Regeneron Pharmaceuticals Research Articles

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: MZL is a heterogeneous disease comprising 3 subtypes, extra-nodal MZL of mucosa-associated lymphoid tissue, nodal MZL, and splenic MZL. Treatment of R/R MZL is similar to other indolent B-cell non-Hodgkin lymphoma (B-NHL) subtypes (e.g., follicular lymphoma [FL]), comprising rituximab-based immunochemotherapy regimens that achieve an objective response rate (ORR) of ∼45%–80%. Options after progression on rituximab-based regimens include the BTK inhibitor ibrutinib, which demonstrated an ORR of 46%, but a compete response (CR) rate of only 3%, in its pivotal trial in R/R MZL. Overall, limited options are available after progression on current therapies, and a need remains for more effective treatments for R/R MZL. Odronextamab is a bispecific antibody that binds CD20-expressing B-NHL cells and CD3 on T cells. In the Phase 1 ELM-1 study, odronextamab monotherapy showed antitumor activity and a manageable safety profile in a range of R/R B-NHL subtypes, including MZL (n = 6; ORR 67%) (Bannerji et al. Lancet Haematol, 2022). In the Phase 2 ELM-2 study, odronextamab elicited an ORR of 82% and CR rate of 75% in patients with heavily pretreated R/R FL (Kim, et al. ASH, 2022). These positive data in an indolent B-NHL subtype support evaluation of odronextamab in R/R MZL. Methods: ELM-2 (NCT03888105) is an open-label study of odronextamab in patients with R/R B-NHL comprising 5 disease-specific cohorts: FL, diffuse large B-cell lymphoma, mantle cell lymphoma, MZL, and other B-NHLs. Each cohort will be evaluated separately, and patients recruited from sites across North America, Europe, and Asia-Pacific regions. The MZL cohort is planned to include 78 patients, who will receive IV odronextamab monotherapy until disease progression or other protocol-defined reason for treatment discontinuation. Odronextamab is administered according to a step-up regimen during the first 21-day cycle (C), consisting of 0.7 mg split over C1 Day (D) 1 (0.2 mg) and C1D2 (0.5 mg), 4 mg split over C1D8 and C1D9, and 20 mg split over C1D15 and C1D16. The full 80 mg dose is given QW during C2 to C4, then 160 mg Q2W from C5 onwards. If a patient achieves a CR and has a durable response for ≥9 months after initial determination of the CR, then dosing interval will be decreased from Q2W to Q4W. Patients eligible for the MZL cohort will be ≥18 years of age; relapsed/refractory to ≥2 prior lines of systemic therapy; ECOG performance status ≤1; and have adequate bone marrow and hepatic functions. Patients with prior allogeneic stem cell transplant or CAR T treatment will be excluded. Primary endpoint is ORR (Lugano classification; assessed by independent central review). Key secondary endpoints include ORR (investigator evaluation); CR rate; progression-free survival; overall survival; duration of response; safety; pharmacokinetics; and patient-reported quality of life outcomes. As of January 2023, 19 patients with MZL had enrolled. Encore Abstract—previously submitted to ASCO 2023 and EHA 2023 The research was funded by: Regeneron Pharmaceuticals, Inc. Keywords: indolent non-Hodgkin lymphoma, immunotherapy, ongoing trials Conflicts of interests pertinent to the abstract. T. M. Kim Consultant or advisory role Boryung, AstraZeneca/MedImmune, Takeda, Novartis, Janssen, Hanmi, and Regeneron Pharmaceuticals, Inc Honoraria: Takeda, Janssen, Regeneron Pharmaceuticals, Inc, Samsung Bioepis, and AstraZeneca Research funding: Celgene, Boryung, Boehringer-Ingelheim, BMS, Bayer, AstraZeneca/MedImmune, Takeda, Roche/Genentech, Novartis, Janssen, Hanmi, Genmab, Merck Serono, Merck Sharp & Dohme, Regeneron Pharmaceuticals, Inc, and Sanofi M. Taszner Consultant or advisory role Roche and Takeda Honoraria: Roche, Takeda, Novartis, and Servier Educational grants: Roche A. Chaudhry Employment or leadership position: Regeneron Pharmaceuticals, Inc Stock ownership: Regeneron Pharmaceuticals, Inc M. Ufkin Employment or leadership position: Regeneron Pharmaceuticals, Inc Stock ownership: Regeneron Pharmaceuticals, Inc A. Uppala Employment or leadership position: Regeneron Pharmaceuticals, Inc Stock ownership: Regeneron Pharmaceuticals, Inc A. Sabir Employment or leadership position: Regeneron Pharmaceuticals, Inc Stock ownership: Regeneron Pharmaceuticals, Inc H. Mohamed Employment or leadership position: Regeneron Pharmaceuticals, Inc Stock ownership: Regeneron Pharmaceuticals, Inc S. Ambati Employment or leadership position: Regeneron Pharmaceuticals, Inc Stock ownership: Regeneron Pharmaceuticals, Inc E. Bachy Consultant or advisory role Roche, Gilead, ADC Therapeutics, Takeda, Novartis, and Incyte Honoraria: Kite, Gilead, Novartis, Roche, Incyte, Miltenyi Biotech, Takeda, and Sanofi Research funding: Amgen and BMS

