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Background: Cardiac disease is the leading cause of premature mortality in Friedreich Ataxia (FA). However, validated prognostic indicators or early imaging biomarkers that can reliably predict cardiac events are lacking. To address this gap, we created a multicenter FA cardiac registry to characterize disease progression and identify early echocardiographic (echo) predictors of major adverse cardiac events (MACE). Methods: FA subjects from 6 North American centers with at least two echos performed ≥5 years apart were included. Demographics, FA-specific disease characteristics, and MACE (a composite of death, heart failure hospitalization, aborted sudden cardiac death, and/or life-threatening arrhythmia) were abstracted. Digital echo images were re-read at a centralized core lab. Paired T tests were utilized for comparison of the normally distributed first and second echo parameters, and logistic regression models were utilized to evaluate for predictors of MACE. Results: Of 115 subjects, 52 (45%) were female. Mean age at diagnosis was 10 ± 3 years, median GAA1 repeat length (a marker of genetic severity) was 700 (range 66–1200), and median age at first analyzed echo was 12 years (range 4-36). MACE occurred in 35 (30%) of the cohort. Serial echocardiograms demonstrated progressive worsening of multiple cardiac parameters over time, including markers of ventricular thickness and hypertrophy, chamber size, systolic function, and novel markers of atrial and ventricular strain (Table 1). On univariate analysis, several markers of hypertrophy and systolic function from the earliest analyzed echo predicted MACE. However, after adjusting for age of diagnosis, GAA1 repeat length, and collinearity among variables, only posterior wall thickness in diastole (PWTd) remained an independent predictor of MACE (odds ratio 1.8 per mm increase, 95% CI 1.1–3.3, p = 0.028). Conclusions: This multicenter FA registry identifies early posterior wall thickness as a significant and independent predictor of major adverse cardiac events in FA. Each millimeter increase in PWTd on early echo is associated with nearly double the odds of MACE. This commonly acquired parameter is often overlooked and may serve as a powerful early marker of cardiac risk. Further investigation of PWTd as a potential surrogate endpoint for therapeutic trials in FA is warranted.

Introduction: Valvular heart disease (VHD) poses a growing global burden, particularly in aging populations. While transcatheter interventions have expanded rapidly over the past two decades, the extent to which trial populations reflect real-world demographics—especially age and sex—is unclear. Understanding enrollment trends and representation gaps is essential to ensure equitable, generalizable evidence for clinical decision-making. Methods: We systematically reviewed VHD interventional trials (2000–2024) indexed in PubMed. Surgical and percutaneous trials across aortic, mitral, tricuspid, and pulmonic valves were included. Trial characteristics, demographics, and interventions were analyzed using descriptive and nonparametric statistics. Results: We included 487 trials enrolling 87,412 participants (45% women). Median trial size increased over time (z = 4.98, p < 0.01), and the mean age of participants also rose significantly (z = 10.08, p < 0.01). Trials involving percutaneous (11% to 45%), bioprosthetic (22% to 53%), aortic valve (27% to 62%), and multinational (2% to 16%) interventions increased over time. Older participants were more commonly enrolled in percutaneous, industry-funded, multinational, bioprosthetic, and aortic valve trials. Female representation remained unchanged across time (median 47%, z = -0.48, p = 0.63), but trials enrolling older participants tended to include more women (ρ = 0.196, p < 0.01). Female representation was highest in mitral (59%) and tricuspid (59%) valve trials, and more common in percutaneous (52%) than surgical (42%) interventions. Conclusion: Over the past two decades, VHD trials have expanded in size and geographic scope, with increased enrollment of older adults, particularly in percutaneous and industry-sponsored studies. However, sex disparities and demographic variability persist. Future trials should prioritize inclusive designs to ensure equitable, generalizable evidence for evolving valve interventions.

