Speakers Bureau Research Articles

239-OR: CGM Has a Specific Effect on the Reduction of Nocturnal Hypoglycemia in People with Type 1 Diabetes on an MDI Treatment Regimen

MDI users with type 1 diabetes may be less able to respond to circadian changes in insulin demand than CSII or AID users, which may increase the risk of nocturnal hypoglycemia. Therefore, we re-analyzed data from the HYPO.DE RCT to evaluate the effect of CGM on the percentage of low glucose levels < 70 mg/dl (% < 70 mg/dl) and < 54 mg/dl (% < 54 mg/dl) during 12 two-hour periods throughout the day. We compared 4-week baseline data from 141 participants using spot glucose monitoring (SMBG) with 4-week outcome data after a 6-month follow-up period in which the control group (n=66) remained on SMBG and the intervention group (n=75) used CGM (Dexcom G5). At baseline without CGM, there were significantly higher proportions of %<70 mg/dl or %54 mg/dl during the night (00:00 am - 06:00 am) than during the day (8.5 ±1.0% vs. 6.5 ±0.6%, p<0.001 respectively 4.0 ±0.6% vs. 2.4 ±0.3%, p<0.001). CGM had a greater effect on nocturnal hypoglycemia than on daytime hypoglycemia (see Figure 1). The greatest reduction in favor of the CGM users was between 04:00 a.m. and 06:00 a.m., with a between-group difference of -8.5% (95% CI -10.4% to -6.7%, p<.001) for %<70 mg/dl and -5.5% (95% CI 4.4 - 6.6%, p<.001) for %<54 mg/dl. The data suggest that CGM provides benefits to MDI users with type 1 diabetes in preventing nocturnal hypoglycemia, potentially compensating for lack of responsiveness to a circadian changing insulin demand. Disclosure N. Hermanns: Speaker's Bureau; Berlin-Chemie AG, Sanofi-Aventis Deutschland GmbH. Research Support; Sanofi-Aventis Deutschland GmbH. Speaker's Bureau; Roche Diabetes Care. Research Support; Roche Diabetes Care. Speaker's Bureau; Dexcom, Inc. Advisory Panel; Abbott Diagnostics, Ypsomed AG. D. Ehrmann: Advisory Panel; Dexcom, Inc. Speaker's Bureau; Dexcom, Inc., Sanofi-Aventis Deutschland GmbH. Advisory Panel; Roche Diabetes Care. Speaker's Bureau; Roche Diabetes Care, Berlin-Chemie AG. B. Kulzer: Advisory Panel; Abbott Diagnostics, Berlin-Chemie AG, Dexcom, Inc., Sanofi, embecta, Novo Nordisk, Roche Diabetes Care. Speaker's Bureau; Bayer Inc., Insulet Corporation, Lilly Diabetes. G. Freckmann: Advisory Panel; Abbott. Research Support; Ascensia Diabetes Care. Advisory Panel; Boydsense, Dexcom, Inc., Lilly Diabetes. Speaker's Bureau; Novo Nordisk. Advisory Panel; Perfood, PharmaSens. Consultant; Roche Diabetes Care. Research Support; Roche Diabetes Care. Consultant; Sinocare. Speaker's Bureau; Terumo Corporation. Consultant; Ypsomed AG. L. Heinemann: Stock/Shareholder; Science Consulting in Diabetes GmbH, Profil Institut für Stoffwechselforschung GmbH. Advisory Panel; embecta. Board Member; Lifecare A/S. Stock/Shareholder; diateam GmbH. Funding The HYPO.DE study was funded by Dexcom, San Diego

982-P: The Dexcom Community Glucose Monitoring Project for People with Type 2 Diabetes—One-Year Outcomes

Background & Objective: Access to CGM for people with type 2 diabetes (T2D) remains limited, especially for those treated in the primary care setting. The objective of this study, a collaboration between a primary care practice and the local public health department, was to evaluate the glycemic impact of CGM access on adults with T2D. Methods: CGM systems (Dexcom G6 and G7) were provided to eligible participants with T2D who were ≥18 years of age, CGM-naïve, and did not have health insurance coverage for CGM. Outcomes included changes in A1C and CGM metrics from baseline to one year. Results: Participants (n=177) were (mean ± SD) 59.1 ± 12.0 years, 41.2% female, BMI 35.5 ± 8.5, duration of diabetes 11.1 ± 9.3 years. After one year, A1C decreased from 9.4% ± 1.6 to 7.1% ± 1.3 (-2.3% ± 1.9, p<0.001). The proportion of participants meeting the ADA target of A1C <7.0% increased from n=1 (0.6%) at baseline to n=91 (51.4%) at one year. Those meeting the HEDIS target of A1C <8.0% increased from 19.2% at baseline to 85.9% at one year. CGM outcomes (n=109) after near-continuous use included an increase in TIR of 9.9% ± 29.4 (p<0.001) and a large increase in TITR (p<0.001, Table). Conclusion: Self-guided use of CGM by primary care patients with T2D for one year was associated with clinically meaningful improvements in A1C and TIR. Disclosure T. Grace: Speaker's Bureau; Sanofi, Novo Nordisk, Eli Lilly and Company, Dexcom, Inc. Employee; Dexcom, Inc. J.E. Layne: Employee; Dexcom, Inc. Stock/Shareholder; Dexcom, Inc. Employee; Verily Life Sciences. C. Hicks: Employee; Dexcom, Inc. C.R. Green: Employee; Dexcom, Inc. T.C. Walker: Employee; Dexcom, Inc. Stock/Shareholder; Dexcom, Inc.

916-P: SGLT2 Inhibitors and Parkinson’s Disease (PD) Risk in Older Populations with Type 2 Diabetes (T2D)

Background: Diabetes increases the risk of Parkinson’s disease (PD). SGLT2 inhibitors show neuroprotective effects in animal models. Yet evidence is limited regarding the effect of SGLT2 inhibitors on PD risk. We thus aimed to assess the association between SGLT2 inhibitors and PD risk in T2D patients. Methods: In this retrospective cohort study, we used 2016-2020 national Medicare Claims data to identify beneficiaries with T2D and without preexisting PD. We compared the risk of PD between new users of SGLT2 inhibitors vs. DPP4 inhibitors. We employed 1:1 propensity score matching to balance the baseline confoundings between the treatment groups and applied Cox regression models to estimate the PD risk. Results: After 1:1 propensity score matching, 26,619 individuals were included in each of the two treatment groups, the PD incidence was 2.48 and 3.54 per 1000 person-years in the SGLT2 inhibitor group and DPP4 inhibitor group, respectively. In the Cox model (Figure), the SGLT2 inhibitor group was associated with a significantly lower risk of incident PD (HR 0.70 [95% CI 0.55-0.89]) than the DPP4 inhibitor group. The risk reduction of PD was particularly profound in non-Hispanic Black individuals (HR 0.24 [95% CI 0.07-0.86]) and insulin users (HR 0.49 [95% CI 0.32-0.77]). Conclusion: Compared to DPP4 inhibitors, SGLT2 inhibitors were associated with a significantly lower risk of indecent PD in people with T2D. Disclosure J. Guo: None. H. Tang: None. H. Shao: Consultant; Eli Lilly and Company. Y. Lu: None. L. Shi: None. V. Fonseca: Consultant; Abbott, Bayer Inc. Stock/Shareholder; BRAVO4HEALTH, LLC. Consultant; Corcept Therapeutics. Speaker's Bureau; Eli Lilly and Company. Research Support; Fractyl Health, Inc. Consultant; Sun Pharmaceutical Industries Ltd. Stock/Shareholder; Amgen Inc. Y. Guo: None. J. Bian: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK133465)