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Radiotherapy (RT) is beneficial for select patients with localized diffuse large B cell lymphoma (DLBCL), in both early stage and in relapsed/refractory settings. Genomic predictors of local response to RT have yet to be adequately explored. We sought to identify genomic signatures of radiosensitivity in localized DLBCL. Methods: We analyzed our database of DLBCL patients with localized measurable disease treated with RT between 2007 and 2022 with pre-existing targeted exome sequencing. This included both Ann Arbor stage I/II patients and those with isolated sites of relapsed/refractory disease in order to increase cohort size. The public NCI LymphGen algorithm was used to further classify genomic subgroups. Using Fisher’s exact test and logistic regression we tested for univariable correlation between specific gene alterations and LymphGen subgroups with initial radiation response, defined by Lugano criteria and decrease in maximum SUV. Results: We identified 38 patients with 52 irradiated tumors. The median (range) RT dose was 36 Gy (4–54), with 35 (67%) tumors receiving at least 30 Gy. 21 (40%) tumors were treated in the early stage setting (10% definitively, 90% as consolidation), while 31 (60%) were treated in the localized relapsed/refractory setting. 54% of tumors were GCB subtype, 31% were ABC subtype, and 15% were not classified. The median (range) of prior lines of systemic therapy were 1 (0–2) and 1 (1–7) in the early stage and localized relapsed/refractory settings respectively. The median (range) lesion SUV at the time of RT was 7.7 (1.1–46.0). 48% of tumors were in complete response (CR) at time of first imaging after RT (median 3.12 months) and the mean (SD) percent decrease in SUV was 60% (43%). The most commonly altered individual genes were KMT2D (37%), MYD88 (33%), and TP53 (31%). LymphGen classified 21% of cases as EZB subtype, 14% as MCD, 2% as BN2, 2% as ST2; 62% were unclassified. Alteration in ETV6 (13% of tumors) was associated with a significantly higher CR rate in response to RT (86% with alteration, 42% without, p = 0.046). After restricting each patient to their first course of RT, ETV6 alteration trended towards significantly higher CR (83% with alteration, 34% without, p = 0.06). Lesions with vs. without ETV6 alteration had similar SUV (p = 0.88) and size (p = 0.8) at time of RT. Alteration in ETV6 (p < 0.0001), PIM1 (p < 0.0001), MYD88 (p < 0.0001), and TNFAIP3 (p = 0.01) were associated with greater reductions in SUV. The LympGen MCD subgroup trended towards increased odds of CR post-RT (log odds 1.9, p = 0.078) and greater reduction of SUV (p = 0.12) compared to the EZB subgroup. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Genomics, Epigenomics, and Other -Omics, Radiation Therapy Conflicts of interests pertinent to the abstract. G. Salles Consultant or advisory role: AbbVie, Aptitude Health, Bayer, BeiGene, Ltd., Bio Ascend, Bristol-Myers Squibb, Celgene, Epizyme, Everest Clinical Research Corporation, GenMab, Genentech, Gilead Pharmaceutical, Incyte, Ipsen, Janssen Pharmaceuticals, Inc., Loxo Oncology, Miltenyi Biotec Incorporated, MorphoSys AG, Nordic Nanovector ASA, Novartis, Physicians' Education Resource, RAPT Therapeutics, Regeneron Pharmaceuticals, Inc., Roche, Scientific Education Support Ltd., Takeda Millennium Stock ownership: Owkin, Inc.

(247) Complication Rates After Penile Prostheses In Men with History of Priapism – A Retrospective Claims Database Cohort Analysis

Abstract Introduction Penile prostheses can be placed in men with a history of priapism who develop erectile dysfunction, or as initial management of acute ischemic priapism. However, little is known about long-term complications associated with prostheses in these men. Objective To assess the risk of penile prosthesis complications in men with a history of priapism. Methods We searched the TriNetX insurance claims database to create a cohort of men ages ≥16 years old with 1) a diagnosis of priapism (ICD-10: N48.4), 2) a diagnosis of erectile dysfunction (ICD-10: N52), and 3) had undergone prosthesis placement (insertion of penile prosthesis inflatable and self-contained [CPT: 54401], insertion of semi-rigid penile prosthesis [CPT 54400], or insertion of multiple component inflatable penile prosthesis [CPT: 54405]). Three complications were assessed: penile prosthesis infection (ICD-10: T83.61), penile prosthesis mechanical breakdown (ICD-10: T83.410A), and penile prosthesis displacement or migration (ICD-10: T83.420). Rates of and duration to IPP removal (CPT: 54415-17, 54406, 54410-11) were also assessed. To compare rates of complications, the priapism cohort was compared to a cohort of men with a diagnosis of erectile dysfunction and prosthesis placement but without a history of priapism or corpora cavernosal irrigation, matched by age, race, diabetes status, and obesity (E66). When assessing risk of prosthesis complications, we utilized 1:1 greedy nearest-neighbor propensity score matching to control for confounding variables. Results A total of 665 men were identified with a diagnosis of priapism and erectile dysfunction who subsequently received a penile prosthesis. A control group of 31,345 patients with erectile dysfunction and a penile prosthesis but without priapism or history of irrigation was identified, and ultimately 660 men in the case and control cohorts were matched by age, race, diabetes status, and obesity. Men of with a history of priapism were more likely to experience penile prosthesis infection (5.0% vs 2.7%; Risk Ratio (RR): 1.83, 95% Confidence Interval (CI) 1.04-3.22) and mechanical breakdown of the prosthesis (7.3% vs 3.8%, RR: 1.92, 95%CI 1.20-3.08). There was no difference in the rate of penile prosthesis displacement or migration (3.5% vs 2.4%, RR: 0.76, 95%CI 0.77-2.70). Overall rates of penile prosthesis explantation were higher in men with a history of priapism 14.6% vs 8.4% (RR: 1.73, 95%CI 1.27-2.36). Rates of early explantation (within 6 months of placement) were similar between the two groups, 3.3% vs 2.9% (RR: 1.16, 95%CI 0.63-2.11). Rate of explantation of semi-rigid prostheses were significantly higher in men with a history of priapism, 27% vs 9.6% (RR: 2.54, 95%CI 1.62-3.93). Of the 17 men undergoing explantation of semi-rigid prosthesis with history of priapism, only 4 men (23%) went on to have a 3-piece penile prosthesis placed. Conclusions In this US claims-based database comparison between prosthetic complications in men with and without a history of priapism, men with priapism were more likely to experience infection, mechanical breakdown and explantation. There was no difference in rate of device displacement or migration, or in timing of device explantation. This real-world data provides context for counseling men with priapism who undergo prosthesis placement. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Urogen Pharma, Janssen Global Services, Regeneron Pharmaceuticals