Abstract INTRODUCTION The Genetic Frontotemporal Initiative (GENFI) and Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)‐Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Longitudinal Frontotemporal Lobar Degeneration Study (ALLFTD) consortia developed Clinical Dementia Rating (CDR)‐derived scales with a motor domain to overcome systematic underestimation of disease severity by the CDR. We calculated disease severity scores using these scales in a mixed neurodegenerative cohort and correlated them with objective motor measures. METHODS The CDR plus National Alzheimer's Coordinating Center (NACC) Frontotemporal Lobar Degeneration (FTLD), CDR + NACC FTLD‐M (Motor), and Multidomain Impairment Rating (MIR) scores and motor measures were determined and correlated in 242 participants. RESULTS Both CDR + NACC FTLD‐M and MIR showed increased disease severity scores and correlated with motor measures. These findings were held in 81 amyotrophic lateral sclerosis (ALS) participants and correlated with the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. Including a motor domain required fewer study participants in a simulated clinical trial sample size calculation. DISCUSSION With a motor domain, CDR + NACC FTLD‐M and MIR improve disease severity classification and correlate with quantitative motor assessments. This addition more fully captures the extent of symptoms across the FTD‐ALS spectrum and improves clinical trial efficiency. Highlights CDR + NACC FTLD‐M and MIR strongly correlate with objective motor measures. The enhanced scales improve disease severity classification in FTD and ALS. Greater clinical trial efficiency is achieved using these enhanced scales.

Background Immune checkpoint therapies targeting programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) have been met with limited clinical responses in the treatment of patients of varying cancer types. Current US Food and Drug Administration (FDA)-approved therapies function to prevent PD-1 binding to PD-L1, thereby preventing T-cell suppression. However, these therapies fail to prevent PD-L1 intrinsic signaling and recycling, which can render these treatments ineffective. Moreover, most research primarily focuses on how these antibodies affect tumor cells and their interactions with T cells. Myeloid cells, which also express PD-L1 and influence T-cell responses, are integral to the efficacy of these therapies. However, strategies that can target these cells to boost antitumor responses have not been effective. Methods Our group has developed a new anti-PD-L1 antibody (H1A), which disrupts PD-L1 recycling and redirects it towards degradation. Due to the loss of available PD-L1 protein, H1A effectively prevents PD-L1 intrinsic signaling. Using in vivo humanized PD-1/PD-L1 mouse tumor models, we evaluated the therapeutic efficacy of H1A against current FDA-approved PD-L1 blocking antibodies. Using human-derived immune cell in vitro assays, we pinpoint the biological consequences of H1A-induced PD-L1 degradation in myeloid cells. Results H1A demonstrated improved tumor control and established immunological memory responses in vivo in the treatment of tumors with moderate immunogenicity that are less responsive to current immunotherapies. This was supported by enhanced activation of myeloid cells (major histocompatibility complex (MHC)-II and CD80) and frequencies of effector T-cell populations found intratumorally. Human myeloid cells treated with H1A were also observed to have increased activation (MHC-II and CD80) and cytokine secretion. Similar to our in vivo findings, human peripheral blood lymphocyte cultures demonstrated increased frequencies of effector T-cell populations and greater tumor cell killing. Conclusions This work highlights the importance of targeting PD-L1 recycling and intrinsic signaling, specifically in myeloid cells, to boost antitumor responses. Our studies suggest that H1A can provide a solution to the lack of responses seen with current therapeutics, while also revealing previously unknown intrinsic functions of PD-L1 in myeloid cells.

