Regeneron Pharmaceuticals Inc Research Articles

A213 DUPILUMAB EFFICACY IN EOSINOPHILIC ESOPHAGITIS PERSISTS FOR HISTOLOGIC, SYMPTOMATIC, AND ENDOSCOPIC OUTCOMES REGARDLESS OF CONCOMITANT HIGH-DOSE PROTON PUMP INHIBITOR USE

Abstract Background Proton-pump inhibitor (PPI) therapy is the most commonly used first-line therapy for eosinophilic esophagitis (EoE) but data informing long-term outcomes are limited. Aims This pre-specified analysis of data from the phase 3 LIBERTY EoE TREET (NCT03633617) study assessed the efficacy of weekly dupilumab vs placebo in patients (pts) with and without concomitant PPI use. Methods Pts with peak intraepithelial eosinophil (eos) count ≥15 eos/high-power field (hpf) after ≥8 weeks’ high-dose PPI were randomized to dupilumab or placebo. Pts on high-dose PPIs at screening remained on a high-dose regimen during the treatment period; switching of PPI types was permitted but new initiation of PPIs was prohibited. Endpoints at Week 24 were: proportion of pts achieving ≤6 eos/hpf, absolute change from baseline in Dysphagia Symptom Questionnaire (DSQ) score, % change in peak eos count, absolute change in Endoscopic Reference Score (EREFS) and Histologic Scoring System (HSS) grade/stage scores. Results In Parts A and B, respectively, 61.9% and 71.3% of pts in the dupilumab group and 64.1% and 72.2% in the placebo group were using PPIs at randomization. For pts treated with dupilumab vs placebo in Parts A and B, respectively, ≤6 eos/hpf was achieved by 69.2% (95% confidence interval [CI] 48.2–85.7) vs 8.0% (95% CI 1.0–26.0) and 59.6% (95% CI 45.8–72.4) vs 7.0% (95% CI 2.0–17.0) of pts using PPIs, and by 43.8% (95% CI 19.8–70.1) vs 0% (95% CI 0–23.2) and 56.5% (95% CI 34.5–76.8) vs 4.5% (95% CI 0.1–22.8) of pts not using PPIs. Least squares mean change from baseline in DSQ score for dupilumab vs placebo was –18.5 vs –12.9 and –21.8 vs –14.0 for pts using PPIs in Parts A and B, respectively, and –27.8 vs –3.8 and –28.4 vs –13.3 for those not using PPIs (Figure 1). Dupilumab improved outcomes vs placebo for secondary endpoints, with comparable results in pts with and without concomitant PPI use. Absolute change from baseline in EREFS score is shown in Figure 1. Dupilumab was generally well tolerated. Conclusions Dupilumab improved histologic, symptomatic, and endoscopic aspects of EoE in adults and adolescents, up to 24 weeks, regardless of concomitant high-dose PPI use. Figure 1. Effect of dupilumab 300 mg qw versus placebo on primary endpoints (A) proportion of patients with peak esophageal intraepithelial eosinophil count of ≤6 eos/hpf (B) absolute change from baseline in DSQ total score at Week 24 (C) absolute change from baseline in EREFS total score at Week 24, by concomitant PPI use CI, confidence interval; DSQ, Dysphagia Symptom Questionnaire; EREFS, endoscopic reference score; eos, eosinophils; hpf, high-power field; LS, least squares; PPI, proton pump inhibitor; pt, patient; qw, once weekly; SE, standard error. Funding Agencies Research sponsored by Sanofi and Regeneron Pharmaceuticals Inc.

A204 DUPILUMAB IMPROVES HISTOLOGIC, ENDOSCOPIC, AND SYMPTOMATIC ASPECTS OF EOSINOPHILIC ESOPHAGITIS IN PATIENTS AGES 1–ampersand:003C12 YEARS

Abstract Background Dupilumab is approved in Canada for eosinophilic esophagitis (EoE) in patients (pts) aged ≥12 years who weigh ≥40 kg; no treatments are approved for pts aged ampersand:003C12 years. Aims The Phase 3 EoE KIDS trial evaluated dupilumab efficacy and safety vs placebo (PBO) in pts aged 1–ampersand:003C12 years with EoE. Methods Part A was a 16-week (W) PBO-controlled study; pts were randomized 2:2:1:1 to weight-tiered dupilumab on a higher-exposure (HE) or lower-exposure (LE) regimen, or PBO (2 groups) to W16. In Part B, pts continued dupilumab, or switched from PBO to dupilumab (HE/LE), to W52. Results At W16 (Part A), the HE dupilumab group had an improved proportion of pts achieving peak esophageal intraepithelial eosinophil count (PEC) ≤6 eosinophils/high-power field (hpf) vs PBO (67.6% vs 2.9%, Pampersand:003C0.0001; primary endpoint). At W52 (Part B), 62.9% of HE dupilumab/dupilumab pts, and 52.9% of PBO/HE dupilumab pts, achieved PEC ≤6. At W16, the following improved with HE dupilumab vs PBO: EoE-Histologic Scoring System grade and stage scores (–0.88 vs +0.02 and –0.84 vs +0.05, respectively, both Pampersand:003C0.0001); EoE-Endoscopic Reference Score (–3.5 vs +0.3, Pampersand:003C0.0001); overall caregiver assessed EoE status (global impression of change mean [SD], 2.1 [1.2] vs 3.3 [1.4]; lower scores represent more improvement). Improvements were maintained with continuous dupilumab and improved in PBO/dupilumab pts at W52. LE dupilumab maintained similar improvements achieved through W52; however, effects were generally either comparable or numerically lower with LE dupilumab vs HE dupilumab. At W16, COVID-19, rash, headache, and injection-site erythema occurred more frequently in patients receiving dupilumab, with higher incidence than PBO; AEs were similar through W52. Conclusions HE dupilumab met the primary endpoint of PEC ≤6 eos/hpf vs PBO, demonstrated significant changes in histologic and endoscopic aspects of EoE, and improved symptoms with benefits maintained/increased to W52. Funding Agencies Research sponsored by Sanofi and Regeneron Pharmaceuticals Inc.