(111) Clinical Practice Patterns for Surgical Shunts and Penile Prosthesis Placement in Men with Priapism – A Retrospective Claims Database Analysis

Abstract Introduction New AUA/SMSNA guidelines for management of acute ischemic priapism have been released, but actual practice patterns can be difficult to assess as overall incidence is low and men often seek care at multiple institutions. Objective To assess the rates of surgical shunting and prosthetic placement for acute ischemic priapism using a large multi-institutional claims database. Methods A US claims database network (TriNetX Diamond Network) was queried from 2010 to 2020. We constructed a cohort of men ages ≥16 years old with 1) a diagnosis of priapism (ICD-10: N48.4) and 2) who had undergone an irrigation of the corpora cavernosa for priapism (CPT: 54220). We assessed the number of men who then had a surgical penile shunt (corpora cavernosa-glans penis fistulation [CPT: 54435], corpora cavernosa-corpus spongiosum shunt [CPT: 54430], or corpora cavernosa-saphenous vein shunt [CPT: 54420]) or penile prosthesis placement (insertion of penile prosthesis inflatable and self-contained [CPT: 54401], insertion of semi-rigid penile prosthesis [CPT 54400], or insertion of multiple component inflatable penile prosthesis [CPT: 54405]). Time to surgical procedure and order of procedures were collected, as well as background information including age, race, diabetes status (ICD-10: E11), hyperlipidemia status (ICD-10: E78), sickle cell status (ICD-10: D57.0-1), and if men were classified to have drug-induced priapism (ICD-10: N48.33). Results 6,392 men were identified with the diagnosis of priapism and the procedure of corpora cavernosa irrigation. Of these men, 693 (11%) proceeded to surgical shunt (94 had corpora cavernosa-glans penis fistulation, 321 men had corpora cavernosa-corpus spongiosum shunt, and 78 men had corpora cavernosa-saphenous vein shunt). 144 men (2%) underwent initial penile prosthesis placement (Figure 1). Of the men undergoing initial penile prosthesis 94 (65%) occurred within the first year of the initial corpora cavernosal irrigation with the majority (81 of 94, 86%) being 3-piece inflatable penile prostheses and the majority in a “delayed” manner between 3 to 12 months after initial priapism irrigation (Table 1). Men who underwent initial penile prosthesis placement were older (55.1±13.0 vs 43.0±13.7 years, p&amp;lt;0.0001) and more often white (23% vs 16%, p=0.03), with higher rates of erectile dysfunction (56% vs 9%, p&amp;lt;0.0001), type 2 diabetes (32% vs 13%, p&amp;lt;0.0001), and hyperlipidemia (47% vs 20%, p&amp;lt;0.0001) when compared to men who underwent initial penile shunt procedure (Table 2). Finally, when assessing choice of initial shunts versus initial penile prosthesis pre- and post-2015, overall rates of initial shunt (10.0% vs 8.5%, p&amp;lt;0.0001) and initial prosthesis (3.1% vs 2.1%, p&amp;lt;0.0001) were significantly lower after 2015 when compared with rates prior to 2015. Conclusions In this US claims-based analysis of men presenting with ischemic priapism and treated with initial irrigation, we found that a small percentage (11%) continued to surgical shunting. Only 2% were managed with an initial prosthesis, most often a 3-piece device in a delayed manner. Men receiving initial prostheses were more likely to have more comorbidities, and overall surgical management of priapism has decreased overtime. In the setting of the new AUA/SMSNA guidelines, this data provides real-world practice patterns. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Urogen Pharma, Janssen Global Services, Regeneron Pharmaceuticals

Dupilumab for COPD with Type 2 Inflammation Indicated by Eosinophil Counts

BackgroundIn some patients with chronic obstructive pulmonary disease (COPD), type 2 inflammation may increase exacerbation risk and may be indicated by elevated blood eosinophil counts. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key drivers of type 2 inflammation.MethodsIn a phase 3, double-blind, randomized trial, we assigned patients with COPD who had a blood eosinophil count of at least 300 per microliter and an elevated exacerbation risk despite the use of standard triple therapy to receive dupilumab (300 mg) or placebo subcutaneously once every 2 weeks. The primary end point was the annualized rate of moderate or severe exacerbations of COPD. Key secondary and other end points that were corrected for multiplicity were the change in the prebronchodilator forced expiratory volume in 1 second (FEV1) and in the scores on the St. George’s Respiratory Questionnaire (SGRQ; range, 0 to 100, with lower scores indicating a better quality of life) and the Evaluating Respiratory Symptoms in COPD (E-RS–COPD; range, 0 to 40, with lower scores indicating less severe symptoms).ResultsA total of 939 patients underwent randomization: 468 to the dupilumab group and 471 to the placebo group. The annualized rate of moderate or severe exacerbations was 0.78 (95% confidence interval [CI], 0.64 to 0.93) with dupilumab and 1.10 (95% CI, 0.93 to 1.30) with placebo (rate ratio, 0.70; 95% CI, 0.58 to 0.86; P<0.001). The prebronchodilator FEV1 increased from baseline to week 12 by a least-squares (LS) mean of 160 ml (95% CI, 126 to 195) with dupilumab and 77 ml (95% CI, 42 to 112) with placebo (LS mean difference, 83 ml; 95% CI, 42 to 125; P<0.001), a difference that was sustained through week 52. At week 52, the SGRQ score had improved by an LS mean of −9.7 (95% CI, −11.3 to −8.1) with dupilumab and −6.4 (95% CI, −8.0 to −4.8) with placebo (LS mean difference, −3.4; 95% CI, −5.5 to −1.3; P=0.002). The E-RS–COPD score at week 52 had improved by an LS mean of −2.7 (95% CI, −3.2 to −2.2) with dupilumab and −1.6 (95% CI, −2.1 to −1.1) with placebo (LS mean difference, −1.1; 95% CI, −1.8 to −0.4; P=0.001). The numbers of patients with adverse events that led to discontinuation of dupilumab or placebo, serious adverse events, and adverse events that led to death were balanced in the two groups.ConclusionsAmong patients with COPD who had type 2 inflammation as indicated by elevated blood eosinophil counts, those who received dupilumab had fewer exacerbations, better lung function and quality of life, and less severe respiratory symptoms than those who received placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; BOREAS ClinicalTrials.gov number, NCT03930732.)