Abstract Background Carbon ion radiotherapy (CIRT), characterized by its Bragg peak and a reduced lateral scattering compared to proton radiotherapy (PT), offers excellent dose conformity in radiation treatment. Meanwhile, compared to PT, CIRT causes more complex and severe DNA damage in tumor cells, which results in a higher relative biological effectiveness (RBE), making it particularly advantageous in treating radioresistant and hypoxia tissues than conventional radiotherapy. However, CIRT's high RBE and the nuclear fragmentation dose tail outside the target presents challenges in sparing organ at risk (OARs). Combining PT and CIRT offers a potential hybrid modality that leverages the biological effectiveness of carbon ions while minimizing normal tissue toxicity with high biological damage. Purpose Despite the potential of combining PT and CIRT, balancing their respective advantages while mitigating disadvantages remains a significant challenge. This study aims to develop an optimized treatment approach that automatically adjusts the relative contributions of protons and carbon ions, improving target dose conformity while minimizing biological impact on OARs. Methods We propose a biological optimization framework for multi‐modality combining PT and CIRT (CCIPRT). The biological dose is modeled as the product of the physical dose and RBE. Through iterative Jacobian‐based linearization, the biological dose of carbon ion is expressed in a linear model, enabling the formulation of a linear least‐square objective. The biological dose of proton is formulated as a linear model using the physical dose and dose‐averaged linear energy transfer (LET). The joint optimization problem is then solved using iterative convex relaxation and the alternating direction method of multipliers. For comparison, single‐modality PT and CIRT were also implemented. Results When the target dose of CCIPRT is prescribed in terms of the physical dose, compared to PT, CCIPRT increased the mean biological dose in the target by 37.7%, 29.6%, and 31.1% for brain, lung, and abdomen, respectively; compared to CIRT, CCIPRT reduced the biological dose in CTV1cm (ring surrounding CTV with 1 cm width) by 47.2%, 32.3%, and 40.4% for brain, lung, and abdomen, respectively. When the target dose of CCIPRT is prescribed in terms of the biological dose, compared to PT, CCIPRT achieved higher conformity index (CCIPRT: 0.96 and 0.97; PT: 0.93 and 0.96 for brain and liver cases, respectively) and reduced the dose in CTV1cm by 9.5% and 7.0% for brain and liver cases, respectively; compared to CIRT, CCIPRT enhanced healthy tissue sparing, reducing the dose to the body by 7.5% and 9.2% for brain and liver cases, respectively. Conclusions A novel multi‐modality CCIPRT treatment planning is developed with demonstrated superior performance over single‐modality PT or CIRT, with enhanced biological effectiveness and dose conformity compared to PT and reduced OAR dose compared to CIRT.

ABSTRACT Patient outcomes in advanced renal cell carcinoma (RCC) remain poor, with five‐year survival rates ranging from ~10% to 30%. Early projections of therapeutic outcomes could optimize precision medicine and accelerate drug development. While machine learning (ML) models integrating tumor growth inhibition (TGI) metrics have improved survival predictions over traditional models, their application in RCC remains unexplored. Herein, we used TGI metrics and baseline data to evaluate parametric (PM) and semi‐parametric (SPM) survival models alongside ML approaches for predicting progression‐free (PFS) and overall survival (OS) in 1839 RCC patients from four trials (evaluating sunitinib, axitinib, sorafenib, interferon‐alpha, and avelumab + axitinib). Data were split into training (70%) and testing (30%), and feature selection was used to determine parsimonious and robust models. Bootstrap resampling ( n = 100) was employed for models' validation, and performance was assessed using C‐index and Integrated Brier Score. In brief, training data results demonstrated that tree‐based ML models (random survival forest (RSF) and XGBoost) outperformed PM and SPM models in predicting PFS (C‐index: 0.783–0.785 vs. 0.725–0.738 for PM and SPM; p < 0.05) and OS (C‐index: 0.77–0.867 vs. 0.750–0.758 for PM and SPM; p < 0.05), with RSF achieving better prediction of PFS and OS using only 3–5 covariates, compared to 9–35 with other tested methods. Tree‐based methods were also superior in the testing data. SHapley Additive exPlanations revealed nonlinear relationships among top predictors, including TGI metrics, underscoring the ability of tree‐based methods to capture complex prognostic interactions. Further validation is required to confirm models' generalizability to additional therapies and patients with differing tumor severity.