1820-LB: Evaluating an HCP Diabetes Training Program in Kasese, Uganda

Introduction & Objective: Health Care Provider (HCP) diabetes educational sessions are core to the mission of Diabetes Empowerment International (DEInt) in Kasese, Uganda. Understanding HCP profiles and their barriers to diabetes education access is essential to shape a successful training program. We evaluated the profile of the HCPs that are trained as well as the feedback received regarding how the training is implemented in patient care. Methods: In person HCP diabetes seminars are held every 8 weeks DCA/DEINt Diabetes Education Center in Kasese, covering a curriculum of key topics related to care of diabetes. Each session hosts over 50 regional HCPs, and over 106 HCPs have attended 23 education seminars. Participant evaluations are performed for each seminar for impact on diabetes knowledge and patient care. Results: The average distance traveled for the conferences was 29.4 km [range 0.5-63.2 km]. The majority of participants are enrolled nurses (n=51, 48.11 %), followed by assistant nursing officers (n=20, 18.87 %), and enrolled midwives (n=11, 10.38 %). The remainder of participants have varied healthcare provider titles. The majority of HCPs reported that there was a diabetes trained doctor in the facility where they worked (n=62, 58.49 %). The mean number of diabetes patients supported was 40 [range 0-418]. A total of 8,733 people with diabetes are being served by the HCPs with 289 type 1 diabetes patients and 770 type 2 diabetes patients. The topics that attendees expressed the most confidence in managing patients with diabetes was checking blood sugars and hypoglycemia. Topics that attendees indicated that they would change how they treat diabetes patients was insulin pumps (n=55, 62.5%) and carbohydrate counting (n=54, 61.36 %). Conclusion: Our diabetes training programs supports a wide range of HCPs. HCP diabetes training can have a far-reaching impact on an underserved population of individuals with diabetes. Disclosure S. Narayanan: Employee; Dexcom, Inc. C. Basch: None. J. Baker: Speaker's Bureau; Insulet Corporation, Dexcom, Inc., Sanofi.

1446-P: Gender Inequalities in Cardiovascular Risk Factors in Primary Prevention Adults Living with Type 1 Diabetes in Germany and France—Findings from DPV and SFDT1

Introduction & Objectives: To evaluate whether medical care for and level of cardiovascular risk factors differ in primary prevention between adult men and women with type 1 diabetes (T1D) in two European countries in 2020-2022. Methods: We included 2657 participants from the DPV registry (Germany, mean age 40±15, diabetes duration 23±14 years; 50.9% men) and 1172 from the SFDT1 study (France, age 39±14, diabetes duration 22±13 years; 53.2% men). Results: HbA1c levels and body mass indexes were similar in women and men with similar proportions of HbA1c<7% (DPV: 36.6 vs. 33.0%, respectively; SFDT1: 22.8 vs. 24.9%; both n.s.). Women had less overweight in DPV (55.4 vs. 61.0%, p<0.05) but not in SFDT1 (48.0 vs. 44.9%, n.s.) and were less prone to smoke (DPV: 19.7 vs. 25.8%, p<0.05; SFDT1: 21.0 vs. 26.0%, n.s.). Systolic blood pressure was lower in women than men (DPV: 124±15 vs. 129±15; SFDT1: 121±16 vs. 126±14mmHg, both p<0.05) with similar rates of antihypertensive therapy in case of systolic/diastolic blood pressure ≥140/90mmHg (DPV: 70.5 vs. 63.6%; SFDT1: 73.3 vs. 68.6%, both n.s.). In case of microalbuminuria, ACEi-ARB were less prescribed in women than men in DPV (21.4 vs 37.6%, p<0.05) but not SFDT1 (70.6 vs 62.0%, n.s.). In women compared to men, HDL-cholesterol levels were higher; triglycerides lower and LDL-cholesterol similar in DPV and SFDT1. In those with LDL-cholesterol >130 mg/dL (DPV: 19.9 vs. 23.9%; SFDT1 17.0 vs. 19.2%, both n.s.), statin therapy was less prescribed in women than men in DPV (7.9 vs. 17.0%, p<0.05), SFDT1 (18.2 vs. 21.0%, n.s.). Conclusion: Women in primary prevention have a better cardiovascular risk profile than men in both studies. We observed a high rate of therapeutic inertia, which might be higher in women for statin and nephroprotection with ACEi-ARB especially in Germany. Disclosure E. Cosson: Advisory Panel; Abbott, AstraZeneca, Lilly Diabetes, Novo Nordisk, Sanofi, Roche Diagnostics, Novartis AG, Amgen Inc. M. Auzanneau: Other Relationship; Insulet Corporation. G.A. Aguayo: None. W. Karges: None. J. Riveline: Board Member; Abbott, Novo Nordisk A/S, Sanofi, Eli Lilly and Company, Medtronic, Dexcom, Inc., Insulet Corporation, Air Liquide, AstraZeneca. P. Augstein: None. L. Sablone: None. P.M. Jehle: None. G. Fagherazzi: Speaker's Bureau; Sanofi. Advisory Panel; Timkl, SAB Biotherapeutics, Inc., Vitalaire, Roche Diabetes Care. R.W. Holl: None.

P123 Safety and efficacy of filgotinib, an update from the DARWIN 3 phase 2 long-term extension with a maximum of 8.2 years of exposure