A Cross-Sectional Study of Home Blood Pressure Monitoring after Stroke (P11-5.015)

<h3>Objective:</h3> In individuals with hypertension, lowering blood pressure after stroke can lower the risk of stroke recurrence, but many patients do not reach goal. Home blood pressure monitoring (HBPM) can help patients achieve their goal. However, rates of use and quality of technique have not been evaluated, which we aim to evaluate in this cross-sectional study. <h3>Background:</h3> Hypertension (HTN) affects approximately 70% of patients with a recent stroke and treatment is highly effective in reducing risk for recurrence. In multiple studies the reduction of blood pressure, by life style changes or pharmacotherapy have significantly reduced the risk for fatal or non-fatal stroke. Therefore, blood pressure lowering is effective for secondary stroke prevention. <h3>Design/Methods:</h3> We conducted a cross-sectional study of patients with stroke. Patients were eligible if they had a stroke within two years, had hypertension, and lived at home. We classified patients as correctly performing HBPM if they used an arm cuff, sat ≥1 min before measurement, took ≥2 measurements, and use within 6 months. The primary outcome was determine HBPM was used correctly. Which we calculated according to race and ethnicity. We ask for additional steps if BP out of range. <h3>Results:</h3> Among 150 participants, 120 (81%) possessed a HBPM and 29 (21%) used it correctly. We observed no significant disparity in rates of possession or correct use between non-Hispanic White participants and participants from underrepresented groups. Seventy percent of non-Hispanic White patients said they would contact their provider if their BP was above goal vs. 52% of underrepresented patients (p=0.21). <h3>Conclusions:</h3> Most patients after stroke have a HBPM, but only about 1 in 5 use it correctly. Approximately half of patients from underrepresented racial or ethnic groups do not have a plan for responding to values above goal. Our results indicate opportunities to improve the dissemination and correct use of HBPM. <b>Disclosure:</b> Dr. Mariscal has nothing to disclose. Dr. Forman has nothing to disclose. Ms. Viscoli has nothing to disclose. Katherine Meuer has nothing to disclose. Dr. Sheth has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ceribell. Dr. Sheth has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Zoll. Dr. Sheth has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for NControl. Dr. Sheth has received stock or an ownership interest from Astrocyte. Dr. Sheth has received stock or an ownership interest from Alva. The institution of Dr. Sheth has received research support from Biogen. The institution of Dr. Sheth has received research support from Novartis. The institution of Dr. Sheth has received research support from Bard. The institution of Dr. Sheth has received research support from Hyperfine. Dr. Sheth has received intellectual property interests from a discovery or technology relating to health care. Dr. Sansing has nothing to disclose. Dr. De Havenon has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Integra. Dr. De Havenon has stock in Certus. The institution of Dr. De Havenon has received research support from NIH/NINDS. The institution of Dr. De Havenon has received research support from Regeneron Pharmaceuticals. The institution of Dr. De Havenon has received research support from AMAG Pharmaceuticals. The institution of Dr. De Havenon has received research support from AMGEN. Dr. De Havenon has received publishing royalties from a publication relating to health care. Dr. Sharma has nothing to disclose. Dr. Kernan has received personal compensation in the range of $50,000-$99,999 for serving as an Expert Witness for various law firms.

Acute and Subacute Neurovascular Impact of Cryptogenic Air Emboli (P12-5.020)

<h3>Objective:</h3> To describe a unique case of severe, delayed ischemia secondary to air embolism. <h3>Background:</h3> Accidental air embolism is a rare cause of ischemic stroke that is becoming increasingly well-described in the literature. However, the mechanism and severity of this type of injury can vary, with significant ischemia typically emerging early in the course of care. To our knowledge, delayed ischemia in this setting has rarely been described. <h3>Design/Methods:</h3> We describe a hospitalized patient who developed cryptogenic air emboli resulting in acute neurologic changes that appeared to improve with emergent care. However, follow up imaging revealed delayed ischemia not identified on initial radiography. <h3>Results:</h3> A stroke code was called for an unresponsive, hospitalized 75-year-old man. On evaluation, he was found to be obtunded with forced left gaze deviation concerning for possible non-convulsive status epilepticus (NCSE). He was treated acutely for seizure and subsequent stat CT head revealed air within the right greater than left hemispheric cortical veins with loss of sulcation, concerning for developing ischemia. On review of his hospitalization, prior TTE showed no PFO. Retrograde movement of air into the cortical veins was the hypothesized etiology,¹ but the source of the air in this case remains cryptogenic. MRI obtained 5.75 hours after the patient’s last known well showed subtle diffusion restriction without definitive cortical infarction and follow up CT head approximately 13 hours afterward showed near complete resolution of the air emboli. However, MRI 4 days later demonstrated diffusion restriction and cerebral edema throughout multiple vascular territories, consistent with venous infarction. <h3>Conclusions:</h3> This case highlights that venous air emboli can cause delayed ischemia that may not be appreciated on initial dedicated brain imaging. As such, affected patients may require intensive neurocritical care irrespective of initial radiographic findings. <b>Disclosure:</b> Dr. Gummerson has nothing to disclose. Dr. Parasram has nothing to disclose. Dr. Peng has nothing to disclose. Dr. Picard has nothing to disclose. Dr. Kahn has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biohaven. Dr. Kahn has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Chronius. Dr. Kahn has stock in Coaptech. Dr. Kahn has stock in Quantum Labs. Dr. Kahn has stock in FVC Health. Dr. Kahn has stock in TEO Science . Dr. Kahn has received intellectual property interests from a discovery or technology relating to health care. Dr. Angelus has nothing to disclose. Dr. Bhatt has nothing to disclose. Dr. De Havenon has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Integra. Dr. De Havenon has stock in Certus. The institution of Dr. De Havenon has received research support from NIH/NINDS. The institution of Dr. De Havenon has received research support from Regeneron Pharmaceuticals. The institution of Dr. De Havenon has received research support from AMAG Pharmaceuticals. The institution of Dr. De Havenon has received research support from AMGEN. Dr. De Havenon has received publishing royalties from a publication relating to health care. Dr. Jasne has nothing to disclose. Dr. Magid-Bernstein has nothing to disclose.