ABSTRACT Sjögren's syndrome (SS) is a chronic autoimmune disorder characterized by lymphocytic infiltration and destruction of exocrine glands, commonly involving the salivary and lacrimal glands, leading to dry mouth and eyes. While SS primarily affects the upper gastrointestinal tract, this case presents a rare small intestine involvement. This patient was diagnosed with SS in 2018 with positive antinuclear antibodies (ANA), rheumatoid factor (RF), SSA antibodies, and salivary lip gland biopsy. By 2021, she developed unusual cyclic episodes of nausea, vomiting, and poor oral intake, resulting in significant weight loss and recurrent hospitalizations. She had frequent hospitalizations due to her recurrent symptoms. Evaluations included esophagogastroduodenoscopy (EGD) and colonoscopy, but pathology was nondiagnostic. Several abdominal and pelvic computed tomography (CT) scans demonstrated bladder edema, pancolitis, and terminal ileitis with mucosal hyperenhancement of the bowel and moderate ascites, likely inflammatory. Her gastric emptying study showed hypermotility. Multiple teams, including Rheumatology, Allergy/Immunology, Gastroenterology, Hematology, and Surgery, were involved. C1 esterase antigen was normal, ruling out hereditary angioedema. PET‐CT scan did not show lymphadenopathy or significant inflammation. Full biopsy for definitive diagnosis was deferred due to concerns of decreased healing with an edematous intestine. She was trialed on Icatibant without benefit. Differentials included lupus peritonitis, protein‐losing enteropathy, and SS intestinal lymphoma. She was discharged on a trial of empiric high‐dose steroids with Rheumatology follow‐up. Symptoms recurred with steroid tapering. Her complement levels decreased with flares and increased with treatment. Rituximab was added, leading to steady clinical improvement and reduced hospitalizations. Bowel involvement has been predominantly described in lupus, often referred to as lupus enteritis or bowel vasculitis. To our knowledge, this represents the first reported case of Sjögren's syndrome. Bowel biopsies are not typically subjected to routine immunohistochemical staining. Consequently, standard testing may be limited in detecting autoimmune processes. This case highlights the diagnostic challenges of SS‐related gastrointestinal manifestations and underscores the importance of considering autoimmune enteropathy, particularly in patients who respond to immunosuppressive therapy.

Abstract Disclosure: R.J. Auchus: Has been involved in contracted research with companies such as Neurocrine Biosciences/Neurocrine UK, LTD, Spruce Biosciences, Corcept Therapeutics, Crinetics Pharmaceuticals, Recordati Rare Diseases, Adrenas Therapeutics, and Mineralys Pharmaceuticals, Served as consultant for organizations like Quest Diagnostics, Corcept Therapeutics, Xeris Pharmaceuticals, Crinetics Pharmaceuticals, Novo Nordisk, Neurocrine Biosciences/Neurocrine UK, LTD, Recordati Rare Diseases, H Lundbeck A/S, Sparrow Pharmaceuticals, Astellas Pharmaceuticals, and Acerand Therapeutics. O. Hamidi: Advisory board member for Neurocrine Biosciences, Corcept Therapeutics, Recordati Rare Diseases, Crinetics Pharmaceuticals, Inc, Camurus, Xeris Pharmaceuticals, Inc, Educational speaking engagement with Recordati Rare Diseases. I. Bancos: None. K. Saag: Recieved grants or contracts from Amgen, Arthrosi, Horizon, LG Pharma, Radius, and Olatec, Received consulting fees from Amgen, Anthrosi, Atom Bioscience, Horizon, LG Pharma, Angitia, and Gruenthal. H. Falhammar: None. U. Srirangalingam: Consulting fees from Crinetics Pharmaceuticals, Diurnal Ltd and H Lundbeck A/S. M. Calanchini: None. E. Jen: Full-time employee of Neurocrine Biosciences, Inc. V.H. Lin: Full-time employee of Neurocrine Biosciences, Inc. J. Sturgeon: 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 the Phase 3 CAHtalyst™ Adult study (NCT04490915), crinecerfont (100 mg BID) significantly reduced adrenal androgens, enabling substantial GC dose reductions from Day 1 baseline (BL) at the end of double-blind placebo-controlled (DBPC) treatment at Week 24, with a least-squares (LS) mean percent change of -27.3% vs. -10.3% for placebo (LS mean difference [LSMD] -17.0%, P&lt;0.0001). At the end of open-label (OL) treatment