Roche Pharma Research Articles

1095-P: Glycemic Trend in Metropolitan versus Non-metropolitan Cities of India: One-Year Results of LANDMARC

Data on glycemic status in patients with diabetes from metropolitan and non-metropolitan cities of India are unavailable. Hence, glycemic trend was evaluated among patients from metropolitan versus non-metropolitan cities during the first year of LANDMARC trial (a 3-year nationwide prospective observational study; CTRI/2017/05/008452). A total of 6236 patients with type 2 diabetes (T2D) taking ≥2 antihyperglycemic medications (with/without glycemic control) were enrolled, of which 5654 completed 1-year follow-up visit. The age, T2D duration, baseline A1C were comparable across patients from metropolitan and non-metropolitan cities (Table). At 1-year, a decrease in all glycemic parameters was noted. However, the difference in fall in A1C from baseline between patients from metropolitan and non-metropolitan cities was not significant (mean [95% CI]: -0.5% [-0.5, -0.4] vs. -0.5% [-0.5, -0.4]; p=0.86). For FPG and PPG, the difference in change from baseline between the two groups was also not significant (p>0.05) (Table). In the first-year, patients from both metropolitan and non-metropolitan cities showed marked improvement in glycemic status with similar trends for change in glycemic parameters. These results help compare the longitudinal glycemic patterns among patients with T2D in metropolitan and non-metropolitan cities across India.View largeDownload slideView largeDownload slide DisclosureA. Unnikrishnan: Advisory Panel; Self; Sanofi-Aventis, Other Relationship; Self; Novo Nordisk A/S, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes. R. Ghosh: Employee; Self; Sanofi. S. Krishnan: Employee; Self; Sanofi. A. Nair: Employee; Self; Sanofi. S. Mohanasundaram: Employee; Self; Sanofi. S. K. Menon: Employee; Self; Sanofi. V. Salvi: Employee; Self; Sanofi. D. Chodankar: Employee; Self; Sanofi. C. Trivedi: None. S. Wangnoo: None. A. H. Zargar: None. A. K. Das: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk, Roche Pharma, Sanofi. N. Rais: None. S. Joshi: Advisory Panel; Self; Abbott, AstraZeneca, Biocon, Franco Indian, Glenmark, Lupin, Marico, Roche, Twinhealth, Zydus, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk, Sanofi, Serdia Pharmaceuticals (India) Pvt. Ltd. A. Mithal: Advisory Panel; Self; Eris Lifesciences Limited, Consultant; Self; Glenmark Pharmaceuticals Limited, Lupin Pharmaceuticals, Inc., USV Private Limited, Speaker’s Bureau; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Intas Pharmaceuticals Ltd., Novo Nordisk, Sanofi. S. Kalra: Speaker’s Bureau; Self; Eli Lilly and Company, Novo Nordisk, Sanofi. K. Kumar: Advisory Panel; Self; Sanofi-Aventis. H. Thacker: None. B. Sethi: None. S. Chowdhury: None.FundingSanofi

95-OR: Safety and Feasibility Evaluation of Closed-Loop Glycemic Management in Pregnant Women with Type 1 Diabetes

Pregnancy complicated by type 1 diabetes (T1D) is associated with increased maternal and fetal morbidity and mortality. We report results from the first clinical trial testing a closed-loop control (CLC) system specifically designed for pregnant women with T1D in the United States. Eight pregnant women with T1D participated in a 48-hour clinical trial at three US sites (NCT04492566). Women were enrolled in the second trimester after organogenesis was completed. CLC sessions used the interoperable artificial pancreas system (iAPS) running a Zone-Model Predictive Control algorithm designed for stricter glycemic targets for pregnancy. Glycemic target zones were 80-110 mg/dL during the day and 80-100 mg/dL overnight, with assertive insulin delivery in the postprandial period. The primary outcome was sensor glucose time in range (TIR) for pregnancy 63-140 mg/dL as per international consensus guidelines. All enrolled subjects completed the trial. Participants had a mean age of 29.3±3.5 years, gestational age of 22.2±3.6 weeks, weight of 77±12.2 kg, and HbA1c of 5.7±0.5%. Mean sensor TIR 63-140 mg/dL was 79.3±12.8% during CLC, compared to 60.8±18.8% for the week prior in open loop at home (p=0.03, Table 1). Unrestricted carbohydrate intake at meals ranged from 7 to 78 grams during the CLC sessions. No severe hypoglycemia or adverse events occurred. CLC in pregnant women with T1D is safe and effective. Disclosure B. Ozaslan: None. M. Church: None. M. Plesser: None. S. K. Mccrady-spitzer: None. C. Bakus: None. S. J. Ogyaadu: None. K. Nelson: None. C. Reid: None. S. Deshpande: None. W. K. Kremers: Research Support; Self; AstraZeneca, Biogen, Roche Pharma. F. J. Doyle: Advisory Panel; Self; Mode AGC, Other Relationship; Self; Dexcom, Inc., Insulet Corporation, Roche Diabetes Care. C. J. Levy: Advisory Panel; Self; Dexcom, Inc., Eli Lilly and Company, Employee; Spouse/Partner; AbbVie Inc., Other Relationship; Self; Dexcom, Inc., Research Support; Self; Abbott Diabetes, Dexcom, Inc., Insulet Corporation, Tandem Diabetes Care. B. Rosenn: None. Y. C. Kudva: Research Support; Self; Dexcom, Inc. E. Dassau: Consultant; Self; Eli Lilly and Company, Employee; Self; Eli Lilly and Company, Research Support; Self; Dexcom, Inc., Tandem Diabetes Care, Speaker’s Bureau; Self; Dexcom, Inc., Roche Diabetes Care, Stock/Shareholder; Self; Eli Lilly and Company. J. E. Pinsker: Advisory Panel; Self; Medtronic, Consultant; Self; Eli Lilly and Company, Tandem Diabetes Care, Research Support; Self; Dexcom, Inc., Insulet Corporation, Medtronic, Tandem Diabetes Care. G. O’malley: Research Support; Self; Abbott Diabetes, Dexcom, Inc., Horizon Therapeutics plc, Tandem Diabetes Care. R. Kaur: None. K. N. Castorino: Consultant; Self; Dexcom, Inc., Research Support; Self; Abbott Diabetes, Abbott Laboratories, Dexcom, Inc., Drawbridge Health, Inc., Lilly Diabetes, Medtronic, Novo Nordisk Inc. C. Levister: Research Support; Self; Abbott Diabetes, Insulet Corporation. M. Trinidad: None. D. Desjardins: None. Funding National Institutes of Health (R01DK120358); Dexcom, Inc. (AP-2020-014)