Impact of Insurance on Acute Stroke Care Cost: A mediation analysis (P1-5.022)

<h3>Objective:</h3> We hypothesized that LOS mediates the association between insurance status and hospital costs for acute stroke patients. <h3>Background:</h3> Length of stay (LOS) is a key quality indicator for stroke hospitalization, impacting costs, resource allocation, and transitions of care. Insurance status often affects stroke LOS through delayed authorization for rehabilitation services. <h3>Design/Methods:</h3> We queried data from a single comprehensive stroke center for all hospital admissions of adults (≥ 18 years) with any stroke (ICD10 I60–I69) from 2017 to 2021. We performed a mediation analysis using linear regression models to understand how much LOS carries the effect of various insurance plans on total acute stroke care cost using Medicare as the referent with age and race/ethnicity as covariates. We calculated non-parametric mediation metrics and bias-corrected-accelerated 95% confidence intervals from 10,000 bootstraps (p &lt;0.05). <h3>Results:</h3> The cohort included 3,604 hospitalized stroke patients: 52.16% men, median (IQR) age 68 (57 – 77) years. Median (IQR) LOS was 3 (1 – 7) days with a median (IQR) total admission cost of $67,426.10 ($37,610 – $132,077). Per patient estimated hospital costs compared to Medicare were lower for Medicaid (−$7,538.14; 95%CI [−$18,303, $3,226.72]; p 0.17) and self-pay (−$22,026.75; 95%CI [− $37,628.14, −$6,425.36]; p &lt;0.01), but higher for commercial plans ($11,139.60; 95%CI [$2,878.89, $19,400.30]; p &lt;0.01). LOS mediated 100% of the effect of Medicaid on hospital costs (p &lt; 0.01), but did not mediate costs for self-pay (p = 0.95) and commercial insurance (p = 0.32). <h3>Conclusions:</h3> In this single center analysis, length of stay fully mediated the effect of Medicaid on acute stroke hospital costs. Hospitals could possibly reduce stroke costs by improving Medicaid authorization and processing times. Further research is warranted to understand higher costs with commercial carriers compared to Medicare. <b>Disclosure:</b> Chad Aldridge has nothing to disclose. Mr. Victoria has nothing to disclose. Dr. Gusler has nothing to disclose. Miss Batton has received personal compensation for serving as an employee of University of Virginia. Dr. De Havenon has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Integra. Dr. De Havenon has stock in Certus. The institution of Dr. De Havenon has received research support from NIH/NINDS. The institution of Dr. De Havenon has received research support from Regeneron Pharmaceuticals. The institution of Dr. De Havenon has received research support from AMAG Pharmaceuticals. The institution of Dr. De Havenon has received research support from AMGEN. Dr. De Havenon has received publishing royalties from a publication relating to health care. Dr. Southerland has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Plaintiffs and Defense Cases related to Stroke and Vascular Neurology.. The institution of Dr. Southerland has received research support from Diffusion Pharmaceuticals. The institution of Dr. Southerland has received research support from American Heart Association. The institution of Dr. Southerland has received research support from National Science Foundation. The institution of Dr. Southerland has received research support from NIH. The institution of Dr. Southerland has received research support from Abbvie Pharmaceuticals, Inc.. Dr. Southerland has received intellectual property interests from a discovery or technology relating to health care. Dr. Southerland has received intellectual property interests from a discovery or technology relating to health care.

Amygdala Atrophy as an Early Manifestation of Alzheimer’s Disease (S39.005)