at Month 12, mean percent decreases from BL in GC dose were -24.6% in participants who continued on crinecerfont (CFT/CFT) and -29.7% in those who switched from placebo (PBO/CFT). Objective: To evaluate clinical outcomes in adults with CAH who received up to 1 year of crinecerfont, in the context of substantial GC dose reductions. Methods: Outcomes related to excess adrenocorticotropic hormone (ACTH)/androgens (e.g., hirsutism in female participants) and GC exposure (e.g., body mass index [BMI], insulin resistance, hyperlipidemia) were analyzed at the end of DBPC treatment (Week 24) and the end of OL treatment (Month 12). DBPC outcomes with P-values are presented as LS mean changes with LSMD. Results: In female participants, mean hirsutism visual analog scale scores (out of 0 [no symptoms] to 100 [very severe symptoms]) were 40.6 (crinecerfont) and 37.4 (placebo) at BL. Changes from BL at end of DBPC (Week 24) and OL (Month 12) were: Week 24 (-9.8 for crinecerfont [n=58] vs -2.8 placebo [n=27], LSMD -7.0, P=0.1564); Month 12 (-11.5 CFT/CFT [n=56], -12.9 PBO/CFT [n=27]). Mean BMI at BL was 30.1 kg/m2 (crinecerfont) and 29.0 kg/m2 (placebo). Changes from BL were: at Week 24 (-0.4 vs. -0.02 for crinecerfont [n=118] vs. placebo [n=57], LSMD -0.40, P=0.1068); at Month 12 (-0.8 CFT/CFT [n=114], -0.4 PBO/CFT [n=56]). Mean homeostatic model assessment of insulin resistance values were high at BL (crinecerfont 3.2, placebo 3.0). Changes from BL were: at Week 24 (-0.6 vs. -0.4 for crinecerfont [n=61] vs placebo [n=29], LSMD -0.29, P=0.3454); at Month 12 (-0.5 CFT/CFT [n=107], -0.9 PBO/CFT [n=54]). Mean values for cholesterol (total, LDL, and HDL) and triglycerides were within normal range or near optimal at BL and remained stable. Conclusion: 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. Presentation: Sunday, July 13, 2025

Abstract Disclosure: S.R. Chacko: None. C.A. Villavicencio Torres: None. K. Yu: None. S.G. Waguespack: None. L. Lu: None. Z. Belaya: None. T. Bandgar: None. A. Sada: None. O. Ragnarsson: None. B. Altieri: None. A. Newman: None. P. Vibhatavata: None. M. Tóth: None. E.V. Varlamov: None. C. Badiu: None. A. Paissan: None. M. St-Jean: None. H. Falhammar: None. N. Imamudeen: None. L. Haberbosch: None. M. Bobrowicz: None. A. Tabarin: None. R. Shah: None. M.R. Gadelha: None. A. Peersen: None. W.F. Young: None. J. Kaplan: None. J. Varghese: None. M.A. Habra: None. O. Golounina: None. G.A. Melnichenko: None. A.R. Lila: None. C. Yamichannaiah: None. I. Bancos: None. Context: Cushing syndrome (CS) due to ectopic ACTH secretion (EAS) is a rare condition, associated with severe hypercortisolism and consequent morbidity and mortality. Its varied and often emergent presentation make diagnosis and treatment challenging. Objectives: 1.Characterize clinical and biochemical presentation of EAS. 2.Describe the scope of hypercortisolism-related complications, overall and CS-specific mortality. 3.Identify factors associated with CS-specific mortality. Methods: We conducted a multicenter retrospective cohort study in patients with EAS at 37 centers. Outcomes were clinical/biochemical severity scores, complications, overall and CS-specific mortality. Results: In 1053 patients [median age at diagnosis 52 years (IQR 37-64), 57% women], metastatic disease was present at diagnosis in 585 (56%). The most common sources of EAS were bronchial neuroendocrine neoplasm (NEN) (304, 29%), pancreatic NEN (114, 11%) and small cell lung carcinoma (114, 11%), with the source of EAS being occult in 192 (18%). Clinical and biochemical severity scores were severe in 475 (45%) and 873 patients (92%) respectively. Hypokalemia was present in 819 patients (78%) in the year prior to diagnosis. Of 342 patients (32%) who had IPSS, 301 (88%) suggested an ectopic source, 7 (2%) a pituitary source, and 23 (7%) were non-diagnostic. Of 595 patients who had both functional and cross-sectional imaging, discordant findings were seen in 122 (21%), concordant lesion was seen on both in 326 (55%), and no lesion in 147 (25%). Of those with discordant results, cross-sectional imaging was accurate in 66 (54%) and functional imaging in 56 (46%).Management included medical therapy alone in 237 (23%), surgical excision of the source of EAS in 158 (15%), bilateral