A206 DUPILUMAB TREATMENT REDUCES THE FREQUENCY OF DYSPHAGIA DAYS AND ACTIONS TO RELIEVE DYSPHAGIA IN PATIENTS WITH EOSINOPHILIC ESOPHAGITIS (EOE): RESULTS FROM THE PHASE 3 LIBERTY EOE TREET STUDY

Abstract Background Dysphagia is the predominant symptom of EoE in adolescents and adults. Aims To assess change in number of days with dysphagia, number of days with action taken to relieve dysphagia, and change in pain associated with dysphagia in patients receiving dupilumab 300 mg once weekly (qw) vs placebo in LIBERTY EoE TREET. Methods Dysphagia Symptom Questionnaire (DSQ) score (range 0–84) was calculated from daily responses over 14 days for Q2 (frequency) and Q3 (severity); Q4 (pain) was separately assessed (range 0–56). Higher scores indicate a worse outcome. Inclusion criteria required patients to have a baseline DSQ score ≥10. Number of days with dysphagia (Q2), action taken to relieve dysphagia (Q3), and pain (Q4) were analyzed at baseline and Week (W) 24 for the placebo-controlled study parts (A and B). P-values are nominal. Results 81 patients enrolled in Part A (dupilumab/placebo: n=42/39) and 159 in Part B (n=80/79). Mean number of days with dysphagia was similar with dupilumab vs placebo at baseline, but lower in the dupilumab group at W24 (Figure). Mean [SD] change from baseline (dupilumab vs placebo) was –6.5 [3.78] vs –3.9 [4.61], Pampersand:003C0.05 in Part A, and –7.8 [4.24] vs –4.7 [4.02], Pampersand:003C0.0001 in Part B. Mean [SD] number of days with any action taken to relieve dysphagia was similar in the dupilumab vs placebo group at baseline (Part A: 7.3 [3.76] vs 8.2 [3.82]; Part B: 9.5 [3.53] vs 8.7 [3.85]) but lower (numerically) in the dupilumab group at W24 (Part A: 3.6 [3.73] vs 5.7 [4.78]; Part B: 3.0 [3.84] vs 5.3 [4.69]). At W24, numerically fewer days with more severe dysphagia (need to cough/gag, vomit, or seek medical attention to relieve dysphagia) occurred with dupilumab vs placebo. Baseline DSQ pain score was similar in dupilumab vs placebo groups. Least squares mean [95% CI] change from baseline at W24 in DSQ pain score was −10.1 [–12.2, –7.9] vs −4.4 [–6.8, –2.0] for dupilumab vs placebo in Part A (difference vs placebo: −5.7 [95% CI −8.67, –2.72]; P=0.0002), and −10.0 [–11.7, –8.1] vs −6.5 [–8.3, –4.6] in Part B (difference vs placebo: −3.5 [95% CI −5.90, −1.03]; P=0.0053). Conclusions At W24, patients in the dupilumab 300 mg qw group experienced fewer days with dysphagia, fewer days with any action taken for dysphagia relief, and less pain associated with dysphagia vs placebo. Funding Agencies Research sponsored by Sanofi and Regeneron Pharmaceuticals Inc.

Dupilumab leads to better-controlled asthma & quality of life in children: the VOYAGE study.

Dupilumab has shown long-term treatment benefits in children with uncontrolled asthma. We assessed in more detail the impact of dupilumab on asthma control and health-related quality of life (HRQoL) in children and their caregivers. Children aged 6-11 years with uncontrolled moderate-to-severe type 2 asthma (baseline blood eosinophils ≥150 cells·µL-1 or fractional exhaled nitric oxide [FeNO] ≥20 ppb; n=350) were treated with dupilumab or placebo for 52 weeks in the VOYAGE study. Primary outcomes of these analyses were asthma control (change from baseline in Interviewer-Administered 7-item Asthma Control Questionnaire [ACQ-7-IA] and achieving a clinically meaningful response of ≥0.5]; proportion of patients achieving well-controlled asthma or better [ACQ-7-IA ≤0.75]), effect on patients' (Standardised Paediatric Asthma Quality of Life Questionnaire [PAQLQ[S]-IA]), and caregivers' (Paediatric Asthma Caregiver's Quality of Life Questionnaire [PACQLQ] score) HRQoL; and allergic rhinitis-related QoL. Dupilumab versus placebo significantly improved children's ACQ-7-IA scores by week 4 with sustained improvements through week 52 (least-squares mean difference at week 52: -0.44, 95% CI -0.59 to -0.30; p<0.0001); a higher proportion achieved a clinically meaningful response (week 52: 86% versus 75%; p=0.0051). At weeks 24 and 52, more children who received dupilumab achieved well-controlled asthma (ACQ-7-IA ≤0.75: 61% versus 43%, p=0.0001; 70% versus 46%, p<0.0001, respectively). Significant improvements in PAQLQ[S]-IA and PACQLQ scores were observed by week 52. In children aged 6-11 years with moderate-to-severe type 2 asthma, dupilumab treatment was associated with rapid, sustained improvements in asthma control. HRQoL was significantly improved for children and their caregivers. Sanofi and Regeneron Pharmaceuticals Inc.

Medicare Part B Spending on Macular Degeneration Treatments Associated With Manufacturer Payments to Ophthalmologists

Age-related macular degeneration (ARMD) therapies aflibercept and ranibizumab are among the highest-cost Medicare Part B drugs, even though off-label use of lower-cost bevacizumab is clinically noninferior. Payments from manufacturers of these ARMD therapies to ophthalmologists are hypothesized to be factors in ophthalmologists' therapeutic choice, controlling for ophthalmologist and patient characteristics. To assess the association between manufacturer payments to ophthalmologists and choice of ARMD treatment as well as to identify ophthalmologist-level characteristics associated with prescribing lower-cost ARMD therapies. This retrospective cross-sectional study of longitudinal (2013-2019) Medicare Part B data was conducted from December 2021 to December 2022. Ophthalmologists prescribing aflibercept (manufactured by Regeneron Pharmaceuticals Inc), rabinizumab, or bevacizumab (both manufactured by Genentech Inc) for ARMD treatment of Medicare Part B beneficiaries were included. Data on manufacturer payments to ophthalmologists were obtained from the Open Payments database. The primary outcome was the percentage of bevacizumab prescribed by ophthalmologists among all ARMD therapies. Regression analysis assessed variation in bevacizumab prescribing by acceptance of manufacturer payments as well as by ophthalmologist and patient characteristics. Ophthalmologist characteristics were duration of practice and Medicare Administrative Contractor region, and patient characteristics were aggregated at the ophthalmologist level and included mean beneficiary age, percentage of dual-eligible beneficiaries, mean beneficiary risk score, and percentage of White beneficiaries. Savings were estimated by projecting the change in bevacizumab use had ophthalmologists not accepted manufacturer payments, controlling for all ophthalmologist and patient characteristics and comparing with observed use and costs. A total of 21 584 ophthalmologists (18 489 males [85.7%]) were included. Ophthalmologists who accepted manufacturer payments were significantly less likely to prescribe bevacizumab (28.0% [95% CI, 24.6%-42.5%] of patients) compared with those who did not accept manufacturer payments (45.8% [95% CI, 44.5%-47.1%]). Ophthalmologists who saw dual-eligible beneficiaries had greater bevacizumab prescribing (50.0% [95% CI, 40.6%-68.3%] in the highest quartile vs 36.1% [95% CI, 33.5%-38.8%] in the lowest quartile; β coefficient, 0.139; P < .001), while those who saw patients with higher mean beneficiary risk scores had lower bevacizumab use (38.0% [95% CI, 23.7%-44.1%] in the highest quartile vs 48.2% [95% CI, 45.5%-50.8%] in the lowest quartile; β coefficient, -0.102, P < .001). Had ophthalmologists who accepted manufacturer payments prescribed ARMD drugs as those who did not accept payments, Medicare spending on these treatments would have been $642 779 703.08 lower from 2013 to 2019, a 2.0% savings. Results of this cross-sectional study suggest that drug manufacturer payments to ophthalmologists were associated with selection of higher-cost therapies for ARMD, which is a factor in increased Medicare and patient spending. Development of manufacturer payment models that encourage ophthalmologists to choose lower-cost therapies are needed.