817-P: Inside CKD: Modeling the Direct Economic Burden of Concomitant Chronic Kidney Disease and Type 2 Diabetes

Background: Inside CKD aims to model the future global clinical and economic burden of chronic kidney disease (CKD). Type 2 diabetes (T2D) is a leading cause of CKD, and concomitant CKD and T2D place a significant burden on healthcare systems worldwide. Methods: We used the Inside CKD country-specific, patient-level microsimulation to model global healthcare costs for patients with concomitant CKD and T2D from 2020 to 2025. We constructed virtual populations using country-specific data including demographics, prevalence of CKD (by stage), T2D and complications, and direct costs, from multiple published sources (e.g., NHANES for US; HSE for UK). Results: Preliminary results from three countries show that annual healthcare costs for patients with both CKD and T2D are expected to increase from 2020 to 2025 (US, $51.1B-95.3B; Canada, C$6.5B-11.5B; UK, £2.3B-2.7B) (Figure). Costs attributable to CKD stage 4 are expected to increase the most (US, 4-9% of overall costs; Canada, 9-13%; UK, 7-11%). Conclusion: Healthcare costs for patients with both CKD and T2D are projected to increase in the UK, US and Canada from 2020 to 2025. Later CKD stages are associated with more pronounced cost increases, likely due to both increased prevalence and greater treatment complexity. Early diagnosis and interventions to slow CKD progression are needed to reduce the economic burden of concomitant stage 3-5 CKD and T2D. Disclosure J. Sanchez: Employee; Self; AstraZeneca, Stock/Shareholder; Self; AstraZeneca. J. Halimi: None. E. Kanda: Speaker’s Bureau; Self; AstraZeneca K. K. G. Li: None. F. Mennini: None. J. Navarro-gonzalez: None. S. T. Nolan: Employee; Self; AstraZeneca, Employee; Spouse/Partner; Biomarin, Stock/Shareholder; Self; AstraZeneca, Stock/Shareholder; Spouse/Partner; Biomarin. A. Power: Advisory Panel; Self; AstraZeneca, Bayer U. S., Napp Pharmaceuticals, Vifor Pharma Management Ltd., Consultant; Self; AstraZeneca, Speaker’s Bureau; Self; Alexion Pharmaceuticals, Inc., AstraZeneca, Napp Pharmaceuticals, Vifor Pharma Management Ltd. L. Retat: Employee; Self; HealthLumen. N. Tangri: Consultant; Self; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., ClinPredict Inc, Eli Lilly and Company, Mesentech, Otsuka America Pharmaceutical, Inc., PulseData, Roche Pharma, Tricida, Inc., Research Support; Self; Janssen Pharmaceuticals, Inc. L. Webber: Employee; Self; HealthLumen. A. Sultan: Employee; Self; AstraZeneca, Stock/Shareholder; Self; AstraZeneca. J. Wish: Advisory Panel; Self; Akebia Therapeutics, Inc., AstraZeneca, Rockwell Medical, Vifor Pharma Management Ltd., Speaker’s Bureau; Self; Akebia Therapeutics, Inc., AstraZeneca. M. Xu: Employee; Self; HealthLumen. J. Arnlov: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Other Relationship; Self; Novartis AG. M. C. Batista: None. C. Cabrera: Employee; Self; AstraZeneca, Stock/Shareholder; Self; AstraZeneca. J. Card-gowers: Employee; Self; HealthLumen . S. Chadban: Advisory Panel; Self; Astellas Pharma Inc., AstraZeneca, Novartis Pharmaceuticals Corporation. G. M. Chertow: Advisory Panel; Self; Ardelyx, Baxter, Cricket Health, DURECT Corporation, Gilead Sciences, Inc., Reata Pharmaceuticals, Inc., Other Relationship; Self; Akebia Therapeutics, Inc., AstraZeneca, Vertex Pharmaceuticals Incorporated. L. Denicola: Consultant; Self; AstraZeneca, Mundipharma International, Novo Nordisk. Funding AstraZeneca

1087-P: Therapy Trends at One Year in the Longitudinal LANDMARC Study on Real-World Outcomes in Type 2 Diabetes Patients in India