Abstract Background/Aims DARWIN 3 (NCT02065700) is a long-term extension (LTE) study assessing the safety and efficacy of filgotinib (FIL) in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX). In the DARWIN 1 (NCT01888874) and DARWIN 2 (NCT01894516) parent studies, patients received FIL in combination with MTX or FIL monotherapy, respectively. To provide an update on the safety and efficacy of FIL 200 mg (FIL200) in patients with RA, with or without MTX, with a maximum of 8.2 years of exposure. Methods Patients completing the DARWIN 1 and DARWIN 2 phase 2 studies could enter DARWIN 3, receiving FIL200[PE1] +/-MTX. The proportion of patients experiencing treatment-emergent adverse events (TEAEs) were reported, comprising data from both the parent and LTE studies. Efficacy was assessed from LTE baseline using the American College of Rheumatology (ACR) 20/50/70 criteria and DAS28-CRP, up to 264 weeks. Low disease activity and remission were defined as DAS28-CRP ≤3.2 and <2.6, respectively. Results In total, 739 patients were enrolled in DARWIN 3. In the FIL + MTX vs FIL monotherapy groups, TEAEs were reported for 90.9% and 92.1% of patients, respectively (Table). The most common TEAE was infection. In both treatment groups, eight patients had a TEAE leading to death (1.6% and 3.3%, respectively). Exposure-adjusted incidence rates, censored at time of first event for major adverse cardiovascular event, venous thromboembolism, herpes zoster, infections, serious infections, non-melanoma skin cancer (NMSC), malignancies excluding NMSC, gastrointestinal perforations and TEAEs leading to death, will be reported. Through five years, ACR20/50/70 responses were maintained in 86.3%/66.7%/50.7% of the FIL + MTX group and 90.8%/74.8%/51.4% of the FIL monotherapy group, respectively (observed data). DAS28-CRP low disease activity and remission rates (non-responder imputation) at DARWIN 3 baseline were 46.1%/40.1% (FIL + MTX) and 29.6%/24.8% (FIL monotherapy). At Week 264, the proportion of patients achieving low disease activity and remission were 34.0%/34.3% (FIL + MTX) and 27.0%/24.8% (FIL monotherapy). Conclusion With a maximum of 8.2 years of exposure in patients with RA, the FIL safety profile is similar between the background MTX and monotherapy treatment arms. Both arms show sustained efficacy over time. Disclosure P. Emery: Consultancies; Consultant of: AbbVie, AstraZeneca, BMS, Boehringer-Ingelheim, Galapagos, Gilead, Lilly, Novartis, Pfizer, Roche, and Samsung. Member of speakers’ bureau; y Speakers bureau: AbbVie, AstraZeneca, BMS, Boehringer-Ingelheim, Galapagos, Gilead, Lilly, Novartis, Pfizer, and Samsung. Grants/research support; Grant/research support from: AbbVie, BMS, Lilly, Novartis, Pfizer, Roche, and Samsung. R. Westhovens: Consultancies; Celltrion, Galapagos, and Gilead,. Member of speakers’ bureau; Celltrion, Galapagos, and Gilead. R.H.E. Alten: Consultancies; AbbVie, Amgen, Biogen, BMS, Celltrion, Gilead, Janssen, Lilly, Medac, MSD, Mylan, Novartis, Pfizer, Roche, Sandoz, SanofiGenzyme, UCB, and VIATRIS. L. Dagna: Consultancies; AbbVie, Amgen, AstraZeneca, Biogen, Boehringer-Ingelheim, BMS, Celltrion, Eli Lilly & Company, Galapagos, GlaxoSmithKline, Janssen, Kiniksa Pharmaceuticals, Novartis, Pfizer, Roche, Sanofi-Genzyme,. Grants/research support; AbbVie, BMS, Celgene, GlaxoSmithKline, Janssen, Kiniksa, Merck Sharp & Dohme, Mundipharma Pharmaceuticals, Novartis, Pfizer, Roche, Sanofi-Genzyme, and SOBI,. A. Kavanaugh: Consultancies; Amgen, AbbVie, BMS, Pfizer, UCB, Janssen, Novartis, and Pfizer. K.L. Winthrop: Consultancies; AbbVie, AstraZeneca, BMS, Eli Lilly & Company, Galapagos, Gilead, GlaxoSmithKline, Novartis, Pfizer, Regeneron, Roche, Sanofi, and UCB. Grants/research support; BMS and Pfizer. J. Barry: Corporate appointments; Galapagos. Shareholder/stock ownership; Galapagos. R. Besuyen: Corporate appointments; Galapagos. Shareholder/stock ownership; Galapagos. C. Corallo: Corporate appointments; Galapagos. Shareholder/stock ownership; Galapagos. C. Watson: Corporate appointments; Galapagos. Shareholder/stock ownership; Galapagos. N. Martin: Consultancies; Galapagos. M. Genovese: Corporate appointments; Gilead Sciences. Shareholder/stock ownership; Gilead Sciences. A.J. Spindler: None. M. Stanislavchuk: Grants/research support; Amgen, AstraZeneca, Celgene, Eli Lilly, Galapagos, Gilead, Human Genome, Janssen, MSD, Nichi-Iko, Pfizer, and Roche. M. Greenwald: Grants/research support; AbbVie, Aclaris, Galapagos, Janssen, Lilly, and Nimbus.

OA11 Maintained improvement in patient reported outcomes in early axial spondyloarthritis following certolizumab pegol dose reduction

Abstract Background/Aims Certolizumab pegol (CZP), a PEGylated TNFi without an Fc region, has previously shown efficacy and safety in patients with axial spondyloarthritis (axSpA). EULAR guidelines recommend that tapering of a biologic can be considered for patients in sustained remission. The C-OPTIMISE trial (NCT02505542) identified early (<5 years) axSpA patients in sustained remission who may benefit from dose tapering or stopping treatment. Here we report whether a reduced CZP maintenance dose is associated with sustained improvements in patient reported outcomes (PROs) in patients with axSpA at Week (Wk) 96. Methods C-OPTIMISE was a two-part, multicentre, phase 3b study in adult patients. Part A: up to Wk48 (open-label), patients received CZP 200mg Q2W. At Wk48 (Part B), patients who achieved sustained remission at Wk32 or 36 (ASDAS <1.3), were randomised 1:1:1 to double-blind CZP 200 mg Q2W (full maintenance dose), CZP 200 mg Q4W (reduced maintenance dose), or placebo (PBO [drug withdrawal]) for additional 48Wks. We report disease activity and PROs (BASDAI, PtGADA, nocturnal apinal pain, morning stiffness, fatigue, and ASQoL) during Part B (Wks48-96). Flare is defined as ASDAS ≥2.1 at two consecutive visits, or ASDAS >3.5 at any visit. Results At Wk48 (Part A), 43.9% (323/736) of patients achieved sustained remission, of which 313 patients were randomised to Part B (Wks48-96). During Wks48-96, 87/104 (83.7%) patients receiving the full maintenance dose, 83/105 (79.0%) patients receiving the reduced maintenance dose, and 21/104 (20.2%) patients receiving PBO remained flare-free. Patients receiving full maintenance and those on reduced dose have similar disease activity measures (BASDAI; mean [SD], 0.8 [0.8] vs 0.8 [1.0]) at Wk96 (Table). Sustained improvements in PROs were similar for CZP full maintenance dose and CZP reduced maintenance dose, including ASQoL, fatigue and nocturnal spinal pain, while PBO showed increased disease activity (Table). Conclusion In axSpA patients who achieved sustained remission, CZP reduced dosage resulted in sustained improvements in disease activity and PROs similar to those receiving full maintenance dose. This suggests that dose reduction can be a viable strategy without compromising PROs. Disclosure A. Chan: Member of speakers’ bureau; AC has received speaker bureau from Novartis, UCB, Abbvie, Janssen, Amgen. Grants/research support; AC has received grant support for service and educational projects from Novartis and UCB Pharma. Other; AC has received honoraria/advisory boards from Novartis, Abbvie, UCB, Janssen, Amgen, Lilly. J. Wood: Other; JW is an employee of UCB Pharma. L. Burns: Other; LBu is an employee of UCB Pharma. R. Tham: Other; RT is employed by Veramed and a contractor for UCB Pharma. T. Kumke: Other; TK is an employee and shareholder of UCB Pharma. B. Hoepken: Other; BH is an employee and shareholder of UCB Pharma. M. Kim: Other; MK is an employee of UCB Pharma. L. Bauer: Other; LBa is an employee and shareholder of UCB Pharma. K. MacKay: Other; KM received consultancy & speaker meetings for UCB, AbbVie, Novartis, Lilly, AZ, Janssen and Roche. K. Gaffney: Shareholder/stock ownership; KG is a shareholder of Rheumatology Events. Grants/research support; KG has received grants/research support from NASS, Versus Arthritis, AbbVie, Pfizer, UCB Pharma, Norvartis, Eli Lilly, Cellgene, Celltrion, Janssen, Gilead and Biogen. Other; KG has received honoraria/ consultation fees from Novartis, AbbVie, UCB Pharma, Lilly and Pfizer, KG has received speaker’s bureau from Novartis, UCB Pharma, AbbVie and Lilly; meeting expenses from AbbVie, Lilly, Roche, Novartis, Pfizer and UCB Pharma.