Efficacy and safety of dupilumab up to 52 weeks in adults and adolescents with eosinophilic oesophagitis (LIBERTY EoE TREET study): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial

Efficacy and safety of dupilumab up to 52 weeks in adults and adolescents with eosinophilic oesophagitis (LIBERTY EoE TREET study): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial

P40 Dupilumab treatment restores skin barrier function in lesional and nonlesional skin of patients with atopic dermatitis and improves patient-reported outcomes

Abstract The objective of this analysis is to report the effect of dupilumab treatment on skin barrier function and patient-reported outcomes (PROs) in adults and adolescents with moderate-to-severe atopic dermatitis (AD). BALISTAD (NCT04447417) was an open-label trial in which transepidermal water loss (TEWL) was assessed repeatedly before and after skin tape stripping (STS) samples were taken from lesional and nonlesional skin of 26 patients with AD treated with dupilumab, and from normal skin of 26 matched healthy volunteers aged 12–65 years over a period of 16 weeks. PROs assessed included Patient-Oriented Eczema Measure (POEM), Peak Pruritus Numerical Rating Scale (PP-NRS) and Dermatological Life Quality Index [DLQI; for patients &amp;gt; 17 years old; Children’s DLQI (CDLQI) for patients aged &amp;gt; 12 to &amp;lt; 17 years]. At baseline, the median TEWL after five STS was statistically significantly higher in the lesional and nonlesional skin of patients with AD compared with healthy skin (P &amp;lt; 0.001 and P &amp;lt; 0.01, respectively) and statistically significantly decreased following dupilumab initiation as early as week 2 (P &amp;lt; 0.001 and P &amp;lt; 0.05, respectively). After 16 weeks of dupilumab treatment, there was no statistically significant difference in adjusted mean TEWL in AD lesional and nonlesional skin compared with matched healthy skin (P = 0.225 and P = 0.163, respectively). Significant improvement from baseline [mean (SD) change from baseline] was seen as early as week 2 in mean POEM [−8.4 (5.1)], DLQI [−5.3 (4.7)], CDLQI [−6.2 (4.7)] and PP-NRS [−2.2 (1.8); P &amp;lt; 0.001 and P &amp;lt; 0.05)] for CDLQI. Improvement was sustained through to week 16 [mean (SD) change from baseline; P &amp;lt; 0.001] for POEM [−13.6 (8.5)], DLQI [−8.6 (7.4)] and PP-NRS [−4.2 (2.6)] and with a P-value of &amp;lt; 0.01 for CDLQI [−9.2 (5.0)]. Dupilumab treatment normalizes epidermal barrier function in lesional and nonlesional skin in patients with moderate-to-severe AD, as measured with TEWL, and improves PROs. Funding sources: research sponsored by Sanofi and Regeneron Pharmaceuticals Inc.

P73 Laboratory safety from a 16-week phase III study of dupilumab in patients aged 6 months–5 years with moderate-to-severe atopic dermatitis

Abstract Previous studies of dupilumab treatment in adults, adolescents and children aged 6–11 years with moderate-to-severe atopic dermatitis (AD) showed no clinically meaningful changes in laboratory parameters. Here, we evaluate laboratory safety data for dupilumab-treated children aged 6 months–5 years with moderate-to-severe AD. In LIBERTY AD PRESCHOOL (NCT03346434 part B), a placebo-controlled phase III trial, 162 children aged 6 months–5 years with moderate-to-severe AD were randomized to receive dupilumab 200 mg or 300 mg every 4 weeks (n = 83) based on baseline weight (200 mg: ≥ 5 to &amp;lt; 15 kg; 300 mg: ≥ 15 to &amp;lt; 30 kg), or placebo (n = 79) for 16 weeks. Low-potency topical corticosteroids were initiated from day −14. At baseline, mean (SD) haematology parameters were similar in both treatment groups: eosinophils [dupilumab: 1.1 × 109 cells L−1 (0.7); placebo: 1.1 × 109 cells L−1 (0.7)], platelets [dupilumab: 397.7 × 109 cells L−1 (103.2), placebo: 385.6 × 109 cells L−1 (112.9)] and neutrophils [dupilumab: 3.54 × 109 cells L−1 (1.56); placebo: 3.85 × 109 cells L−1 (1.73)]. Mean (SD) counts of neutrophils [dupilumab: 3.18 × 109 cells L−1 (1.94); placebo: 3.79 × 109 cells L−1 (1.91)] remained within the normal reference interval (RI) at week 16. Mean (SD) change in platelet count at week 16 was −16.3 × 109 cells L−1 (78.5) in the dupilumab group and 17.4 × 109 cells L−1 (106.6) in the placebo group. In the dupilumab group, the mean (SD) change in eosinophil count increased at week 4 [0.48 × 109 cells L−1 (1.8)] and trended downward by week 16 [0.31 × 109 cells L−1 (1.4)], while minimal changes were noted in the placebo group at week 4 [0.1 × 109 cells L−1 (0.7)] and week 16 [−0.2 × 109 cells L−1 (0.7)]. The mean (SD) values for creatine kinase [dupilumab: 144.2 U L−1 (84.8); placebo: 130.7 U L−1 (46.39)], alkaline phosphatase [dupilumab: 273.4 U L−1 (80.01); placebo: 233.2 U L−1 (65.98)] and lactate dehydrogenase [dupilumab: 283.8 U L−1 (44.74); placebo: 317.4 U L−1 (67.58)] at week 16 remained within the normal RI in all treatment groups. Two patients treated with dupilumab reported cases of severe and moderate eosinophilia. Neither event was associated with clinical symptoms nor led to the discontinuation of study treatment. No clinically meaningful changes in haematology or chemistry laboratory safety parameters in children aged 6 months–5 years with moderate-to-severe AD were seen with 16 weeks of dupilumab treatment. These data demonstrate that, as with adults, adolescents and older children, routine laboratory monitoring is unnecessary in this population. Funding sources: research sponsored by Sanofi and Regeneron Pharmaceuticals Inc.