Therapy patterns were examined across various subgroups during the first year of LANDMARC, a 3-year prospective observational study (CTRI/2017/05/008452) that included patients with T2D on ≥2 antihyperglycemic medications. Of 6236 patients (mean baseline values - age: 52.1 years, T2D duration: 8.6 years and A1C: 8.05%) enrolled, 5654 completed 1-year follow-up visit. Therapeutic management was at the discretion of the treating physician. At the end of the first year, the proportion of patients taking insulin + OAD increased (baseline: 24%; 1-year: 30.7%); while, those taking only OADs decreased (baseline: 74.4%; 1-year: 67.3%). Biguanides and sulfonylureas were the most commonly used OAD classes, the highest increase in use was seen for DPP4 inhibitors (baseline: 48.9%; 1-year: 58.7%). Overall, at 1-year, glycemic parameters improved significantly (p≤0.001); HbA1c improved more in the insulin versus insulin naïve subgroup (p<0.0001) (Table); but no statistical difference was noted in those who received >3 versus ≤3 OADs. All glycemic parameters improved in those receiving basal or premix insulins. Overall, 1-year data indicate that timely initiation of insulin may play an important role in improving glycemic parameters.View largeDownload slideView largeDownload slide DisclosureH. Thacker: None. R. Ghosh: Employee; Self; Sanofi. S. Krishnan: Employee; Self; Sanofi. A. Nair: Employee; Self; Sanofi. S. Mohanasundaram: Employee; Self; Sanofi. S. K. Menon: Employee; Self; Sanofi. V. Salvi: Employee; Self; Sanofi. D. Chodankar: Employee; Self; Sanofi. C. Trivedi: None. S. Wangnoo: None. A. H. Zargar: None. A. K. Das: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk, Roche Pharma, Sanofi. N. Rais: None. S. Joshi: Advisory Panel; Self; Abbott, AstraZeneca, Biocon, Franco Indian, Glenmark, Lupin, Marico, Roche, Twinhealth, Zydus, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk, Sanofi, Serdia Pharmaceuticals (India) Pvt. Ltd. A. Mithal: Advisory Panel; Self; Eris Lifesciences Limited, Consultant; Self; Glenmark Pharmaceuticals Limited, Lupin Pharmaceuticals, Inc., USV Private Limited, Speaker’s Bureau; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Intas Pharmaceuticals Ltd., Novo Nordisk, Sanofi. S. Kalra: Speaker’s Bureau; Self; Eli Lilly and Company, Novo Nordisk, Sanofi. A. Unnikrishnan: Advisory Panel; Self; Sanofi-Aventis, Other Relationship; Self; Novo Nordisk A/S, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes. K. Kumar: Advisory Panel; Self; Sanofi-Aventis. B. Sethi: None. S. Chowdhury: None.FundingSanofi

514-P: In Search of “Glycemic Happiness”: Interim Analysis of an Observational Survey of Persons Living with Type 2 Diabetes Mellitus

Background: ‘Happiness’ is an essential component of type 2 diabetes (T2DM) management which potentially affects the treatment outcomes and psychosocial well-being of persons with T2DM. An observational survey was undertaken to understand and define “Glycemic Happiness” among persons with T2DM. Methods: A prospective, multicentric, cross sectional, observational survey involving 200 persons diagnosed with T2DM across 40 tertiary care centers in India. Interim analysis of 57 persons with T2DM is presented here. Survey (10 questions, Box 1) was based on a simple questionnaire developed by an expert panel and administered by designated personnel at study centers. Results: Responses correspond to either agree or strongly agree on a 5-point Lickert scale. To date, among 57 persons with T2DM, 53 (92.98%) and 52 (91.22%) agreed that a flexible and a convenient treatment regimen is linked to glycemic happiness respectively. Around 49 (85.96%) opined that glycemic happiness is affected by how happy and satisfied they are with their current life. A further 48 (84.22%) believed that glycemic happiness can be influenced by their understanding of T2DM. Conclusion: Apart from good glycemic control, a flexible and a convenient treatment regimen, level of diabetes education and their current satisfaction with life are important determinants of glycemic happiness in persons living with T2DM. Disclosure S. Kalra: Advisory Panel; Self; Dr Reddy’s Laboratories. A. K. Das: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk, Roche Pharma, Sanofi. G. Priya: Advisory Panel; Self; Dr. Reddy’s Laboratories. N. K. Polavarapu: Employee; Self; Dr. Reddy’s Laboratories. K. Gaurav: Employee; Self; Dr. Reddy’s Laboratories. A. Mane: Employee; Self; Dr. Reddy’s Laboratories. C. S. Pinto: Employee; Self; Dr. Reddy’s Laboratories. Funding Dr. Reddy’s Laboratories, Ltd.

1030-P: Cardiorenal Complications in Young-Onset T2DM Compared between White Caucasian and African American in the USA

Aim: Complex associations between T2DM, CKD and HF challenge treatment strategies and results in significant life years loss. Risk of CKD and HF in young- and usual-onset T2DM among White Caucasian (WC) and African American (AA) were explored.Methods: From nationally representative EMRs of USA, 1491672 WC and 31133 AA diagnosed with T2DM from 2000-2018 within age 18-39 /40-49/50-59/ 60-69 yrs were identified. The restricted mean time (RMT) to CKD and HF in AA and WC were compared, adjusting for anthropometric and time-varying disease confounders.Results: At T2DM Dx, 10 /12% and 2 /4% of WC /AA had existing CKD and HF; 48 /57% and 39 /32% had hypertension and dyslipidaemia. With mean 5 yrs follow-up, 95% CIs of CKD+HF incidence rates/1000PY were: (23-24) /(37-38) /(53-54) /(82-83) in 18-39 /40-49 /50-59/ 60-69 yrs grps for WC and (30-31) /(47-49) /(66-68) /(93-95) for AA.Compared to WC, AA had significantly higher risk of CKD and HF across all age groups (HR CI range: 1.1-2.4). In AA/WC aged 18-39 yrs, RMT (CI) in yrs to CKD [8.3 (7.8-8.7) /8.9 (8.5-9.2)] and HF [9.4 (8.6-10.3) /11.4 (9.8-12.9)] was on average only 3.2 /3.2 yrs and 2.7 /3.3 longer compared to those aged 60-69 yrs at Dx (Fig).Conclusion: Developing cardio-renal complications within 10 yrs of young-onset T2DM and significant higher risk among AA compared to WC call for more intense prevention strategies in young-onset population, particularly in AA.View largeDownload slideView largeDownload slide DisclosureS. K. Paul: Advisory Panel; Self; Sanofi, Consultant; Self; Roche Pharma. O. Montvida: None.