<h3>Objective:</h3> To investigate whether structural changes in the amygdala occur during the earliest stages of Alzheimer’s disease (AD). <h3>Background:</h3> Neuropsychiatric symptoms are common early manifestations of AD, suggesting that the amygdala may be an early target of AD pathology. While prior studies have investigated amygdala atrophy in AD, little is known about amygdala atrophy during the earliest stages of AD including the preclinical stage. <h3>Design/Methods:</h3> This retrospective cross-sectional study included subjects from the Alzheimer’s Disease Neuroimaging Initiative with age≥50, 3T 3D T1-weighted magnetic resonance imaging (MRI) scans, and cerebrospinal fluid (CSF) AD biomarkers. Clinical Dementia Rating (CDR) of 0 was defined as cognitively normal. Positive AD pathology was based on previously established CSF criteria. 466 subjects met all inclusion criteria (112 cognitively normal with negative CSF biomarkers (CN), 38 preclinical AD (PAD), 106 early mild cognitive impairment (EMCI), 100 late mild cognitive impairment (LMCI), and 110 AD dementia). Total amygdala volumes were assessed and normalized to intracranial volume (FreeSurfer v7.2). Multiple linear regression analysis adjusting for appropriate covariates was conducted to determine associations between amygdala volume and CSF AD biomarkers or neuropsychiatric measures. <h3>Results:</h3> Amygdala volumes were significantly lower with worsening disease severity (CN &gt; PAD &gt; EMCI &gt; LMCI &gt; AD dementia, p &lt;0.001). Amygdala volumes were correlated with CSF amyloid-beta42 (β=0.28653, p &lt;0.001), total tau (β=−0.8881, p &lt;0.001) and phosphorylated tau181 (β=−7.558, p &lt;0.001) levels. Moreover, Neuropsychiatric Inventory (NPI) disinhibition and aberrant motor behavior scores were negatively correlated with the amygdala volume (NPI disinhibition, β=−28.556, p &lt;0.05; NPI aberrant motor, β=−57.427, p &lt;0.05). <h3>Conclusions:</h3> Lower amygdala volumes were seen in the early stages of AD that worsened with increasing clinical severity. Furthermore, amygdala volumes were associated with CSF AD biomarkers and neuropsychiatric symptoms. These findings support amygdala atrophy as an early target of AD pathology. <b>Disclosure:</b> Miss Al-Ani has nothing to disclose. Ms. Tao has nothing to disclose. Jonathan Dyke, 673 has nothing to disclose. Gloria Chiang has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Life Molecular Imaging. The institution of Gloria Chiang has received research support from NIH/NIA. Gloria Chiang has received personal compensation in the range of $500-$4,999 for serving as a Invited Speaker for CME with Horizons CME. Dr. Ishii has stock in Regeneron Pharmaceuticals. The institution of Dr. Ishii has received research support from NIH. The institution of Dr. Ishii has received research support from BrightFocus Foundation. The institution of Dr. Ishii has received research support from Alzheimer’s Association. Dr. Ishii has received personal compensation in the range of $0-$499 for serving as a Author/Contributor with Relias Media.

Genetic Analyses of Oral Health and Neuroimaging Markers of Brain Health in Persons without Stroke (S49.001)

<h3>Objective:</h3> We hypothesize that genetically-determined poor oral health leads to worse neuroimaging brain health profiles in persons without stroke. <h3>Background:</h3> Oral health is a modifiable risk factor for stroke. However, the role of oral health on brain health among clinically asymptomatic persons remains understudied. <h3>Design/Methods:</h3> We conducted a two-sample Mendelian Randomization (MR) study. As instruments, we used 105 genetic variants known to be associated (p&lt;5×10⁻⁸) with a composite of caries, dentures and missing teeth in the Gene-Lifestyle Interactions in Dental Endpoints (GLIDE) Consortium. In stroke-free participants enrolled in the UK Biobank, we tested for associations between these genetic variants and white matter hyperintensity volume (natural log-transformed), fractional anisotropy and mean diffusivity. For the last two neuroimaging traits, we evaluated composite scores defined by the first principal component of measurements obtained across 48 brain regions. <h3>Results:</h3> Our primary analysis using the inverse variance-weighted MR method indicated that genetically-increased risk of poor oral health was associated with: (1) higher burden of silent cerebrovascular disease, as represented by a 30 % increase in white matter hyperintensities volumes (beta=0.30, SE=0.06 p-value=3×10⁻⁶), and (2) increased microstructural damage, as represented by a 43% change in composite FA scores (beta=0.43, SE=0.06; p=6×10⁻¹¹) and a 10% change in composite MD scores (beta=0.10, SE=0.03; p=0.005). Sensitivity analyses identified horizontal pleiotropy in our primary results, but an outlier-corrected analysis confirmed each of our findings (all p-values &lt;0.001). <h3>Conclusions:</h3> Among persons without stroke, genetically-determined poor oral health is associated with worse neuroimaging brain health profiles. Because gene-disease associations are immune to confounding, our results suggest that this association is causal. Early treatment of poor oral health may lead to significant brain health benefits, even in persons without stroke. <b>Disclosure:</b> Dr. Rivier has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pyxis Partners. Dr. Renedo has nothing to disclose. Dr. De Havenon has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Integra. Dr. De Havenon has stock in Certus. The institution of Dr. De Havenon has received research support from NIH/NINDS. The institution of Dr. De Havenon has received research support from Regeneron Pharmaceuticals. The institution of Dr. De Havenon has received research support from AMAG Pharmaceuticals. The institution of Dr. De Havenon has received research support from AMGEN. Dr. De Havenon has received publishing royalties from a publication relating to health care. Sam Payabvash has nothing to disclose. Mr. Torres-Lopez has nothing to disclose. Thomas Gill has nothing to disclose. Dr. Sheth has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ceribell. Dr. Sheth has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Zoll. Dr. Sheth has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for NControl. Dr. Sheth has received stock or an ownership interest from Astrocyte. Dr. Sheth has received stock or an ownership interest from Alva. The institution of Dr. Sheth has received research support from Biogen. The institution of Dr. Sheth has received research support from Novartis. The institution of Dr. Sheth has received research support from Bard. The institution of Dr. Sheth has received research support from Hyperfine. Dr. Sheth has received intellectual property interests from a discovery or technology relating to health care. The institution of Dr. Falcone has received research support from NIH. The institution of Dr. Falcone has received research support from AHA.