Does the association between short-chain fatty acids and depressive symptoms vary with age? A large population-based study

IntroductionFat plays an important role in brain function; 60% of the brain’s dry weight is fat. Among fats, omega-3 fatty acids, which are long-chain fatty acids, have been reported to reduce depressive symptoms. On the other hand, there are few studies on short-chain fatty acids (SCFAs), and those that do exist are mostly animal studies, with only a few human studies (about 100 cases). This is the first study to examine the association between fecal short-chain fatty acids and depressive symptoms on a large scale in the general population.ObjectivesWe examined the association of fecal SCFAs with depressive symptoms. In addition, we analyzed the associations stratified by age and examined differences in the associations.MethodsThis study was conducted using data from the Dynamics of Lifestyle and Neighborhood Community on Health Study (DOSANCO Health Study). The target population was all residents of the city of Suttu, Hokkaido, Japan, excluding residents of special nursing homes (n=2638). 579 individuals (22% of the target population) aged 18 years and older who were able to measure fecal SCFA participated in this study with written informed consent. Approval was obtained from the Ethics Committee of Hokkaido University School of Medicine (15-002 and 15-045). Fecal SCFA was measured by high-performance liquid chromatography. We examined the association of fecal concentrations of SCFA subtypes (i.e., acetate, butyrate, and propionate) and total SCFA concentrations (mg/g wet weight as a continuous variable) with total Patient Health Questionnaire-9 (PHQ-9) scores using multiple regression analysis. We adjusted for age, sex, habitual exercise, total energy intake, and total dietary fiber intake. We performed additional multiple regression analyses with stratification by age group (18-59 years and 60 years or older). Two-tailed tests were used for all analyses with a significance level of P < 0.05.ResultsThe mean age (standard deviation) of the study participants (n=534) was 58.3 (16.0) years. Among them, 48% were 18-59 years old and 54% were female. Fecal propionate concentration was significantly associated with total PHQ-9 score (beta=0.62, p<0.01). Other SCFAs and total SCFA were not significantly associated with total PHQ-9 score. In addition, using stratification analyses by age group, the associations between fecal propionate concentration and total PHQ-9 score showed a different trend by age group (beta=0.18, p=0.62 for 18-59 years; beta=0.80, p<0.01 for 60 years or older).ConclusionsThe study showed an association between higher concentrations of fecal propionic acid and higher levels of depressive symptoms. The association was particularly pronounced in older people, those aged 60 years and older. The results suggest that improving dietary habits to reduce fecal propionic acid may be effective in preventing depression in the elderly.Disclosure of InterestR. Okubo Shareolder of: None, Grant / Research support from: A Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science (No. 22K17844), Consultant of: None, Employee of: None, Paid Instructor of: None, Speakers bureau of: Speakers bureau from Takeda Pharmaceutical Company Limited, R. Yamamura: None Declared, S. Ishikawa: None Declared, T. Kimura: None Declared, S. Ukawa: None Declared, K. Nakamura: None Declared, A. Tamakoshi: None Declared

Exploring Cariprazine’s Potential in Late-Stage Schizophrenia Treatment

IntroductionSchizophrenia is a chronic neuropsychiatric disorder that often requires long-term pharmacotherapy to manage symptoms and prevent relapse. There are important clinical differences between early-stage versus late-stage schizophrenia, like the predominant symptomatology. In later stages, negative, cognitive, and anxiety/depressive symptoms dominate the clinical picture, with relapses further potentiating the emergence of positive symptoms. Therefore, it is crucial to establish the efficacy of an antipsychotic medication in the later stages of schizophrenia as well. Cariprazine is a novel dopamine D3-preferring D3/D2 receptor partial agonist that has shown efficacy in treating schizophrenia across the symptom spectrum.ObjectivesThe aim of this poster is to present the findings of cariprazine’s efficacy in treating late-stage schizophrenia, especially in symptoms that are more commonly occurring in this phase of the disorder.MethodsThis poster reports the results of a post-hoc pooled analysis of three 6-week, double-blind, placebo-controlled trials (NCT01104766, NCT01104779, NCT00694707) that assessed the efficacy of cariprazine in schizophrenia. The primary outcome was the change in Positive and Negative Syndrome Scale (PANSS) Total Scores from baseline to endpoint. The analysis focused on patients with late-stage schizophrenia (defined as having an illness-duration of more than 15 years) who received cariprazine at doses between 1.5 mg/day to 6.0 mg/day. The changes in PANSS-derived Marder Factor Scores for Negative, Disorganised Thought (i.e., Cognitive) and Anxiety/Depression symptoms were further examined. The least square mean differences (LSMDs) between cariprazine and placebo groups were calculated using mixed-models for repeated measures (MMRM).ResultsAltogether, 128 placebo-, and 286 cariprazine-treated patients were identified as having schizophrenia for more than 15 years. The mean age of patients was about 45 years, while the mean illness-duration was about 24 years. The mean baseline PANSS scores were the same between the two groups. In the late-stage schizophrenia population, at Week 6, cariprazine yielded statistically significantly greater reductions on the PANSS Total Score (LSMD -6.7, p<0.01). Cariprazine further showed superiority over placebo in reducing negative (LSMD -1.4, p<0.05), disorganised thought (LSMD -1.3, p<0.01), and anxiety/depression (LSMD -0.9, p<0.05) symptoms.ConclusionsCariprazine showed efficacy in treating patients with late-stage schizophrenia. It improved overall schizophrenia symptoms, as well as the negative, cognitive and anxiety/depression symptoms that are more prevalent in this phase of the disorder.Disclosure of InterestP. Falkai Consultant of: Janssen-Cilag, AstraZeneca, Lilly, and Lundbeck, Speakers bureau of: AstraZeneca, Bristol Myers Squibb, Lilly, Essex, GE Healthcare, GlaxoSmithKline, Gedeon Richter, Janssen Cilag, Lundbeck, Otsuka, Pfizer, Servier, and Takeda, R. Csehi Employee of: Gedeon Richter Plc, K. Acsai Employee of: Gedeon Richter Plc, G. Németh Employee of: Gedeon Richter Plc