162-LB: Plasma Glycated CD59 Predicts Postpartum Glucose Intolerance after Gestational Diabetes

pGCD59 is an emerging biomarker for diabetes and GDM. In studies of women undergoing GDM screening either early in pregnancy (week &amp;lt;20) or at pregnancy weeks 24-28, pGCD59 classified GDM subjects with high sensitivity and specificity and was associated with the prevalence of large for gestational age (LGA) babies (Diabetes Care 2017 and JCEM 2020). GDM developed early in pregnancy imparts a seven-fold increased risk of subsequent glucose intolerance and diabetes. Since HbA1c is not sensitivity to detect glucose intolerance in early postpartum, professional organizations including ADA, recommend that women with GDM should undergo OGTT testing 6-12 weeks postpartum. However, the cumbersome nature of OGTT makes compliance with this requirement very low, highlighting the need for alternative biomarkers that can be used postpartum to test women with GDM for potential conversion glucose intolerance. To assess the ability of pGCD59 to identify postpartum conversion to glucose intolerance in women with GDM, levels of pGCD59 were measured in samples from participants in the Belgian Diabetes in Pregnancy (BEDIP-N, Diabetes Care 2018) cohort study who underwent OGTT testing 6-12 weeks postpartum. Among 105 samples from women with GDM, 36 subjects met OGTT criteria for glucose intolerance (cases) and 70 had normal OGTT (matched controls). Maternal age, race/ethnicity, and BMI were similar among Cases and Controls. pGCD59 was significantly higher in cases than in controls (1.5 ±0.6 SPU vs. 1.0 ±0.6 SPU, p &amp;lt; 0.001) and accurately predicted the postpartum conversion to glucose intolerance as indicated by an AUCROC of 0.72 (95% CI 0.62-0.83). A 0.5-unit increase in postpartum pGCD59 was associated with an OR of 2.0 (95% CI 1.34-2.95, p&amp;lt;0.001) for glucose intolerance. Our results indicate that pGCD59 is a simpler biomarker to assess postpartum conversion to glucose intolerance in women with GDM and represents an alternative to improve compliance with postpartum screening for glucose intolerance. Disclosure K. Benhalima: None. D. Ma: None. M. Toth castillo: None. A. Laenen: None. C. Mathieu: Advisory Panel; Self; Novo Nordisk, Sanofi, Merck Sharp and Dohme Ltd., Eli Lilly and Company, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Medtronic, ActoBio Therapeutics, Pfizer, Insulet and Zealand Pharma, Research Support; Self; Medtronic, Novo Nordisk, Sanofi and ActoBio Therapeutics, Speaker’s Bureau; Self; Novo Nordisk, Sanofi, Eli Lilly and Company, Boehringer Ingelheim, AstraZeneca and Novartis. J. Halperin: Board Member; Self; Mellitus, LLC. Funding National Institutes of Health (R01DK118528, DK101442); Belgian National Lottery; Fund of Academic Studies of UZ Leuven; Yvonne and Jacques François-de Meurs of the King Boudewijn Foundation

675-P: Effects of Liraglutide in T1D by Baseline Anthropometrics in ADJUNCT One and Two