HSV-2 Retinitis and Encephalitis Masquerading as Giant Cell Arteritis and Acute Ischemic Stroke of the Midbrain (P12-10.002)

<h3>Objective:</h3> To describe a unique case of stroke mimicry. <h3>Background:</h3> Non-vascular causes of acute neurological symptoms may clinically and radiographically mimic ischemic strokes. In the brainstem, such considerations are generally restricted to neoplastic, demyelinating, or infectious etiologies. HSV-2 may very rarely cause isolated mesencephalitis. <h3>Design/Methods:</h3> We describe a patient who presented with headache, arthralgias, and visual dysfunction who was initially diagnosed with giant cell arteritis (GCA) but was eventually found to have HSV-2 infection. <h3>Results:</h3> A 75-year-old man with past medical history notable for atrial fibrillation (on apixaban), hypertension, hyperlipidemia, and rheumatoid arthritis (on adalimumab) presented for evaluation of gait instability. Four weeks prior to presentation, he developed bitemporal headaches without visual symptoms and arthralgias. His rheumatologist checked an ESR (40) and ordered a temporal artery biopsy. He presented the day his apixaban was held prior to biopsy (1 week prior to this presentation) with right eye inferior visual field loss. Fundoscopy revealed disc edema felt consistent with anterior ischemic optic neuropathy. He was treated with pulse-dose steroids out of concern for GCA and underwent bilateral temporal artery biopsy before being discharged home on an oral steroid taper and resumed anticoagulation. CT, CTA, and MRI were reportedly normal and the biopsies were ultimately negative. He then presented this admission with gait instability and MRI exhibited a diffusion restricting lesion with T2-FLAIR hyperintensity without hemorrhage in the left cerebral peduncle. His visual symptoms progressed and he underwent right eye anterior chamber paracentesis with fluid resulting PCR positive for HSV-2. Subsequent CSF sampling also revealed lymphocytic pleocytosis and HSV-2 positivity. Despite maximal medical therapy, he lost vision in both eyes over a matter of weeks before developing Charles-Bonnet syndrome. <h3>Conclusions:</h3> HSV-2 encephalitis may cause mesencephalic, non-hemorrhagic, restricting lesions mimicking acute ischemic stroke. HSV may also cause a necrotizing retinitis, initially mimicking ischemic, even arteritic, optic neuropathy. <b>Disclosure:</b> Dr. Sutherland has received personal compensation in the range of $0-$499 for serving as a Consultant for McGraw-Hill. Dr. Gummerson has nothing to disclose. Dr. De Havenon has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Integra. Dr. De Havenon has stock in Certus. The institution of Dr. De Havenon has received research support from NIH/NINDS. The institution of Dr. De Havenon has received research support from Regeneron Pharmaceuticals. The institution of Dr. De Havenon has received research support from AMAG Pharmaceuticals. The institution of Dr. De Havenon has received research support from AMGEN. Dr. De Havenon has received publishing royalties from a publication relating to health care.

Aldosterone Level Predicts Hypertension After ICH in the REDUCE Trial (P3-5.013)

Aldosterone Level Predicts Hypertension After ICH in the REDUCE Trial (P3-5.013)

A randomized, controlled trial of low-fat diet for fatigue in multiple sclerosis (P6-3.008)

<h3>Objective:</h3> Determine if a low-fat diet is effective at ameliorating fatigue in people with multiple sclerosis (PwMS) through a randomized controlled trial (RCT). Primary outcome is reduction in fatigue assessed via Modified Fatigue Impact Scale (MFIS) at 16 weeks. <h3>Background:</h3> Fatigue is a common, disabling symptom of multiple sclerosis (MS). A dietary intervention to improve fatigue is desirable given the minimal risk of adverse events. <h3>Design/Methods:</h3> PwMS were assigned to a low-fat diet (active) or wait-list (control) group. The active group received 4 weeks of data collection/nutrition counseling followed by adherence to the diet for 12 weeks. We measured diet adherence using monthly Food Frequency Questionnaire and 24-hr food recall. The principal statistical analysis used linear mixed models, with a random effect for subject to account for the within-subject correlation, in an intent-to-treat (ITT) framework to determine the effect of diet on the outcomes of MFIS and Fatigue Severity Scale (FSS). Sensitivity analysis was conducted by excluding potential outliers in both groups. <h3>Results:</h3> 39 participants were recruited with 20 in the active group and 19 in the control group. At baseline, participants’ mean age was 50 years (±12 years), mean BMI was 31 kg/m² (±7 kg/m²), and mean EDSS was 3.8 (±1.4). Mean MFIS decreased by −4.00 (95% CI: −12.04, 4.04) and mean FSS decreased by −0.41 (95% CI: −1.18, 0.36) from baseline to the end of the RCT in active group compared to control. Sensitivity analysis strengthened the magnitude of association with a mean MFIS decrease of −13.93 (95% CI: −20.65, −7.20) and mean FSS decrease of −1.22 (95% CI: −1.94, −0.50) in active group compared to control. Percent calories from fat decreased by 10.56% (95% CI: −18.50%, −2.97%) in active group compared to control. <h3>Conclusions:</h3> This 16-week long low-fat dietary intervention reduced the fatigue score significantly in the active group compared to controls. <b>Disclosure:</b> Dr. Chen has received research support from OHSU Foundation. Mrs. Chase has nothing to disclose. Dr. Lane has nothing to disclose. The institution of Dr. Wooliscroft has received research support from National Institutes of Health. Claire Adams has nothing to disclose. Mrs. Srikanth has nothing to disclose. Dr. Silbermann has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Neurology. Dr. Silbermann has received research support from VA. Dr. Rice has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Greenwich Pharmaceuticals. Dr. Hollen has nothing to disclose. Allison Fryman has nothing to disclose. Dr. Martin has received research support from Tartar Trust. The institution of Dr. Martin has received research support from OHSU Foundation. Ms. Vong has nothing to disclose. Anna Orban has nothing to disclose. Dr. Khan has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Dompe Pharmaceuticals. The institution of Dr. Khan has received research support from United Therapeutics. The institution of Dr. Khan has received research support from Janssen pharmaceuticals. The institution of Dr. Khan has received research support from Eli Lilly. The institution of Dr. Khan has received research support from 4D Medical. The institution of Dr. Khan has received research support from Regeneron Pharmaceuticals. The institution of Dr. Khan has received research support from BOA Medical. Dr. Horgan has nothing to disclose. Dr. Yadav has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen Pharmaceuticals. Dr. Yadav has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bristol Myers Squibb Foundation. Dr. Yadav has received personal compensation in the range of $500-$4,999 for serving as a Consultant for EMD-Serono . The institution of Dr. Yadav has received research support from Department of Veterans Affairs. Dr. Yadav has received research support from NIH. Dr. Yadav has received research support from PCORI. Dr. Yadav has received research support from NMSS. The institution of Dr. Yadav has received research support from Department of Veterans Affairs. The institution of Dr. Yadav has received research support from Tykeson Family Foundation Endowed Professorship.