P71 Dupilumab improves patient-reported itch and other signs and symptoms of disease in adults with prurigo nodularis (LIBERTY-PN PRIME and PRIME2)

Abstract Prurigo nodularis (PN) is characterized by the presence of itchy nodules on the trunk/extremities and is often accompanied by skin pain and sleep disruption. Patient needs are highest regarding symptom control and improvement of itch, which is one of the main hallmarks of PN. Using pooled blinded data from two randomized, double-blind, placebo-controlled phase III trials of dupilumab in adults with PN uncontrolled on topical therapies, LIBERTY-PN PRIME (NCT04183335) and PRIME2 (NCT04202679), the psychometric validation and within-patient meaningful change thresholds for three patient-reported outcome (PRO) instruments of the trial were assessed in patients with PN: Worst Itch Numerical Rating Scale (WI-NRS), Skin Pain-NRS and Sleep-NRS. The proportion of patients achieving clinically meaningful improvement in these PRO scores in LIBERTY-PN PRIME and PRIME2 was investigated in this post hoc analysis. Adults with PN inadequately controlled on topical prescription therapies, or when those therapies were not advisable, were randomized 1 : 1 to dupilumab 300 mg every 2 weeks or matched placebo. Here, we report the proportion of patients meeting a defined improvement threshold in weekly averages from baseline to week 24 of ≥ 4 points in WI-NRS, ≥ 4 points in Skin Pain-NRS and ≥ 2 points in Sleep-NRS (within-patient meaningful improvement thresholds defined in the context of the LIBERTY-PN PRIME and PRIME2 studies, range 0–10), and the proportion of patients who achieved a new composite endpoint, meaningful improvement in WI-NRS and either Skin Pain-NRS or Sleep-NRS at week 24. A total of 311 patients were randomized (dupilumab, n = 153; placebo, n = 158). Baseline scores for WI-NRS, Skin Pain-NRS and Sleep-NRS were balanced between treatment groups. Significantly more patients treated with dupilumab vs. placebo achieved in-­patient meaningful improvement in WI-NRS (58.8% vs. 19.0%; P &amp;lt; 0.001), Skin Pain-NRS (49.7% vs. 20.9%; P &amp;lt; 0.001) and Sleep-NRS (42.5% vs. 23.4%; P &amp;lt; 0.001) from baseline to week 24. More patients treated with dupilumab experienced clinically meaningful improvement in WI-NRS and either Skin Pain-NRS or Sleep-NRS vs. placebo (53.6% vs. 18.4%; P &amp;lt; 0.001). Adults with PN uncontrolled on topical therapies treated with dupilumab achieved statistically significant and clinically meaningful improvement in itch, skin pain and sleep quality individually, and in itch combined with either skin pain or sleep. The safety profile of dupilumab was consistent with the known safety profile in its approved indications. Funding sources: research sponsored by Sanofi and Regeneron Pharmaceuticals Inc.

P93 Dupilumab treatment in children with moderate-to-severe atopic dermatitis increases levels of bone mineralization biomarkers

Abstract Children with atopic dermatitis (AD) are at risk for lower bone mineral density (BMD) and lower alkaline phosphatase (ALP) levels than healthy children. Low BMD and ALP in children could contribute to a higher lifetime prevalence of fractures, osteopenia and osteoporosis. Dupilumab is a fully humanized monoclonal anti-interleukin (IL)-4R antibody approved for the treatment of AD in children. The objective of this analysis is to report the impact of dupilumab treatment on markers of bone mineralization in children aged 6–12 years with moderate-to-severe AD vs. reference intervals (RIs). Analysis was performed retrospectively on sera from participants in LIBERTY AD PEDS, a phase III placebo-controlled trial of 16 weeks (NCT03345914) and LIBERTY AD PED-OLE (NCT02612454), an open-label extension trial in which eligible patients received dupilumab until week 52. Biomarkers, including bone ALP (BALP), procollagen type 1 N-terminal propeptide (P1NP), C-terminal crosslinking telopeptide of β-1 collagen (β-CTX), osteocalcin (OC) and insulin-like growth factor 1 (IGF-1), were analysed at baseline, 8, 12 and 16 weeks; only BALP was measured at 52 weeks. Both dupilumab dosing regimens led to significant increases in geometric mean (SE) levels of BALP at 8, 12 and 16 weeks compared with placebo. For the 100/200-mg Q2W group, at week 8 the BALP level was 72.7 (1.03) μg L−1 vs. 62.0 (1.05) μg L−1 (P &amp;lt; 0.0001), at week 12 it was 74.7 (1.03) μg L−1 vs. 64.3 (1.05) μg L−1 (P &amp;lt; 0.001) and at week 16 it was 78.0 (1.03) μg L−1 vs. 65.0 (1.04) μg L−1 (P &amp;lt; 0.001). For the 300-mg Q4W group, at week 8 the BALP level was 76.7 (1.03) μg L−1 vs. 62.0 (1.05) μg L−1 (P &amp;lt; 0.001), at week 12 it was 73.3 (1.04) μg L−1 vs. 64.3 (1.05) μg L−1 (P = 0.002) and at week 16 it was 77.3 (1.03) μg L−1 vs. 65.0 (1.04) μg L−1 (P &amp;lt; 0.001). At 52 weeks, BALP levels were statistically significantly increased compared with baseline [placebo vs. placebo transitioned to dupilumab: 64.2 (1.04) μg L−1 vs. 82.9 (1.04) μg L−1 (P &amp;lt; 0.001); 100/200 mg Q2W: 62.0 (1.05) μg L−1 vs. 83.8 (1.03) μg L−1 (P &amp;lt; 0.001); 300 mg Q4W: 64.1 (1.04) μg L−1 vs. 78.7 (1.04) μg L−1 (P &amp;lt; 0.001)] and also increased within RIs. From baseline to week 16, OC, P1NP and β-CTX levels improved from below to within the RIs, and levels of IGF-1 increased from the lower limit of the RI. However, data points were limited due to insufficient sera volumes, preventing statistical analyses for these biomarkers. The overall results suggest an increase in bone mineralization biomarkers in paediatric patients with moderate-to-severe AD following dupilumab treatment. Funding sources:research sponsored by Sanofi and Regeneron Pharmaceuticals Inc.

207-OR: Myostatin Inhibition Synergizes with GLP-1R Agonism to Accelerate Weight Loss in Male, Obese Nonhuman Primates