We re-evaluated the efficacy and safety of liraglutide, a GLP-1 analog, for use as adjunctive therapy in people with type 1 diabetes (T1D). Results from the two ADJUNCT trials suggested that residual beta-cell function is associated with more pronounced benefits and less risk of hypoglycemia. Here we analyze results of the two trials according to other baseline anthropometrics. ADJUNCT ONE (NCT01836523) and TWO (NCT02098395) were randomized controlled phase 3 trials in broad T1D populations (1398 and 835 participants, respectively) treated with liraglutide (1.8, 1.2 or 0.6 mg) or placebo. ADJUNCT ONE was a 52-week trial with a treat-to-target design and no limits on insulin titration; ADJUNCT TWO was a 26-week trial with an individual maximal insulin dose. In a post hoc analysis, we evaluated certain estimated placebo-adjusted treatment effects across clinically relevant participant subgroups. At week 26 in ADJUNCT ONE, placebo-adjusted reductions in HbA1c, body weight (BW) and daily insulin dose (up to -0.30 %-points, -5.0 kg and -12%, respectively, with liraglutide 1.8 mg) were significant (p&amp;lt;0.05) and greater than at week 52. In both trials, the placebo-adjusted reductions in HbA1c, BW and daily insulin dose with liraglutide did not depend (p&amp;gt;0.05) on baseline HbA1c or BMI at neither week 26 nor 52. The risk of clinically significant hypoglycemia (symptomatic episodes with blood glucose &amp;lt;3.1 mmol/L) or hyperglycemia with ketosis did not differ significantly (p&amp;gt;0.05 vs. placebo) by baseline HbA1c, BMI or insulin regimen. In ADJUNCT ONE and TWO, the efficacy and glycemic safety of liraglutide did not depend on key baseline anthropometrics. This leaves residual beta-cell function the only identified parameter impacting the treatment effect of the GLP-1 analog used as an adjunct to insulin in T1D. Together with recent progress in the understanding of T1D and of the benefits of GLP-1 receptor agonism, these findings suggest a role for GLP-1 receptor agonists in T1D, warranting further study. Disclosure T. F. Dejgaard: Advisory Panel; Self; Novo Nordisk, Consultant; Self; Boehringer Ingelheim International GmbH, Research Support; Self; AstraZeneca, Novo Nordisk, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk. L. Bardtrum: Employee; Self; Novo Nordisk A/S, Stock/Shareholder; Self; Novo Nordisk A/S. E. Christiansen: None. F. Kreiner: Employee; Self; Novo Nordisk A/S, Stock/Shareholder; Self; Novo Nordisk A/S. S. Madsbad: Advisory Panel; Self; AstraZeneca; Boehringer Ingelheim; Eli Lilly; Merck Sharp &amp; Dohme; Novo Nordisk; Sanofi, Research Support; Self; Novo Nordisk, Boehringer Ingelheim, Speaker’s Bureau; Self; AstraZeneca; Boehringer Ingelheim; Merck Sharp &amp; Dohme; Novo Nordisk; Sanofi. M. G. Von herrath: Employee; Self; Novo Nordisk A/S, Stock/Shareholder; Self; Novo Nordisk A/S. B. Von scholten: Employee; Self; Novo Nordisk A/S, Stock/Shareholder; Self; Novo Nordisk A/S. C. Mathieu: Advisory Panel; Self; Novo Nordisk, Sanofi, Merck Sharp and Dohme Ltd., Eli Lilly and Company, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Medtronic, ActoBio Therapeutics, Pfizer, Insulet and Zealand Pharma, Research Support; Self; Medtronic, Novo Nordisk, Sanofi and ActoBio Therapeutics, Speaker’s Bureau; Self; Novo Nordisk, Sanofi, Eli Lilly and Company, Boehringer Ingelheim, AstraZeneca and Novartis. Funding Novo Nordisk A/S

726-P: Glucose Control Using Fast-Acting Insulin Aspart in a Real-World Setting: A One-Year Multicenter Study in People with Type 1 Diabetes Using Continuous Glucose Monitoring

Objective: Data on switching from traditional mealtime insulin analogs to fast-acting insulin aspart (Fiasp) in routine clinical practice are sparse. The aim was to evaluate the efficacy and safety of this switch in a “real-world” clinical practice setting in adult people with type 1 diabetes (PWD1) who were using intermittent or real-time continuous glucose monitoring (iCGM or rtCGM) in Belgium. Research Design and Methods: Data from 438 adult PWD1 (60% men, age 44.6±16.1 y, duration of diabetes 21.5±14.0 y, iCGM/rtCGM: 391/47, multiple daily injections/pump: 409/29), who initiated Fiasp between January 2018 and May 2020 were retrospectively analyzed. The primary endpoint was the evolution of time in range (TIR, 70-180 mg/dl) at 6 (n=416) and 12 months (n=380). Secondary endpoints included change in HbA1c, BMI, insulin doses, time below range (T&amp;lt;70 and T&amp;lt;54 mg/dl) and time above range (T&amp;gt;180 and T&amp;gt;250 mg/dl). Results: TIR improved from 50.3±15.6% to 54.3±15.1% at 6 months and 55.5±15.2% at 12 months (p&amp;lt;0.0001), corresponding to an increase of 75 minutes/day at 12 months. T&amp;lt;70 mg/dl evolved from 7.4±5.5% to 7.6±5.8% and to 6.8±5.5% (p=0.037), and T&amp;lt;54 mg/dl evolved from 3.1±3.3% to 3.1±3.7% and 2.5±3.0% (p=0.003) at 6 and 12 months, respectively. Also, T&amp;gt;180 mg/dl decreased from 42.3±16.7% to 38.1±16.5% and to 37.7±16.9% (p&amp;lt;0.0001), and T&amp;gt;250 mg/dl evolved from 16.5±12.8% to 13.8±11.8% and to 13.1±12.5% (p&amp;lt;0.0001) at 6 and 12 months. At 12 months HbA1c (from 7.8±1.1% to 7.7±1.0%), insulin doses (0.66±0.24 to 0.62±0.21 units/kg body weight/day and ratio bolus/basal from 1.28 to 1.30) and BMI (from 25.8±4.0 to 26.2±4.1 kg/m2) did not change significantly. Conclusions: In a Belgian real-world setting of adult PWD1, switching to Fiasp resulted in a 5% increased TIR, corresponding to 75 min/day, in combination with less time spent below and above range. Disclosure L. Billion: None. F. W. Peiffer: None. K. P. Van dessel: None. C. Mathieu: Advisory Panel; Self; Novo Nordisk, Sanofi, Merck Sharp and Dohme Ltd., Eli Lilly and Company, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Medtronic, ActoBio Therapeutics, Pfizer, Insulet and Zealand Pharma, Research Support; Self; Medtronic, Novo Nordisk, Sanofi and ActoBio Therapeutics, Speaker’s Bureau; Self; Novo Nordisk, Sanofi, Eli Lilly and Company, Boehringer Ingelheim, AstraZeneca and Novartis. P. Gillard: None. C. De block: Advisory Panel; Self; A. Menarini Diagnostics, Abbott Diagnostics, AstraZeneca, Boehringer Ingelheim , Eli Lilly and Company, MSD, Novartis AG, Novo Nordisk, Roche Diagnostics, Sanofi, Research Support; Self; AstraZeneca, Novo Nordisk, Speaker’s Bureau; Self; A. Menarini Diagnostics, Abbott Diagnostics, Boehringer Ingelheim , Eli Lilly and Company, Novo Nordisk, Sanofi. S. Charleer: None. L. Verbraeken: None. M. Sterckx: None. K. Vangelabbeek: None. N. De block: None. C. Janssen: None. N. Bolsens: Advisory Panel; Self; Medtronic. E. L. Dirinck: None.