Elevated herpesvirus antibody levels linked to schizophrenia and bipolar disorder

IntroductionPrevious research has implicated herpes simplex virus 1 (HSV1) and cytomegalovirus (CMV) in severe mental illness (SMI) with conflicting results. Both pathogens have high universal seroprevalence, are neurotropic and after the primary infection typically establish a persistent latent infection with periodic reactivations. Increased immunoglobin G (IgG) concentrations are considered to be attributable to an increased infection severity with more frequent reactivations or host immune system alterations.ObjectivesWe assessed the HSV1 and CMV IgG concentrations in previously infected (seropositive) patients with SMI and healthy controls (HC). We hypothesized that seropositive patients would show higher IgG concentrations than seropositive HC.MethodsWe included 765 patients, 515 with schizophrenia (SZ) and 250 with bipolar disorder (BP), and 541 HC. HSV1 and CMV IgG seropositivity and concentrations were measured with immunoassays. 355 patients, mean age 33 years, 45% females, and 238 HC, mean age 35 years, 44% females, were HSV1 seropositive (HSV1+) while 447 patients, mean age 33 years, 50% females, and 296 HC, mean age 34 years, 47% females, were CMV seropositive (CMV+). In our main analysis among seropositive participants, we investigated the main effect of patient/control status on HSV1 and CMV IgG concentrations.ResultsThere were no significant differences in CMV or HSV1 seropositivity frequencies between patients with SZ, patients with BP and HC. Among seropositive participants, patients had higher HSV1 (p<0.001) and CMV (p=0.018) IgG concentrations than HC; stratifying by diagnosis, both patients with SZ (p=0.001) and patients with BP (p=0.001) had higher HSV1 IgG concentrations than HC, while patients with SZ, but not BP, had higher CMV (p=0.045) IgG concentrations than HC (Image). For HSV1, higher IgG concentrations were associated with higher general (p=0.017), negative (p=0.041) and positive (p=0.028) psychotic symptom scores.Image:ConclusionsSeropositive patients with SMI showed higher HSV1 and CMV IgG concentrations than seropositive HC suggesting that patients suffer a more severe infection or exhibit an altered immune response when contracting the pathogens. For HSV1, higher IgG concentrations were linked to more psychotic symptoms.Disclosure of InterestD. Andreou: None Declared, N. E. Steen: None Declared, K. N. Jørgensen: None Declared, T. Ueland: None Declared, L. Wortinger: None Declared, L. Mørch-Johnsen: None Declared, R. Yolken: None Declared, O. Andreassen Consultant of: Consultant to HealthLytix, Speakers bureau of: Received speaker’s honorarium from Lundbeck and Sunovion, I. Agartz Speakers bureau of: Received speaker’s honorarium from Lundbeck

Efficacy of Silexan in Patients with a Major Depressive Episode – First Results from a Multi-centre, Double-blind, Randomised, Placebo- and Reference-controlled Phase III Trial

IntroductionSilexan [1], an essential oil from Lavandula angustifolia flowers, is the active substance of a medicinal product for oral use in the treatment of anxiety disorders. It has been shown to be effective in the treatment of patients suffering from mixed anxiety and depression.[1] Silexan® is a special essential oil from Lavandula angustifolia, Dr. Willmar Schwabe GmbH & Co. KG, Karlsruhe, GermanyObjectivesThe trial (ISRCTN36202964) was conducted to investigate the antidepressant efficacy of Silexan in patients with a major depressive episode compared to placebo and Sertraline.MethodsAdult patients (≥18 years) suffering from a major depressive episode of mild to moderate severity according to ICD‑10 were included. Further inclusion criterion was a total score of 19 – 34 points in the Montgomery-Asberg-Depression Rating Scale (MADRS). Randomised patients took 80 mg Silexan, 50 mg Sertraline, or placebo once daily over 8 weeks. Primary efficacy endpoint was the change of the MADRS total score between baseline and week 8. Response (a reduction of the MADRS total score ≥50%), remission (MADRS total score <10 at the end of the treatment), the Patient Health Questionnaire PHQ-9, the Beck Depression Inventory, the Clinical Global Impressions, and the Sheehan Disability scale served as secondary endpoints.Results The full analysis set consisted of 498 patients. Between the start and end of treatment, the MADRS total score decreased by 12.1 (13.3, 11.0) points (adjusted mean, 95% confidence interval) in patients treated with Silexan, by 12.6 (13.7, 11.5) points in patients treated with Sertraline, and by 9.95 (11.1, 8.77) points under placebo. The confirmatory analysis proved that Silexan was significantly superior to placebo (p<0.01, ANCOVA). Internal validity could be shown since the treatment effects of the active comparator Sertraline were also more pronounced compared to placebo (p<0.01). There were no relevant differences between Silexan and Sertraline. Response was achieved by 53.5% of the patients in the Silexan group, by 54.0% of the patients in the Sertraline group, and by 41.5% of the patients in the placebo group. 44.4% of the patients treated with Silexan were remitter, compared to 45.2% under Sertraline and 32.6% under placebo. In both active treatment groups responder and remission rates were higher than in the placebo group (p < 0.05). Results of the secondary endpoints were in line with the results of the primary endpoint.Conclusions In a large phase III clinical trial, Silexan was more effective than placebo and not different to Sertraline in patients with a major depressive episode. Treatment effects were clinically relevant.Disclosure of InterestS. Kasper Consultant of: In the past 3 years Dr Kasper served as a consultant or on advisory boards for Angelini, Biogen, Boehringer, Esai, Janssen, IQVIA, Mylan, Recordati, Rovi, Sage and Schwabe; and he has served on speakers bureaus for Angelini, Aspen Farmaceutica S.A., Biogen, Janssen, Recordati, Schwabe, Servier, Sothema, and Sun Pharma., Speakers bureau of: In the past 3 years Dr Kasper served as a consultant or on advisory boards for Angelini, Biogen, Boehringer, Esai, Janssen, IQVIA, Mylan, Recordati, Rovi, Sage and Schwabe; and he has served on speakers bureaus for Angelini, Aspen Farmaceutica S.A., Biogen, Janssen, Recordati, Schwabe, Servier, Sothema, and Sun Pharma., E. Seifritz Consultant of: Schwabe, Janssen, Speakers bureau of: Schwabe, Janssen, H.-P. Volz Consultant of: Schwabe, Janssen, Speakers bureau of: Schwabe, Janssen

The preponderance of major depressive disorder among women of reproductive age and the clinical utility of sertraline