adrenalectomy in 77 (7%) and multimodal therapies in 498 patients (47%). Complications within 5 years after diagnosis included hospitalization related to CS or its therapy in 351 (33%), infection in 337 (32%), thromboembolic event in 102 (10%), cardiovascular event in 83 (8%) and cerebrovascular event in 27 (3%). During a median follow-up of 35 months (IQR 20-122) from CS diagnosis, death occurred in 462 patients (44%), with the cause of death related to CS in 149 (14%). CS-specific mortality was higher in metastatic compared with non-metastatic disease (19% vs. 7%, P&lt;0.001). On multivariable analysis of age, sex, clinical and biochemical severity, older age (HR 1.03, 95% CI: 1.02-1.04) and lower clinical severity score (HR 0.97, 95% CI: 0.94-0.99), were associated with higher CS-specific mortality. Conclusion: Our interim analysis, the largest worldwide, found that most patients with EAS had severe hypercortisolism and hypokalemia. Metastatic disease was present in 56%, and the source of EAS was occult in 18%. CS-related death occurred in 14%, emphasizing the need for urgent management. Presentation: Monday, July 14, 2025

Abstract Disclosure: I. Bancos: None. H. Falhammar: None. J. Young: None. R. Pivonello: Received research funding from Corcept Therapeutics, Neurocrine Biosciences, Recordati AG, Spruce Bioscience and Xeris Pharmaceuticals (Strongbridge Biopharma), Consultant for Corcept Therapeutics, Crinetics Pharmaceuticals, HLundbeck A/S and Recordati Rare Diseases.. G. Russo: None. M.R. Stancampiano: None. V.H. Lin: Full-time employee of Neurocrine Biosciences, Inc. J. Sturgeon: Full-time employee of Neurocrine Biosciences, Inc. J.L. Chan: Full-time employee of Neurocrine Biosciences, Inc. Background: In patients with classic congenital adrenal hyperplasia (CAH), chronic glucocorticoid (GC) treatment, especially at supraphysiologic doses, can lead to weight gain or obesity. Crinecerfont, a corticotropin releasing factor type 1 receptor (CRF1) antagonist, is a first-in-class medication that is FDA-approved for adjunctive treatment to GC replacement to control androgens in patients with CAH. In CAHtalyst™ Adult (NCT04490915), least-squares mean (LSM) percent changes in GC dose at Week 24 (end of double-blind placebo-controlled [DBPC] period) indicated a significant reduction with crinecerfont (-27.3% vs 10.3% for placebo; LSM difference [LSMD] -17.0%; P&lt;0.0001) while androstenedione was maintained or improved relative to Day 1 baseline (BL). At Month 12 (end of open-label [OL] period), mean percent decreases from BL were -24.6% in participants continuing crinecerfont (CFT/CFT) and -29.7% in those switched from placebo (PBO/CFT). Objective: To evaluate weight-related outcomes in adults with CAH who received up to 1 year of crinecerfont. Methods: Mean change from Day 1 BL in body mass index (BMI) and mean percentage change from BL in weight were analyzed at Week 24 and Month 12. Achievement of &gt;5% reduction in weight was also analyzed, with results presented as % (n/N: n=number meeting response threshold, N=number who were overweight/obese [BMI ≥25 kg/m2]) at BL and had available data at assessment [Week 24 and Month 12]). For predefined endpoints in the DBPC period, results are presented as LSM changes with LSMD and P-value. Results: Mean BMI at BL was 30.1 kg/m2 (crinecerfont) and 29.0 kg/m2 (placebo), and &gt;70% of participants were overweight or obese (74.6% [91/122] crinecerfont; 63.3% [38/60] placebo). At Week 24, LSM changes from BL for crinecerfont vs placebo were as follows: BMI (-0.42 vs -0.02; LSMD: 0.40, P=0.1068); percent change in weight (1.45% vs -0.07%; LSMD: 1.38%, P=0.0856). At Month 12, further mean reductions from BL were observed with crinecerfont in BMI (-0.81 kg/m2 CFT/CFT, -0.44 kg/m2 PBO/CFT) and weight (-2.72% CFT/CFT, -1.37% PBO/CFT). Among participants who were overweight or obese at BL, a higher percentage achieved &gt;5% reduction in weight at Week 24 with crinecerfont 18.4% (16/87) versus placebo 13.5% (5/37). At Month 12, 27.4% (23/84) and 38.9% (14/36) achieved this threshold in the CFT/CFT and PBO/CFT groups, respectively. Conclusion: 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 &gt;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. Presentation: Sunday, July 13, 2025