732-P: CGM-Derived Parameters for Once-Weekly Insulin Icodec vs. Once-Daily Insulin Glargine U100 in Insulin-Naïve Patients with T2D

Insulin icodec* (icodec) is a once-weekly basal insulin in development. This post hoc analysis used data from the NCT03951805 trial to investigate CGM-derived time in, above, below range (TIR, TAR, TBR) and glycemic variability measured as coefficient of variation (CV%). Insulin-naive patients with T2D (N=205) received insulin glargine U100 (IGlar U100; pre-breakfast SMBG target 80-130 mg/dL, adjusted ±4U/day), icodec titration A (80-130 mg/dL, ±21U/week), B (80-130 mg/dL, ±28U/week; most relevant comparator to IGlar U100), or C (70-108 mg/dL, ±28U/week). Treatments were titrated weekly. TIR (70-180 mg/dL), TAR (>180 mg/dL), TBR ( 70% from weeks 7 and 8, TAR decreased to 70% TIR and TBR 70% TIR and TBR Disclosure I. Lingvay: Advisory Panel; Self; Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Consultant; Self; TARGET PharmaSolutions, Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk, Pfizer Inc., Zealand Pharma A/S, Research Support; Self; Mylan N. V., Sanofi. R. Beck bang: Employee; Self; Novo Nordisk A/S. M. M. Koefoed: Employee; Self; Novo Nordisk. J. K. Mader: Advisory Panel; Self; Becton, Dickinson and Company, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Roche Diabetes Care, Speaker’s Bureau; Self; Abbott Diabetes, Novo Nordisk A/S, Roche Diabetes Care, Sanofi, Stock/Shareholder; Self; decide Clinical Software GmbH. J. Pettus: Advisory Panel; Self; Novo Nordisk, Sanofi, Consultant; Self; Diasome Pharmaceuticals, Inc., Insulet Corporation, Lilly Diabetes, MannKind Corporation, Tandem Diabetes Care. L. Wagner: None. C. Mathieu: Advisory Panel; Self; Novo Nordisk, Sanofi, Merck Sharp and Dohme Ltd., Eli Lilly and Company, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Medtronic, ActoBio Therapeutics, Pfizer, Insulet and Zealand Pharma, Research Support; Self; Medtronic, Novo Nordisk, Sanofi and ActoBio Therapeutics, Speaker’s Bureau; Self; Novo Nordisk, Sanofi, Eli Lilly and Company, Boehringer Ingelheim, AstraZeneca and Novartis.

1111-P: Integrating Longitudinal Clinical and Baseline Multiomics Data for Predicting C-Peptide Progression in Newly Diagnosed Type 1 Diabetes

Background: Development of disease-modifying therapy for type 1 diabetes (T1D) is hampered by the limited understanding of pathogenesis, heterogeneity, lack of disease biomarkers and stratifiers. Using the INNODIA consortium pan-European infrastructure to collect prospective clinical data from newly diagnosed subjects combined with multi-omics data, we mined integrated datasets using deep learning to identify novel relationships that could transform the disease monitoring landscape. Method: Samples collected &amp;lt;6 weeks from diagnosis from 100 islet autoantibody positive participants were prioritised for omics analysis and the data integrated with clinical parameters and C-peptide (CP) from mixed meal tolerance tests (at 3, 6 and 12 months). SNP array data, plasma metabolomics, lipidomics and miRNAs, serum proteomics, whole blood RNA-sequencing and multiFACS immunomics from PBMCs were collected. We applied a variational autoencoder (VAE) to simultaneously integrate the data and learn CP progression over 12 months. The latent (lower dimensional) representation of the VAE integrated data was clustered to identify clinically meaningful subgroups. Results: Clustering identified five age-independent subgroups with significantly different progression patterns (p&amp;lt;0.05). Cluster 1 and 3 associated with lower fasted and stimulated CP. Cluster 2 and 5 associated with higher fasted CP, while cluster 4 most strongly associated with higher stimulated CP. Cluster 1 had the lowest stimulated CP at baseline, cluster 5 the lowest fasted CP and cluster 4 the highest fasted and stimulated CP at baseline. Investigation of the most predictive signals from the omics data is ongoing. Discussion: The preliminary results suggest that the VAE can learn meaningful progression patterns from integrated clinical and multi-omics data, which holds great promise to uncover important data structures not readily discovered when analyzing single data types. Disclosure C. Brorsson: Employee; Spouse/Partner; Novo Nordisk A/S. J. Almagro armenteros: None. G. Mazzoni: Employee; Self; Novo Nordisk A/S. S. Kaur: None. A. M. Schulte: None. C. Mathieu: Advisory Panel; Self; Novo Nordisk, Sanofi, Merck Sharp and Dohme Ltd., Eli Lilly and Company, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Medtronic, ActoBio Therapeutics, Pfizer, Insulet and Zealand Pharma, Research Support; Self; Medtronic, Novo Nordisk, Sanofi and ActoBio Therapeutics, Speaker’s Bureau; Self; Novo Nordisk, Sanofi, Eli Lilly and Company, Boehringer Ingelheim, AstraZeneca and Novartis. S. Brunak: Board Member; Self; Intomics A/S, Proscion A/S, Stock/Shareholder; Self; Hoba Therapeutics Aps, Novo Nordisk A/S. On behalf of the innodia consortium: n/a. Funding INNODIA (115797)