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have become standard-of-care for the pharmacological treatment of obesity by inducing clinically meaningful weight loss through a reduction in appetite. While these agents potently reduce fat mass, the caloric restriction also reduces skeletal muscle mass. Strategies to preserve skeletal muscle in the presence of caloric restriction are needed to improve weight loss quality in obese patents. Trevogrumab (∝-MSTN) and garetosmab (∝-ActA) are fully human monoclonal antibodies that potently inhibit two mediators of skeletal muscle atrophy: myostatin (MSTN) and activin A (ActA). We first tested the effects of ∝-MSTN, ∝-ActA and GLP-1RA (Semaglutide [Sema]) on body composition of diet-induced obese mice either alone or in combination. Sema (-29.8%) and ∝-MSTN/∝-ActA (-23.4%) produced significant reduction in fat mass after 4 weeks of treatment vs baseline. Adding MTSN and ActA blockade to Sema produced an additive effect on fat mass (-54.2%). This combination also increased lean mass by 9.8% vs a 1.9% loss with Sema alone. To test this in primates, we performed a 20-week study with the combined administration of either Sema + ∝-MSTN or Sema + ∝-MSTN and ∝-ActA in obese male cynomolgus monkeys. The combination of ∝-MSTN + Sema was sufficient to cause an additive effect on fat mass -43.9% vs -25.1% for Sema alone. The addition of ∝-ActA to the combination produced a similar reduction in fat (-49.6%). The Sema control group also lost -2.5% lean mass after 20 weeks; despite the significant reduction in fat mass, the addition of ∝-MSTN to Sema slightly increased lean mass over the same period (0.5%); the addition of ∝-ActA increased lean mass even further (6.2%). These data suggest the blockade of MSTN and ActA to GLP-1RA treatment could greatly improve the quality of weight loss with this class of anti-obesity agents. Disclosure J.Mastaitis: Employee; Regeneron Pharmaceuticals Inc., Stock/Shareholder; Regeneron Pharmaceuticals Inc. D.Gomez: Employee; Regeneron Pharmaceuticals Inc., Stock/Shareholder; Regeneron Pharmaceuticals Inc. V.Le rouzic: Employee; Regeneron Pharmaceuticals Inc., Stock/Shareholder; Regeneron Pharmaceuticals Inc. M.Stec: Employee; Regeneron Pharmaceuticals Inc., Stock/Shareholder; Regeneron Pharmaceuticals Inc. N.Khan: Employee; Regeneron Pharmaceuticals Inc., Stock/Shareholder; Regeneron Pharmaceuticals Inc. E.Na: Employee; Regeneron Pharmaceuticals Inc., Stock/Shareholder; Regeneron Pharmaceuticals Inc. T.Mcwilliams: None. S.Min: Employee; Regeneron Pharmaceuticals Inc., Stock/Shareholder; Regeneron Pharmaceuticals Inc. M.Sleeman: Employee; Regeneron Pharmaceuticals Inc. Funding Regeneron Pharmaceuticals Inc.

1380-P: Heterogeneity in the Association of Diet and Obesity in Asian, Pacific Islander, and Multiracial People

Background: Disaggregation of Asian, Pacific Islander (PI), and multiracial API people is needed to assess the subgroup-specific impact of diabetes. This study examined the association between diet quality and obesity. Methods: We used CVD case-control data from two integrated healthcare systems. Diet was measured using the Rapid Eating and Activity for Patient Survey. Results: Among all groups, Native Hawaiians had the lowest mean diet quality while Asian Indians had the highest diet quality (Table 1). Better diet was associated with lower odds of obesity in all groups except Japanese, Native Hawaiian, Other PI, and some multiracial groups after adjustment (Table 2). Conclusion: For some race groups better diet quality was associated with lower odds of obesity. Future work should examine groups where this was not the case. Disclosure S.L.Gibbs: None. A.M.Bacong: None. T.B.Frankland: Research Support; Pfizer Inc., Stock/Shareholder; AbbVie Inc., Pfizer Inc., CVS Health Corp, Regeneron Pharmaceuticals Inc. J.Li: None. Y.G.Daida: Research Support; GlaxoSmithKline plc. L.Palaniappan: None. S.P.Fortmann: Research Support; Pfizer Inc. Funding National Heart, Lung, and Blood Institute (R01HL126172)

1608-P: Phenotype of Liver-Specific MC3R Knockout Mice

The melanocortin 3 receptor (MC3R) is a key regulator of energy homeostasis and feeding behavior. Global Mc3r knockout mice exhibit greater fat mass and reduced lean mass. Our previous research has found that Mc3r transcripts can be detected in liver and the MC3R deficiency phenotype is partially reversed in liver-specific MC3R recovery mice on a chow diet, in both male and female mice, and high fat diet, in females only. To further examine the role of hepatic MC3R, we produced a liver-specific Mc3r knockout model by crossing mice expressing albumin-Cre recombinase (Alb-Cre+/+) to mice with a floxed Mc3r gene (LoxP+/+), and placed them on a 45 kcal% energy from fat diet for 12 weeks. Female liver-specific Mc3r-deficient mice with diet-induced obesity displayed nonsignificant trends towards worsened glucose tolerance during a glucose tolerance test (glucose AUC Lox+/+, Alb-Cre+/+: n=10, 24036±1644; Alb-Cre+/+: n=10, 19745±1364; BL/6: n=11, 21072±1152 min*mg/dL, p=0.059) and insulin resistance during a glucose tolerance test (glucose AUC LoxP+/+, Alb-Cre+/+: n=10, 14938±812.2;Alb-Cre+/+: n=14, 13062±850; BL/6: n=11, 11725±1024 min*mg/dL, p=0.12), but no differences in morning serum C-peptide (LoxP+/+, Alb-Cre+/+: n=8, 0.74±0.07; Alb-Cre+/+: n=4, 0.55±0.15; BL/6: n=8, 0.29±0.05 ng/mL, p=0.32). Similar patterns were observed for total food consumption (LoxP+/+, Alb-Cre+/+: n=10, 37.2±1.2; Alb-Cre+/+: n=15, 34.5±0.7; BL/6: n=10, 35.7±1.4 g/15 days, p=0.082), with no differences in feeding efficiency (LoxP+/+, Alb-Cre+/+: n=10, 0.027±0.008; Alb-Cre+/+: n=15, 0.009±0.011; BL/6: n=10, 0.017±0.025 g/kcal, p=0.19). No notable trends were observed in male mice. These data suggest that hepatic Mc3r deficiency alone is at most a minor contributor to the obesity phenotypes associated with HFD-treated Mc3r-deficient mice. Additional analysis of tissue samples from these mice and future studies examining Mc3r function in the liver will further elucidate the role of hepatic MC3R. Disclosure J.Chen: None. J.K.Elmquist: Research Support; Regeneron Pharmaceuticals Inc. J.A.Yanovski: Research Support; Hikma Pharmaceuticals, Rhythm Pharmaceuticals, Inc., Soleno Therapeutics, Inc., Versanis Bio Inc. T.P.Patel: None. A.Jain: None. D.Elizondo: None. E.K.Altman: None. N.Tugarinov: None. M.Hollis: None. R.Roberson: None. A.Caron: None.