IntroductionMajor depressive disorder (MDD) is twice as common in women than men and is more frequently reported during their reproductive years (Shi et al. Front. Psychiatr 2021; 12 589687). MDD affects up to 12.7% of pregnant women and can significantly impact foetal and maternal health. Hence, clinical practice guidelines recommend focused screening and expedited management of MDD in women (Guo et al. Obstet. Gynecol 2018; 131(4) 671-679). Despite this, drug labelling or dosing recommendations rarely account for gender or physiological differences between sexes, even though sex steroid level variations can impact drug absorption, distribution, metabolism, and activity both pharmacokinetically and pharmacodynamically (Soldin et al. Clin Pharmacokinet. 2009; 48(3): 143–157). Sertraline, an SSRI approved for the treatment of MDD, is one of the safer agents which can be given to childbearing or breastfeeding women (Cuomo et al. Expert Opin Drug Saf 2018; 17(7) 719-725). However, studies on the efficacy of sertraline for the treatment of MDD among women of childbearing age are limited.ObjectivesThis post-hoc pooled analysis evaluated the efficacy of sertraline in women with MDD, with a particular focus on women of reproductive age.MethodsA pooled data analysis of 8 short-term clinical studies of sertraline in persons with MDD (comprising 1600 participants from North America and Europe, of whom 947 were females; with moderate to severe MDD [mean±SD baseline HAM-D17 score was 23.73±3.58 for sertraline and 23.37± 3.47 for placebo]; sertraline dose, 50-200 mg) was performed. HAM-D17 total score was used to assess the efficacy of sertraline compared with placebo. The study period was 8 weeks. An MMRM method was used to analyse changes over time and ANCOVA to evaluate the change from baseline at week 8 with LOCF employed to manage missing data.ResultsThe analysis set consisted of 947 women (sertraline, 612; placebo, 335). The change from baseline in HAM-D17 total score was significantly higher for sertraline than for placebo at the end of 8 weeks (LS mean difference, 95% CI: -1.81 [-3.01, -0.62], p=0.0029, Figure 1A). This change from baseline was statistically significant starting from week 2 and increased over time (Week 2-8; Figure 2A).The analysis set for women of child-bearing age consisted of 572 participants aged 18-44 (sertraline, 359; placebo, 213) from 7 clinical studies. The change from baseline in HAM-D17 total score was significantly higher for sertraline than for placebo at the end of 8 weeks (LS mean difference, 95% CI: -2.08 [-3.52, -0.64], p=0.0047, Figure 1B). This change from baseline was statistically significant starting from week 2 (Figure 2B).Image:Image 2:Conclusions Significant improvement in HAM-D17 scores was observed in the analysis, suggesting that sertraline is efficacious in treating women with MDD, including those in the childbearing age.Disclosure of InterestA. Fagiolini Grant / Research support from: Angelini, Boheringer Ingelheim, Janssen, Consultant of: Angelini, Biogen, Boheringer Ingelheim, Lundbeck, Janssen, Mylan, Neuraxpharm, Otsuka, Pfizer, Recordati, Rovi, Sanofi Aventis, Viatris, Speakers bureau of: Angelini, Apsen, Biogen, Boheringer Ingelheim, Glaxo Smith Kline, Lundbeck, Janssen, Mylan, Neuraxpharm, Otsuka, Pfizer, Recordati, Rovi, Sanofi Aventis, Viatris, Vifor, M. Mariano Consultant of: Johnson & Johnson, Otsuka Pharmaceutical Inc., Speakers bureau of: Viatris Pharmaceuticals, Inc. Otsuka (Philippines) Pharmaceutical, Inc. H. Lundbeck A/S, Johnson & Johnson Philippines, Inc., E. Biesheuvel Employee of: Viatris Inc. Netherlands, P. Purushottamahanti Employee of: Viatris Inc. India

“They say I’m crazy, but I’ve lived through hell.”

IntroductionMigration has been present in the evolution of human beings throughout history. Economic inequalities give rise to a permanent flow of people trying to improve their lives. In addition, there are people who are forced to seek asylum or refuge due to wars or political violence. Therefore, the migratory flow, gives rise to a clinical scenario in which, the arrival of immigrant people demands an adaptation of the psychiatric paradigm.ObjectivesThe objective of this paper is to review the international scientific literature published on the impact of the migration process on mental health.MethodsWe propose a review of the international scientific literature published in recent years on psychiatry and migration.We present the case of a 27-year-old male, diagnosed with paranoid schizophrenia, who arrived in the Canary Islands after a 2-year migration process from his country of origin (Senegal).ResultsThe limits between normality and pathology of certain types of behavior vary from one culture to another.In the case of a patient with a mental disorder who has undergone a migration process, an approach based on the cultural formulation of the case should be made, taking into account the process of adaptation to the culture of the host country, as well as the impact of the culture of origin on the patient’s interpretation of his or her psychopathology.ConclusionsCulture can influence the acceptance or rejection of a diagnosis and treatment, affecting the course of the disease and recovery.Therefore, understanding the cultural context in which the disease is experienced is essential for a good diagnostic evaluation and effective clinical management.Disclosure of InterestN. Molina Pérez: None Declared, J. Pereira López: None Declared, M. I. Santana Ortiz: None Declared, P. Rivero Rodríguez: None Declared, A. R. Del Rosario Grant / Research support from: Jansen Pharmaceuticals, Inc., Consultant of: Jansen Pharmaceuticals, Inc.; Lundbeck, Inc., Employee of: Universidad de Las Palmas de Gran Canaria, Speakers bureau of: Jansen Pharmaceuticals, Inc.; Lundbeck, Inc.; Otsuka Pharmaceutical Co.; Pfizer Inc.; Esteve Pharmaceuticals, S.A.; AstraZeneca Pharmaceuticals LP.; Angelini Pharma S.L.U.; Laboratorios Farmacéuticos ROVI SA., M. Grimal: None Declared, V. Acosta Pérez: None Declared

Early-onset obsessive-compulsive disorder: sociodemographic and clinical characterization of a large outpatient cohort

IntroductionObsessive-compulsive disorder (OCD) is a prevalent and disabling condition characterized by a wide variety of phenotypic expressions. Several studies have reinforced the hypothesis of OCD heterogeneity by proposing subtypes based on predominant symptomatology (Mataix-Cols et al., 2005), course (Tukel et al., 2007), and comorbidities (Mahasuar et al., 2011). Early-onset OCD could be considered a neurodevelopmental subtype of OCD, with evidence of distinct neurocircuits supporting disease progression (Park et al., 2022).ObjectivesThe aim of the present study is to evaluate the sociodemographic and clinical differences between the early-onset and late-onset subtypes in a large patient cohort.MethodsTwo hundred and eighty patients diagnosed with OCD were consecutively recruited from the OCD Tertiary Clinic at Luigi Sacco University Hospital in Milan. Sociodemographic and clinical variables were analyzed for the entire sample and compared between the two subgroups (EO: early-onset, age <18 years [40%]; LO: late-onset, age ≥ 18 years [60%]).ResultsThe EO group showed a higher frequency of male gender (65.5% vs 34.5%, p< .001, see Figure 1a), a higher presence of lifetime psychiatric comorbidities (75.7% vs 24.3%, p =.025), and higher rates of Tic and Tourette disorders (7.2% vs 0%, p=.006) compared to the LO group. Additionally, in the EO subgroup, a longer duration of untreated illness was observed (9.05 ± 10.0 vs 5 ± 7.17; p<.001, see Figure 1b), along with a lower presence of insight (33.3% vs. 66.7%, p =.024). No significant differences emerged in the Yale-Brown Obsessive-Compulsive Scale scores between the groups.Image:Image 2:ConclusionsThe early-onset OCD subtype highlights a more severe psychopathological profile compared to the late-onset group. Exploring distinct manifestations and developmental trajectories of OCD can contribute to a better definition of homogeneous subtypes, useful for studying risk factors and defining targeted therapeutic strategies for treatment.Disclosure of InterestB. Benatti Speakers bureau of: Angelini, Lundbeck, Janssen, Rovi, N. Girone: None Declared, M. Vismara: None Declared, C. Bucca: None Declared, B. Dell’Osso Grant / Research support from: Angelini, Lundbeck, Janssen, Pfizer, Otzuka, Neuraxpharm, and Livanova, Speakers bureau of: Angelini, Lundbeck, Janssen, Pfizer, Otzuka, Neuraxpharm, and Livanova.