PET-guided eBEACOPP treatment of advanced-stage Hodgkin lymphoma (HD18): follow-up analysis of an international, open-label, randomised, phase 3 trial

The German Hodgkin Study Group's HD18 trial established the safety and efficacy of PET-guided eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses) for the treatment of advanced-stage Hodgkin lymphoma. However, because of a protocol amendment during the enrolment period (June 1, 2011) that changed standard treatment from eight to six cycles, the results of the HD18 trial have been partially immature. We report a prespecified 5-year follow-up analysis of the completed HD18 trial. HD18 was an international, open-label, randomised, phase 3 trial done in 301 hospitals and private practices in five European countries. Patients aged 18-60 years with newly diagnosed, advanced-stage Hodgkin lymphoma and an Eastern Cooperative Oncology Group performance status of 0-2 were recruited. After receiving an initial two cycles of eBEACOPP (1250 mg/m2 intravenous cyclophosphamide [day 1], 35 mg/m2 intravenous doxorubicin [day 1], 200 mg/m2 intravenous etoposide [day 1-3], 100 mg/m2 oral procarbazine [day 1-7], 40 mg/m2 oral prednisone [day 1-14], 1·4 mg/m2 intravenous vincristine [day 8], and 10 mg/m2 intravenous bleomycin [day 8]), patients underwent a contrast-enhanced CT and PET scan (PET-2). Patients with positive PET-2 were randomly assigned to receive standard therapy (an additional six cycles of eBEACOPP; ie, eight cycles in total) or experimental therapy (an additional six cycles of eBEACOPP plus 375 mg/m2 intravenous rituximab; ie, eight cycles in total) until June 1, 2011. After June 1, 2011, all patients with positive PET-2 were assigned to the updated standard therapy with an additional four cycles of eBEACOPP (ie, six cycles in total). Patients with negative PET-2 were randomly assigned (1:1) to receive standard therapy (an additional six cycles of eBEACOPP [ie, eight cycles in total] until June 1, 2011; an additional four cycles of eBEACOPP [ie, six cycles in total] after June 1, 2011) or experimental therapy (an additional two cycles of eBEACOPP; ie, four cycles in total). Randomisation was done centrally with the minimisation method, including a random component, stratified by centre, age, stage, international prognostic score, and sex. The primary endpoint was progression-free survival. HD18 aimed to improve 5-year progression-free survival by 15% in the PET-2-positive intention-to-treat cohort and to exclude inferiority of 6% or more in 5-year progression-free survival in the PET-2-negative per-protocol population. This study is registered with ClinicalTrials.gov, NCT00515554, and is completed. Between May 14, 2008, and July 18, 2014, 2101 patients were enrolled and 1945 were assigned to a treatment group according to their PET-2 result. In the PET-2-positive cohort, with a median follow-up of 73 months (IQR 59 to 94), 5-year progression-free survival was 89·9% (95% CI 85·7 to 94·1) in 217 patients assigned to eight cycles of eBEACOPP before the protocol amendment and 87·7% (83·1 to 92·4) in 217 patients assigned to eight cycles of rituximab plus eBEACOPP (p=0·40). Among 506 patients who received six cycles of eBEACOPP after the protocol amendment, 5-year progression-free survival was 90·1% (95% CI 87·2 to 92·9), with a median follow-up of 58 months (IQR 39 to 66). In the PET-2-negative cohort, with a median follow-up of 66 months (IQR 54 to 85) in the combined pre-amendment and post-amendment groups, 5-year progression-free survival was 91·2% (95% CI 88·4 to 93·9) in 446 patients who received eight or six cycles of eBEACOPP and 93·0% (90·6 to 95·4) in 474 patients who received four cycles of eBEACOPP (difference 1·9% [95% CI -1·8 to 5·5]). In the subgroup of PET-2-negative patients randomly assigned after protocol amendment, 5-year progression-free survival was 90·9% (95% CI 86·8 to 95·1) in 202 patients assigned to receive six cycles of eBEACOPP and 91·0% (86·6 to 95·5) in 200 patients assigned to receive four cycles of eBEACOPP (difference 0·1% [-5·9 to 6·2]). Long-term follow-up confirms the efficacy and safety of PET-2-guided eBEACOPP in patients with advanced-stage Hodgkin lymphoma. The reduction from eight to four cycles of eBEACOPP represents a benchmark in the treatment of early-responding patients, who can now be potentially cured with a short and safe treatment approach. Deutsche Krebshilfe, Swiss State Secretariat for Education, Research and Innovation SERI (Switzerland), and Roche Pharma. For the German translation of the abstract see Supplementary Materials section.

P193 Clinical features of patients with active ankylosing spondylitis who did not respond to adalimumab but responded to ixekizumab: a post-hoc analysis