1242-P: Obesity Disparities in a Multiracial Sample of Asian American and Pacific Islander (API) Adults

Background: Asians have higher diabetes rates than Non-Hispanic white (NHW) people, despite having lower BMI. Studies on Asians often present monoracial groups. We examined obesity rates among mono- and multiracial APIs. Methods: We examined obesity and other factors by self-reported race using case-control data from two integrated healthcare systems with large API populations. Results: Obesity varied by race, ranging from 8.5% (Chinese) to 53.5% (Other Pacific Islander) (Table 1). Obesity was high for multiracial API. Demographic, behavioral, and clinical factors explained some, but not all the differences in obesity rates (Table 2). Conclusion: Multiracial API people had higher obesity rates than monoracial API and NHW people. Robust data on multiracial people are needed to understand health disparities among this group. Disclosure A.M.Bacong: None. S.L.Gibbs: None. T.B.Frankland: Research Support; Pfizer Inc., Stock/Shareholder; AbbVie Inc., Pfizer Inc., CVS Health Corp, Regeneron Pharmaceuticals Inc. J.Li: None. Y.G.Daida: Research Support; GlaxoSmithKline plc. S.P.Fortmann: Research Support; Pfizer Inc. L.Palaniappan: None. Funding National Heart, Lung, and Blood Institute (R01HL126172)

Abstract P2-11-13: High PD-L2 Protein Expression in Cancer Cells is an Independent Marker of Unfavorable Prognosis in Luminal Breast Tumors

Abstract Background PD-1 inhibitors have shown significant efficacy in triple negative breast cancer (BC), however, durable responses are less common in estrogen receptor-positive (ER+) BC. Better markers are therefore needed that will identify likely responders to PD-1 inhibitors among patients with luminal BC. While most efforts have focused on the immune checkpoint protein PD-L1, the alternative PD-1 ligand, PD-L2, has been largely overlooked. We aimed to determine if PD-L2 is associated with unfavorable prognosis in ER+ BC. Methods PD-L2 protein levels in cancer cells and stromal cells were measured retrospectively by quantitative immunofluorescence histocytometry in tissue microarrays of therapy-naïve, localized or locoregional ER+ BC and correlated with progression-free survival (PFS). Evaluable tumor PD-L2 data were derived from a main study cohort A diagnosed between 1988-2005 (n=684) with extensive clinical and outcome data and from an independent validation cohort B diagnosed between 1992-2012 (n=273). Patients received standard-of-care adjuvant therapy without immune checkpoint inhibitors after tumor resection. Results Univariate analysis of the main cohort A revealed that high PD-L2 expression in cancer cells was associated with shorter PFS (HR=1.8; 95%CI:1.3-2.6; p=0.001), an observation that was validated in an independent cohort B (HR=2.3, 95%CI:1.1-4.8; p=0.026). Approximately one third of ER+ BC cases were classified as high PD-L2. After multivariable adjustment for common clinicopathological variables, high cancer cell levels of PD-L2 remained independently predictive of early recurrence (HR=2.0; 95%CI:1.4-2.9; p&amp;lt; 0.001). Sub-analysis of ER+ BC cases treated with adjuvant chemotherapy (n=197) suggested that high PD-L2 levels in cancer cells was associated with particularly increased risk of progression (multivariable HR=3.4; 95%CI:1.9-6.2; p&amp;lt; 0.001). The observed frequent expression of PD-L2 protein in BC provided scientific rationale for the design of our ongoing phase II clinical trial (NCT04243616) of neoadjuvant combined PD-1 inhibitor (cemiplimab; Regeneron Pharmaceuticals Inc) and chemotherapy in patients diagnosed with PD-L1+ and/or PD-L2+ BC. The primary objective of this trial is to assess pathologic responses to neoadjuvant treatment with secondary objective of assessing the correlation between PD-L1/PD-L2 status and tumor responses. Pathologist review of PD-L1 and PD-L2 expression in an initial set of ER+ tumors (n=15) screened for trial eligibility revealed frequent discordance between cancer cell positivity for PD-L1 and PD-L2 protein (PD-L1: median=0%; range 0-2% vs. PD-L2: median=18%; range &amp;lt; 1-60%) as well as immune cell positivity (PD-L1: median=5%; range 0-50% vs. PD-L2: median=0; range 0-50%). Conclusions In treatment-naïve ER+ breast tumors, high cancer cell expression of PD-L2 protein was an independent predictor of poor clinical outcome, with evidence of further elevated risk of progression in patients who received adjuvant chemotherapy. Preliminary analyses of ER+ tumors from our ongoing clinical trial showed frequent discordance between baseline PD-L1 and PD-L2 protein expression in both cancer cells and immune cells. Collectively, our analyses indicate that PD-L2 has prognostic value for ER+ BC, and our progress justify further studies to determine whether PD-L2, alone or in combination with PD-L1, may serve as a predictive marker of response to PD-1 inhibitors. Citation Format: Lubna N. Chaudhary, Inna Chervoneva, Amy R. Peck, Yunguang Sun, Misung Yi, John F. Langenheim, Julie M. Jorns, Sailaja Kamaraju, Yee Chung Cheng, John Burfeind, Christopher R. Chitambar, Jeffrey A. Hooke, Albert J. Kovatich, Craig Shriver, Hai Hu, Juan P. Palazzo, Marluce Bibbo, Terry Hyslop, Richard Pestell, Edith P. Mitchell, Hallgeir Rui. High PD-L2 Protein Expression in Cancer Cells is an Independent Marker of Unfavorable Prognosis in Luminal Breast Tumors [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-13.

1200-P: The Prevalence of Obesity-Associated Loss of Lean Muscle Mass

Sarcopenia, originally defined as age-related low muscle mass and function, has also been used to describe the loss of muscle mass and quality among certain populations, such as sarcopenic obesity (SO) . SO refers to loss of muscle and function in obese subjects; however, given age is not a factor in SO, we classified SO as obesity with low lean muscle mass (OLLMM) . Given the paucity of data in OLLMM, the purpose was to describe the prevalence of OLLMM in the US. Data from NHANES 2017-2018 were used to estimate the prevalence of OLLMM in adults ≥20 yrs of age. OLLMM was defined as DEXA-assessed low appendicular lean mass, adjusted for BMI (men &amp;lt;0.789, women &amp;lt;0.512) and obesity (body fat%: men &amp;gt;25%, women &amp;gt;35%) . Since DEXA was only measured in those aged 20-59 in NHANES 2017-2018, we utilized logistic regression models to predict OLLMM from NHANES 1999-20for those ≥60 yrs. The prevalence of OLLMM was estimated overall, by sex, age group, and diabetes status (prediabetes and T2DM) . We extrapolated results to the US using NHANES sampling weights. Of the 4174 adults (representing 181M US adults) , we identified 827 (28.8M, 15.9% of the US pop.) with OLLMM. Older adults had higher prevalence of OLLMM as did those with prediabetes and T2DM (Figure 1) . The prevalence of OLLMM in the US is high. While the prevalence of OLLMM was higher with age, its prevalence was also high in diabetics, regardless of age. Clinicians should monitor for OLLMM among obese T2DM patients. Disclosure D.J. Murdock: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. N. Wu: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. D.J. Glass: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. J.S. Grimsby: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. R.A. Calle: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. S. Donahue: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. M. Sleeman: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. R.J. Sanchez: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. Funding Supported by Regeneron Pharmaceuticals, Inc.