Genetically-Determined LDL Negatively Impacts Clinical Evolution of Ischemic Stroke Survivors (S3.003)

<h3>Objective:</h3> We aim to study the contribution of genetically-determined lipid levels to the clinical trajectories of stroke survivors. <h3>Background:</h3> Ischemic Stroke survivors are at high risk of stroke recurrence. Understanding the genetic risk factors for stroke recurrence will help guide future prevention strategies. <h3>Design/Methods:</h3> We analyzed clinical and genetic data from the Vitamin Intervention Stroke Prevention (VISP) clinical trial, which examined high-dose vitamins in stroke survivors. Genetic susceptibility to increased LDL-c was modeled through a polygenic risk score built with genetic data on 38 known genetic risk variants for LDL-cholesterol (variants influencing other lipid traits were excluded). We divided the LDL-related polygenic risk score into 0–20, 20–80, and 80–100 percentile categories labeled as low, intermediate and high genetic predisposition to high LDL. We fitted multivariable (adjusting for age, sex, vascular risk factors, and statin treatment) Cox proportional hazards and logistic regression models to test whether higher polygenic risk for elevated LDL-c was associated with observed LDL-c, ischemic stroke recurrence, and composite risk of ischemic stroke and myocardial infarction. <h3>Results:</h3> Of the 2,164 stroke survivors enrolled in VISP, 1,567 (72%) had available LDL-c and genetic data. The mean LDL in the low, intermediate and high polygenic risk categories was 114.5 (SD 2.21), 123.2 (SD 1.23), and 128.8 (SD 2.35), respectively (unadjusted p&lt;0.001). Compared to stroke survivors with low polygenic risk, intermediate (HR 1.52, 95% CI 0.91–2.54) and high (HR 2.03, 95% CI 1.14–3.61) polygenic risk groups had significantly higher stroke recurrence risk (p test-for-trend 0.01). We observed similar associations when evaluating the composite risk of stroke and myocardial infarction (all p&lt;0.05). <h3>Conclusions:</h3> A higher polygenic risk for increased LDL-c is associated with worse clinical trajectories after stroke. Further research is needed to determine whether stroke survivors with an elevated genetic risk benefit from unique care pathways with additional monitoring and treatment. <b>Disclosure:</b> An immediate family member of Mr. Wu has received personal compensation for serving as an employee of Bristol-Myers Squibb. Mr. Wu has received research support from NIH. Dr. Rivier has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pyxis Partners. Mr. Demarais has nothing to disclose. Ms. Conlon has nothing to disclose. Dr. Renedo has nothing to disclose. Mr. Torres-Lopez has nothing to disclose. Dr. Sharma has nothing to disclose. Dr. De Havenon has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Integra. Dr. De Havenon has stock in Certus. The institution of Dr. De Havenon has received research support from NIH/NINDS. The institution of Dr. De Havenon has received research support from Regeneron Pharmaceuticals. The institution of Dr. De Havenon has received research support from AMAG Pharmaceuticals. The institution of Dr. De Havenon has received research support from AMGEN. Dr. De Havenon has received publishing royalties from a publication relating to health care. Dr. Sheth has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ceribell. Dr. Sheth has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Zoll. Dr. Sheth has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for NControl. Dr. Sheth has received stock or an ownership interest from Astrocyte. Dr. Sheth has received stock or an ownership interest from Alva. The institution of Dr. Sheth has received research support from Biogen. The institution of Dr. Sheth has received research support from Novartis. The institution of Dr. Sheth has received research support from Bard. The institution of Dr. Sheth has received research support from Hyperfine. Dr. Sheth has received intellectual property interests from a discovery or technology relating to health care. The institution of Dr. Falcone has received research support from NIH. The institution of Dr. Falcone has received research support from AHA.

Evaluation of the Biodistribution, Efficacy, and Side-Effect Profile of Deflazacort, Prednisolone and Vamorolone in a DMD Mouse Model (S34.010)

Evaluation of the Biodistribution, Efficacy, and Side-Effect Profile of Deflazacort, Prednisolone and Vamorolone in a DMD Mouse Model (S34.010)

A Phase 3, Open-Label, Multicenter Study To Evaluate Eculizumab In Adolescents With Refractory Generalized Myasthenia Gravis (S5.009)

A Phase 3, Open-Label, Multicenter Study To Evaluate Eculizumab In Adolescents With Refractory Generalized Myasthenia Gravis (S5.009)

Subgroup outcomes from RAISE: A randomized, Phase 3 trial of zilucoplan in generalized myasthenia gravis (P1-5.006)

Subgroup outcomes from RAISE: A randomized, Phase 3 trial of zilucoplan in generalized myasthenia gravis (P1-5.006)

Overview of the Safety Profile from Efgartigimod Clinical Trials in Participants with Diverse IgG-Mediated Autoimmune Diseases (P1-5.001)

Overview of the Safety Profile from Efgartigimod Clinical Trials in Participants with Diverse IgG-Mediated Autoimmune Diseases (P1-5.001)

Dose Selection and Clinical Development of Efgartigimod PH20 Subcutaneous in Patients with Generalized Myasthenia Gravis (P1-5.017)

Dose Selection and Clinical Development of Efgartigimod PH20 Subcutaneous in Patients with Generalized Myasthenia Gravis (P1-5.017)

Efgartigimod Demonstrates Consistent Improvements in Generalized Myasthenia Gravis Patients of Shorter Disease Duration (P1-5.015)

Efgartigimod Demonstrates Consistent Improvements in Generalized Myasthenia Gravis Patients of Shorter Disease Duration (P1-5.015)