Treatment adherence across different psychiatric disorders: findings from a large patient cohort

IntroductionMedication adherence was defined by the WHO as “the extent to which a person’s behavior coincides with the medical advice given” (WHO, 2003). Existing literature indicates that approximately 49% of patients with major psychiatric disorders do not fully adhere to their prescribed psychopharmacological therapy (Colom et al, 2002). Non-adherence can lead to partial therapeutic responses or treatment resistance, increased risk of relapse, re-hospitalization, elevated suicide risk, and overall poorer functioning, thereby compromising the patient-doctor therapeutic relationship (Garcìa et al, 2016).ObjectivesThe aim of the present study was to assess potential differences in terms of clinical features related to adherence to treatment in a large cohort of psychiatric patients of an Italian psychiatric department.MethodsThe study included 307 psychiatric patients, of any gender or age, diagnosed with unipolar depression (UD), bipolar depression (BD), anxiety disorders (AD), schizophrenic spectrum disorders (SS) or a primary diagnosis of personality disorders (PD), based on DSM-5 criteria. Patients were consecutively recruited from the Department of Psychiatry at Luigi Sacco University Hospital, in Milan. The patient’s adherence to treatment was evaluated using the Clinician Rating Scale (CRS), with a cut-off of ≥ 5 defining adherence subgroups (A+: score ≥ 5; A-: score < 5). Comparative and predictive analysis were performed for the whole sample and the two adherence subgroups.ResultsOverall, nearly one-third of the whole sample reported suboptimal medication adherence. Specifically, rates were approximately 35.3% and 32.7% for BD and SS, respectively, followed by 30.8% for PD, 28% for AD and, 20.3% for UD (see Figure 1). Patients with A- showed significantly higher current substance abuse (17.8% vs 4.5%, p<.001), along with a higher rate of lifetime substance abuse, although with a trend towards significance (31.5% vs 20.5%; p=.057). Moreover, the A- group had a significantly higher number of lifetime hospitalizations (1.35 ± 1.8 vs 0.73 ± 1.11; p<.001) and higher rate of previous psychotropic treatment dropouts compared to the A+ group (90% vs. 36.2%; p<.001, see Figure 2).Image:Image 2:ConclusionsApproximately one-third of the whole sample reported a suboptimal medication adherence, with varying rates across different diagnoses. Current and lifetime substance abuse appears to be an unfavorable transdiagnostic factor. Additionally, severe outcomes such as increased hospitalizations and a more acute disease presentation are linked to poorer adherence. Recognizing the characteristics of adherence patterns within specific diagnostic categories is crucial for designing precise interventions to enhance patient outcomes and optimize the overall effectiveness of treatment.Disclosure of InterestN. Girone: None Declared, B. Benatti Speakers bureau of: Angelini, Lundbeck, Janssen, Rovi., M. Cocchi: None Declared, F. Achilli: None Declared, C. Viganò: None Declared, M. Vismara: None Declared, B. Dell’Osso Grant / Research support from: Angelini, Lundbeck, Janssen, Pfizer, Otzuka, Neuraxpharm, and Livanova, Speakers bureau of: Angelini, Lundbeck, Janssen, Pfizer, Otzuka, Neuraxpharm, and Livanova

Dehydrated human amnion/chorion membrane to treat venous leg ulcers: a cost-effectiveness analysis.

To evaluate the cost-effectiveness of dehydrated human amnion/chorion membrane (DHACM) in Medicare enrolees who developed a venous leg ulcer (VLU). This economic evaluation used a four-state Markov model to simulate the disease progression of VLUs for patients receiving advanced treatment (AT) with DHACM or no advanced treatment (NAT) over a three-year time horizon from a US Medicare perspective. DHACM treatments were assessed when following parameters for use (FPFU), whereby applications were initiated 30-45 days after the initial VLU diagnosis claim, and reapplications occurred on a weekly to biweekly basis until completion of the treatment episode. The cohort was modelled on the claims of 530,220 Medicare enrolees who developed a VLU between 2015-2019. Direct medical costs, quality-adjusted life years (QALYs), and the net monetary benefit (NMB) at a willingness-to-pay threshold of $100,000/QALY were applied. Univariate and probabilistic sensitivity analyses (PSA) were performed to test the uncertainty of model results. DHACM applied FPFU dominated NAT, yielding a lower per-patient cost of $170 and an increase of 0.010 QALYs over three years. The resulting NMB was $1178 per patient in favour of DHACM FPFU over the same time horizon. The rate of VLU recurrence had a notable impact on model uncertainty. In the PSA, DHACM FPFU was cost-effective in 63.01% of simulations at the $100,000/QALY threshold. In this analysis, DHACM FPFU was the dominant strategy compared to NAT, as it was cost-saving and generated a greater number of QALYs over three years from the US Medicare perspective. A companion VLU Medicare outcomes analysis revealed that patients who received AT with a cellular, acellular and matrix-like product (CAMP) compared to patients who received NAT had the best outcomes. Given the added clinical benefits to patients at lower cost, providers should recommend DHACM FPFU to patients with VLU who qualify. Decision-makers for public insurers (e.g., Medicare and Medicaid) and commercial payers should establish preferential formulary placement for reimbursement of DHACM to reduce budget impact and improve the long-term health of their patient populations dealing with these chronic wounds. Support for this analysis was provided by MiMedx Group, Inc., US. JLD, and RAF are employees of MiMedx Group, Inc. WHT, BH, PS, BGC and WVP were consultants to MiMedx Group, Inc. VD, AO, MRK, JAN, NW and GAM served on the MiMedx Group, Inc. Advisory Board. MRK and JAN served on a speaker's bureau. WVP declares personal fees and equity holdings from Stage Analytics, US.

