournal of the Endocrine Society | https://doi.org/10.1210/jendso/bvae163 | A69J Endocrine Soc, Volume 8, Issue Supplement_1, October–November 2024A69Downloaded from https://academic.oup.com/jes/article/8/Supplement_1/bvae163.127/7813354 by Jose Baselga user on 24 December 2024

7317 CAHtalyst Pediatric: Results From The Randomized, Double-Blind, Placebo-Controlled Period Of A Phase 3 Trial Of Crinecerfont, A Corticotropin-Releasing Factor Type 1 Receptor Antagonist, In Children And Adolescents With Classic Congenital Adrenal Hyperplasia

https://scientiasalut.gencat.cat/bitstream/11351/12380/1/7317_cahtalyst_pediatric_results_randomized_double_blind_placebo_controlled_period_a_phase_3_trial_crinecerfont_a_corticotropin_releasing_factor_type_1_receptor_antagonist_children_adolescents_2024.pdf

7317 CAHtalyst Pediatric: Results From The Randomized, Double-Blind, Placebo-Controlled Period Of A Phase 3 Trial Of Crinecerfont, A Corticotropin-Releasing Factor Type 1 Receptor Antagonist, In Children And Adolescents With Classic Congenital Adrenal Hyperplasia

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