1198-P: Prevention of COVID-with Subcutaneous Administration of CAS+IMD in Individuals with Diabetes and Other Risk Factors for Severe Disease

Background: Subcutaneous (SC) administration of the monoclonal antibody combination casirivimab and imdevimab (CAS+IMD) decreased the risk of COVID-in a phase 3 trial of uninfected adolescents/adults who shared a household with a SARS-CoV-2–infected individual (NCT04452318) . Here, we present a subgroup analysis of this study, assessing the efficacy and safety of CAS+IMD in preventing symptomatic COVID-in individuals with diabetes and other risk factors for progression to severe disease. Methods: Healthy individuals aged ≥12 years, identified within 96 hours of collection of a positive test from a household contact, were randomized 1:1 to receive SC CAS+IMD 1200 mg or placebo. The primary endpoint was the proportion of participants who developed symptomatic COVID-during the 28-day efficacy assessment period among those who were SARS-CoV-2 RT-qPCR negative at baseline. Post hoc analyses assessed efficacy and safety by diabetes history, body mass index (BMI) , and the presence/absence of ≥1 high-risk factor for severe COVID-19. Results: The efficacy analysis included 2067 participants who were enrolled from July 13, 2020–January 28, 2021 and were RT-qPCR negative at baseline. In participants with diabetes (n=139) , the relative risk reduction (RRR) of developing symptomatic COVID-with CAS+IMD vs. placebo was 76.3%. Similar results were observed in participants with BMI ≥30 kg/m2 (n=728; RRR=74.9%) and in those with ≥1 high-risk factor for severe COVID-at baseline (n=620; RRR=77.5%) . Across subgroups, injection-site reaction was more common with CAS+IMD versus placebo whereas asymptomatic COVID-19, COVID-19, and headache were more common with placebo versus CAS+IMD. Conclusions: In study participants with diabetes and those with other risk factors for severe COVID-19, treatment with SC CAS+IMD decreased the risk of developing symptomatic COVID-19, consistent with results in the overall population. Disclosure M.O'brien: Employee; Regeneron Pharmaceuticals Inc., Other Relationship; Regeneron Pharmaceuticals Inc., Stock/Shareholder; Regeneron Pharmaceuticals Inc. R.V.Barnabas: Other Relationship; Regeneron Pharmaceuticals Inc. M.S.Cohen: Other Relationship; COVPN, Fogarty, HPTN, McGill, National Institutes of Health, Prime Global Options, Regeneron Pharmaceuticals Inc. A.Mahmood: Employee; Regeneron Pharmaceuticals Inc., Stock/Shareholder; Regeneron Pharmaceuticals Inc. G.A.Herman: Employee; Regeneron Pharmaceuticals Inc., Other Relationship; Regeneron Pharmaceuticals Inc., Stock/Shareholder; Regeneron Pharmaceuticals Inc. G.D.Yancopoulos: Employee; Regenacy Pharmaceuticals, Inc., Other Relationship; Regeneron Pharmaceuticals Inc., Stock/Shareholder; Regeneron Pharmaceuticals Inc. D.M.Weinreich: Employee; Regeneron Pharmaceuticals Inc., Stock/Shareholder; Regeneron Pharmaceuticals Inc. The covid-phase 3 prevention trial team: n/a. E.Forleo-neto: Employee; Regeneron Pharmaceuticals Inc., Stock/Shareholder; Regeneron Pharmaceuticals Inc. E.Oviedo orta: Employee; Regeneron Pharmaceuticals Inc., Stock/Shareholder; Regeneron Pharmaceuticals Inc. J.Mcginniss: Employee; Regeneron Pharmaceuticals Inc., Stock/Shareholder; Regeneron Pharmaceuticals Inc. P.Hou: Employee; Regeneron Pharmaceuticals Inc., Stock/Shareholder; Regeneron Pharmaceuticals Inc. F.Isa: Employee; Regeneron Pharmaceuticals Inc., Other Relationship; Regeneron Pharmaceuticals Inc., Stock/Shareholder; Regeneron Pharmaceuticals Inc. K.Chan: Employee; Regeneron Pharmaceuticals Inc., Stock/Shareholder; Regeneron Pharmaceuticals Inc. N.Sarkar: Employee; Regeneron Pharmaceuticals Inc., Stock/Shareholder; Regeneron Pharmaceuticals Inc. B.J.Musser: Employee; Regeneron Pharmaceuticals Inc., Stock/Shareholder; Regeneron Pharmaceuticals Inc. Funding Supported by Regeneron Pharmaceuticals, Inc., and F. Hoffmann-La Roche Ltd. This trial was conducted jointly with the COVID-Prevention Network, which was funded by the National Institute of Allergy and Infectious Diseases (NIAID) , National Institutes of Health (NIH) .

47-OR: Efficacy, Durability, and Safety of Faricimab in Diabetic Macular Edema: Two-Year Results from the Phase 3 YOSEMITE and RHINE Trials

Diabetic macular edema (DME) is a major cause of vision loss for people with diabetes. Intravitreal anti-vascular endothelial growth factor (VEGF) therapy is the standard of care for DME; however, there is an unmet need for new strategies that address the multifactorial nature of DME, reduce treatment burden, and optimize patient outcomes. Angiopoietin-2 and VEGF-A synergistically drive vascular instability in DME; therefore, dual pathway inhibition with faricimab, the first bispecific antibody designed for intraocular use, may promote vascular stability and durable efficacy beyond current anti-VEGF therapies. YOSEMITE (NCT03622580) and RHINE (NCT03622593) were randomized, double-masked, active comparator-controlled, phase 3 trials designed to assess the efficacy, durability, and safety of faricimab in patients with DME (YOSEMITE, N = 940; RHINE, N = 951) . Patients were randomized 1:1:1 to faricimab 6.0 mg every 8 weeks (Q8W) after 6 initial every-4-week (Q4W) doses, faricimab 6.0 mg per personalized treatment interval (PTI) after 4 initial Q4W doses, or aflibercept 2.0 mg Q8W after 5 initial Q4W doses. The PTI algorithm was a protocol-driven treat-and-extend regimen, with dosing intervals extended, maintained, or reduced (from Q4W up to every 16 weeks [Q16W]) based on prespecified vision and anatomic criteria. Efficacy and safety endpoints were assessed at Q4W study visits through week 100. At 1 year, faricimab Q8W or per PTI offered durable vision gains that were noninferior to aflibercept Q8W and were achieved with Q16W dosing in &amp;gt; 50% of patients in the PTI arms. Faricimab Q8W or per PTI demonstrated anatomic improvements versus aflibercept Q8W and was well tolerated, with low rates of intraocular inflammation. Year 2 results from YOSEMITE/RHINE will be presented at the meeting, and will examine whether early vision gains, anatomic improvements, and extended (up to Q16W) dosing with faricimab are maintained over 2 years. Disclosure C.J. Danzig: Advisory Panel; Genentech, Inc. Consultant; Adverum Biotechnologies, Genentech, Inc., Novartis Pharmaceuticals Corporation, Regeneron Pharmaceuticals Inc. Research Support; Adverum Biotechnologies, Genentech, Inc., Kodiak Pharmaceuticals, Novartis Pharmaceuticals Corporation, Regeneron Pharmaceuticals Inc., Roche Pharmaceuticals. Speaker's Bureau; Novartis Pharmaceuticals Corporation. J.A. Wells: Advisory Panel; Genentech, Inc. Research Support; Adverum, Alimera, Bayer AG, DRCR Retina Network, Genentech, Inc., Gyroscope, Iveric, Kodiak, Lowy Medical institute, Regeneron Pharmaceuticals Inc. D. Eichenbaum: Consultant; Genentech, Inc., Regeneron Pharmaceuticals Inc. Research Support; Bayer AG, Genentech, Inc., Regeneron Pharmaceuticals Inc. Speaker's Bureau; Bayer AG, Genentech, Inc. J.I. Lim: Consultant; Cognition, Eyenuk, Genentech, Inc., Iveric Bio, Novartis AG, Quark, Santen, Luxa, Veridian, Aura, Unity. Research Support; Aldeyra, Chengdu Pharmaceuticals, Regeneron Pharmaceuticals Inc., Stealth, NGM. K. Asik: None. Z. Haskova: Employee; Genentech, Inc. S. Mohan: None. D. Silverman: Employee; Roche Pharmaceuticals. Y. Tang: Employee; Genentech, Inc. H. Lin: Employee; Genentech, Inc. Funding F. Hoffmann-La Roche Ltd. (Basel, Switzerland)