Provide the Public With Answers, Procedures About Your Speakers Bureau

Provide the Public With Answers, Procedures About Your Speakers Bureau

Patients with Atopic Dermatitis Not on Systemic Therapy have High Rates of Severe, Uncontrolled Disease, and Considerable Impact on Quality of Life

Patients with Atopic Dermatitis Not on Systemic Therapy have High Rates of Severe, Uncontrolled Disease, and Considerable Impact on Quality of Life

Synthetic Introns Identify the Novel RNA Splicing Factor GPATCH8 As Required for Mis-Splicing Induced By SF3B1 Mutations

Disclosures Mutations in the core RNA splicing factor SF3B1 are common across MDS, CLL, and clonal hematopoiesis. Prior studies have elucidated that mutations in SF3B1 result in neomorphic widespread changes in splicing due to usage of aberrant intronic branchpoint nucleotides. However, the molecular basis by which mutant SF3B1 induces mis-splicing is not established and therapeutic means to correct mis-splicing due to mutant SF3B1 do not exist. Recently, the aberrant gain-of-function splicing activity of mutant SF3B1 was harnessed to regulate expression of proteins in a mutant selective manner using synthetic version of endogenous mRNA sequences uniquely recognized by mutant SF3B1. Here, we utilized this technology to engineer a synthetic intron derived from MAP3K7 that interrupts the coding sequence of the fluorescent protein mEmerald such that mutant SF3B1 produces lower mEmerald expression than SF3B1 wild-type (WT) cells (Fig.A). This fluorescent splicing reporter was then used to perform positive enrichment whole genome CRISPR screens to identify genes whose deletion corrects SF3B1 mutant aberrant splicing. GPATCH8 was the single most robust hit. GPATCH8 knockout strongly corrected mis-splicing of both synthetic and endogenous MAP3K7 introns (Fig.A). A previously unexplored protein, GPATCH8 has domains characteristic of RNA splicing factors including a G-patch motif, thought to be important in activating RNA helicases. Interestingly, recent work suggests that mutations in SF3B1 result in mis-splicing by disrupting physical interaction of SF3B1 to the RNA helicase DHX15 via the G-patch domain containing protein SUGP1. We therefore compared SUGP1 to GPATCH8 activity, evaluating first their transcriptome-wide binding sites using TRIBE-seq. We found that both proteins predominantly target intronic sequences over other genomic regions suggesting roles in splicing. RNA-seq of SF3B1 mutant and WT cells with or without GPATCH8/SUGP1 deletion revealed that ~33% of SF3B1 mutant splicing alterations are corrected by GPATCH8 deletion, while ~60% of SF3B1 mutant splicing alterations are recapitulated upon SUGP1 deletion. GPATCH8 regulated splicing events have stronger branchpoints indicating a potential role for GPATCH8 in 3' splice site recognition. To further understand the connection between GPATCH8 and mutant SF3B1, we performed mass spectrometry studies of immunoprecipitated endogenous GPATCH8 in SF3B1 WT and mutant knockin cells. This revealed strong interaction between GPATCH8 and DHX15. GPATCH8 interacts with DHX15 at the same sites previously shown to be occupied by SUGP1 in crystal structures of the SUGP1/DHX15 interaction. These data and further biochemical studies elucidated that GPATCH8 competes with SUGP1 for interaction to DHX15. As such, deletion of GPATCH8 corrects SF3B1 mutant mis-splicing by enhancing the interaction of SUGP1 and DHX15 to the mutant SF3b complex. Given that GPATCH8 is required for a large proportion of the splicing alterations induced by mutant SF3B1, we next evaluated the phenotypic effect of correcting SF3B1 mutant mis-splicing. We first tested the impact of anti-Gpatch8 shRNAs in bone marrow from WT mice as well as animals with conditional knockin of Sf3b1 K700E, K666N, or R625H mutations. While each Sf3b1 mutation results in impaired colony formation of hematopoietic precursors in methylcellulose assays, silencing of Gpatch8 rescued colony formation from hematopoietic precursors of each of the different Sf3b1 mutant mice and was tolerated by normal hematopoietic precursors (Fig.B). Moreover, while CRISPR base-edited knockin of the SF3B1 K700E mutation in adult CD34 + cells impaired erythroid development, this erythroid differentiation defect was rescued by GPATCH8 deletion in the same cells (Fig.B). These data identify GPATCH8 as a novel RNA splicing factor involved in quality control of RNA branchpoint selection whose expression is required for mis-splicing by the different mutant forms of SF3B1. GPATCH8 antagonizes the activity of SUGP1 by competing for interaction with DHX15. These findings suggest that disrupting GPATCH8/DHX15 interaction could have important therapeutic benefit for the multitude of SF3B1 mutant hematopoietic diseases. This study also demonstrates the power of synthetic intronic splicing assays for discovery of trans factors and druggable proteins required by leukemia-associated mutant RNA splicing factors. Abdel-Wahab: AbbVie, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Loxo/Lilly: Consultancy; Nurix Therapeutics: Research Funding; Minovia Therapeutics: Research Funding; Amphista Therapeutics: Consultancy; AstraZeneca: Consultancy; Harmonic Discovery: Current holder of stock options in a privately-held company. Figure 1

2493. Barriers and Facilitators to Hepatitis B Screening, Vaccination, and Treatment Amongst West African Immigrants in The Bronx

Abstract Background There is a high burden of hepatitis B virus (HBV) in West Africa. Over the past 20 years, West African immigration to the U.S. has been increasing, especially to the Bronx. Prevalence of HBV infection in West Africa has been reported to be as high as 5-10%. We sought to understand knowledge and attitudes of and barriers and facilitators to HBV screening, vaccination, and treatment in a cohort of people living with and at risk for HBV. Methods We recruited participants through an HBV outreach program (The Starfish Program) which provides free HBV education, screening, and vaccination with a focus on West Africans. We conducted one-on-one in-depth, in-person qualitative interviews with West African immigrants over the age of 18 residing in the Bronx. Our interviews were guided by the modified socioecological model (SEM), which includes individual, social network, community, and societal domains. The interviews assessed participants’ understanding of HBV, social issues surrounding HBV in their community, and structural factors affecting their ability to seek healthcare. Data were analyzed in an iterative process using a thematic analysis. Results Participants (n=23) had origins in 6 different West African nations, although mainly from Ghana and Nigeria, with a median age of 49.5 (IQR 40-66). 56.5% were female. 7 were HBV surface antigen (HBsAg) positive, 6 were HBsAg negative, and 10 had unknown status at the time of interview. Median time since immigrating was 15.5 years (IQR 4-21). Key barriers included limited knowledge of HBV, HBV-related stigma, lack of health insurance, and undocumented immigration status/fear of deportation. Key facilitators included trust in U.S. healthcare providers and healthcare system, social support networks, and ease of accessing healthcare after obtaining health insurance. Demographics of interview participants Conclusion Raising awareness of HBV, addressing social and structural barriers such as stigma and health insurance, and improving access to culturally sensitive programs among West African communities could help increase HBV screening, vaccination, and treatment in this vulnerable population. Disclosures Samuel Sigal, MD, Eli Lilly: Grant/Research Support|Gilead Sciences: Grant/Research Support|Gilead Sciences: Speakers Bureau|Intercept: Grant/Research Support|Mallenchrodt: Advisor/Consultant|Mallenchrodt: Grant/Research Support