1084-P: Trends in Cardiovascular Risk Factors (CRF) for Youth with Incident Diabetes: The SEARCH for Diabetes in Youth Study

To examine CRF trends that may impact future CVD risk, the SEARCH study assessed CRF for diabetes-related complications in incident cohorts established from 2002 - 2016. Linear regression was used to assess trends over each incident year for non-HDL-c, LDL-c, VLDL-c, TG, BMI z-score, systolic and diastolic blood pressure (BP) z-scores, albumin/creatinine ratio (ACR) and eGFR. Models were stratified by diabetes type (Type 1, N=4600; Type 2, N=932) , adjusted for age at diagnosis, sex, DM duration and race/ethnicity. An interaction analysis was conducted to assess differential time trends by type. For youth with type 1, non-HDL-c, BP, BMI and ACR &amp;gt;30 decreased while HDL-c increased over time. For youth with type 2, non-HDL-c, and eGFR decreased, and BMI increased over time (table) . Significant time change interactions by type were seen for HDL-c and for BMI z-score and BP measures (table) .We observed small but significant changes in several CRFs over time in youth with incident DM, especially lipids, with greater improvements seen in youth with type 1. Youth with type 2 had worsening trends over time in BMI, BP, and kidney function. Further research is needed to better understand these trends and their implications for long term CVD risk. Disclosure R.A.Bell: None. A.D.Liese: None. E.Lustigova: None. S.M.Marcovina: None. L.Merjaneh: None. D.J.Pettitt: n/a. C.Pihoker: None. A.S.Shah: None. A.M.South: None. L.E.Wagenknecht: None. J.Rigdon: None. A.Bellatorre: None. D.Dabelea: None. R.Dagostino: Consultant; Aetion, Inc., AstraZeneca, Biogen, Bristol-Myers Squibb Company, Daiichi Sankyo, Merck &amp; Co., Inc. J.Divers: None. L.M.Dolan: None. G.Imperatore: None. E.T.Jensen: Consultant; Regeneron Pharmaceuticals Inc. Funding Centers for Disease Control and Prevention U18DP006131

92-OR: Persistence of Impaired Awareness of Hypoglycemia, Severe Hypoglycemic Events, and Suboptimal Glycemic Control Despite Advanced Diabetes Technologies

Trials of continuous glucose monitors (CGMs) and hybrid closed-loop systems (HCLS) demonstrate improvements in glycemia with reductions in hypoglycemia in T1D, but there is limited real-world data on how these technologies impact the prevalence of impaired awareness of hypoglycemia (IAH) , severe hypoglycemic events (SHEs) , and glycemic control. We conducted a one-time online survey of adults with T1D in the T1D Exchange Registry and online communities. Self-reported medical histories (insulin delivery method, HbA1c, IAH, SHEs) and CGM data were collected. 2044 patients (mean age 43 y, mean T1D duration 26 y, 72% female, 95% White) completed the survey. Most reported using CGMs (92%) ; 953 also used HCLS. Mean HbA1c was 6.89%; 41.5% had an HbA1C of ≥7%; 30.7% reported IAH; 19.8% had ≥1 SHE in the prior year; 12.0% had ≥2 SHEs in the prior year; 9.6% had IAH + ≥1 SHE; and 6.6% had IAH + ≥2 SHEs (Table) . Rates of SHEs and IAH + SHEs were lower in CGM users and CGM + HCLS users than in non-CGM users; however, among CGM + HCLS users, 16.6% reported ≥1 SHE, 8.7% ≥2 SHEs, 7.8% IAH + ≥1 SHE, and 4.7% IAH + ≥2 SHEs. Also, 35.6% of CGM + HCLS users had an HbA1C of ≥7%. In a patient cohort with high rates of technology adoption, rates of SHEs and IAH remained high, with a significant proportion of patients not achieving targeted glycemic control, indicating the need for novel T1D treatments. Disclosure J. Pettus: Advisory Panel; Lilly, MannKind Corporation, Novo Nordisk, Sanofi. Consultant; Carmot Therapeutics, Inc., Diasome. L. Titievsky: Employee; Intercept Pharmaceuticals, Inc., Pfizer Inc., Vertex Pharmaceuticals Incorporated. Stock/Shareholder; Intercept Pharmaceuticals, Inc., Pfizer Inc., Vertex Pharmaceuticals Incorporated. K. Hagan: Employee; Vertex Pharmaceuticals Incorporated. T. Liu: Employee; Takeda Pharmaceutical Company Limited, Vertex Pharmaceuticals Incorporated. Stock/Shareholder; Seattle Genetics, Inc. K. Chandarana: Employee; Vertex Pharmaceuticals Incorporated. J.L. Gaglia: Advisory Panel; Dompé, Regeneron Pharmaceuticals Inc. Consultant; Vertex Pharmaceuticals Incorporated. Research Support; Avotres Inc., Dompé, Janssen Research &amp; Development, LLC, Provention Bio, Inc. Stock/Shareholder; Vertex Pharmaceuticals Incorporated. W. Wolf: None. J. Bispham: Employee; PPD Inc., T1D Exchange. K.S.M. Chapman: None. D. Finan: None. J. Sherr: Advisory Panel; Bigfoot Biomedical, Inc., Cecelia Health, Insulet Corporation, Medtronic, Vertex Pharmaceuticals Incorporated. Consultant; Insulet Corporation, Lexicon Pharmaceuticals, Inc. Research Support; Dexcom, Inc., Insulet Corporation, Jaeb Center for Health Research, JDRF, Medtronic, National Institute of Diabetes and Digestive and Kidney Diseases. Speaker's Bureau; Lilly Diabetes.