Abstract Background/Aims Biologic treatment in ankylosing spondylitis (AS) are currently limited to TNF and IL-17A inhibitors (IL-17Ai). It is unknown whether there are predictors of AS patients who only respond to 1 of these mechanisms of action or respond to switching from TNF-blocker to IL-17Ai. This post-hoc analysis evaluated whether patients who did not respond to TNF inhibitor adalimumab (ADA) but did subsequently respond to IL-17Ai ixekizumab (IXE) differed from those that responded to both ADA and subsequent IXE. Methods The analysis included patients from the phase-3 COAST-V trial in bio-naive patients with active AS (BASDAI≥4 and back pain≥4 on VAS of 0-10). There were 341 patients randomized 1/1/1/1 to IXE80mg/2weeks (wks) (Q2W), IXE 80mg/4wks (Q4W), ADA 40mg Q2W (reference arm), and placebo (PBO) for the 16-week blinded-treatment period. Of these, 329 entered the dose double-blind extended treatment period (wks16 to 52). Those who received PBO or ADA were re-randomized to receive IXE 80mg Q4W or Q2W. Patients were stratified as responders or non-responders based on their Assessment of Spondyloarthritis International Society (ASAS) 40 response at wks16 and 52. Data for the 2 IXE dose groups were pooled. Results Overall, more patients responded to IXE than ADA at wk16. Based on ASAS40 response at wks16 and at wk52, 30.9% of patients responded to both initial ADA and subsequent IXE, 23.5% of patients did not respond to initial ADA but did respond to subsequent IXE, 45.9% of patients responded to IXE at both time points, and 12.3% of patients did not respond to IXE at wk16 but did so at wk52. Across the groups, patients were of similar age and predominantly males, though there were proportionally more women among those who did not respond to either ADA or IXE at wk16. However, ADA non-responders at wk16/IXE responders at wk52 had numerically lower baseline (mean[SD]) C-reactive protein (11.2 [11.2]), lower MRI Spondyloarthritis Research Consortium of Canada (SPARCC) scores of the spine (11.6 [12.1]), and lower MRI SPARCC score of the sacroiliac joints (1.1 [2.2]) than ADA responders at wk16/IXE responders at wk52 patients (16.0 [17.1], 24.6 [32.6], and 5.5 [9.8]), respectively. Conclusion In this analysis, patients who did not respond to ADA but subsequently responded to IXE exhibited overall lower levels of inflammation, as measured by CRP and MRI of the spine or sacroiliac joints, compared with patients who responded on ADA and also after switching to IXE. Along with comparative findings in patients who continuously received IXE and responded at both wks16 and 52 or wk52 only, these data indicate that IXE is efficacious in patients with active AS irrespective of inflammation level, assessed by CRP and MRI. Alternatively, lower baseline inflammation may be a predictor of delayed response. Disclosure X. Baraliakos: Consultancies; X. Baraliakos has served as a consultant for AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Merck Sharp &amp; Dohme, Novartis, Pfizer, Roche, and UCB Pharma. Grants/research support; X. Baraliakos has received research grants from AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Merck Sharp &amp; Dohme, Novartis, Pfizer, Roche, and UCB Pharma. R. Bolce: Shareholder/stock ownership; R. Bolce is a shareholder and employee of Eli Lilly and Company. D. Sandoval Calderon: Shareholder/stock ownership; D. Sandoval Calderon is a shareholder and employee of Eli Lilly and Company. S. Liu Leage: Shareholder/stock ownership; S.L. League is a shareholder and employee of Eli Lilly and Company. V. Geneus: Shareholder/stock ownership; V. Geneus is a shareholder and employee of Eli Lilly and Company. D. Adams: Shareholder/stock ownership; D. Adams is a shareholder and employee of Eli Lilly and Company. A. Deodhar: Consultancies; A. Deodhar has served as a consultant for AbbVie, Amgen, Boehringer Ingelheim, Celgene, Eli Lilly and Company, Galapagos NV, GlaxoSmithKline, Janssen, Novartis, Pfizer, and UCB Pharma. Grants/research support; A. Deodhar has received grants from AbbVie, Eli Lilly and Company, GlaxoSmithKline, Novartis, Pfizer, and UCB Pharma. J. Walsh: Consultancies; J. A. Walsh has received consultancy fees from AbbVie, Eli Lilly and Company, Novartis, and UCB Pharma. Grants/research support; J. A. Walsh has received grant/research support from AbbVie and Pfizer. J. Sieper: Consultancies; J. Sieper is a consultant for: AbbVie, Eli Lilly and Company, Novartis, Merck, Janssen, Pfizer. Other; J. Sieper has served as a speaker for: AbbVie, Janssen, Novartis, Merck, Pfizer, and UCB.

P134 Radiographic progression of structural joint damage over 5 years of baricitinib treatment in patients with RA: results from RA-BEYOND

Abstract Background/Aims Baricitinib (BARI) is an oral, reversible, selective JAK1/2 inhibitor. Treatment with once-daily oral BARI resulted in low rates of radiographic progression for up to 2 years in patients with rheumatoid arthritis (RA). Here, we evaluate the radiographic progression of structural joint damage in patients with RA over 5 years of treatment with BARI. Methods This included patients who completed three Phase 3 trials, RA-BEGIN (DMARD-naive), RA-BUILD (csDMARD-IR), or RA-BEAM (MTX-IR), and enrolled in long-term extension study, RA-BEYOND. Patients receiving blinded BARI at the conclusion of Phase 3 trials remained on that dose (2mg/4mg, once daily) in RA-BEYOND. At 52 weeks, DMARD-naive patients receiving methotrexate(MTX) or combination therapy(BARI 4mg+MTX) were switched to BARI 4mg monotherapy; MTX-IR patients receiving adalimumab(ADA) were switched to BARI 4mg on background MTX. At 24 weeks, csDMARD-IR patients receiving placebo(PBO) were switched to BARI 4mg on background csDMARD. Analysis population included patients who had baseline and at least one radiograph collected after 2 years. Radiographic progression of structural joint damage (Years 3-5) was determined by changes from baseline in van der Heijdemodified Total Sharp Score(ΔmTSS), erosion score, and joint space narrowing. Proportion of patients showing no progression was assessed based on change from baseline mTSS(ΔmTSS) from originating study, using thresholds of 0.5 or smallest detectable change(SDC). Mixedmodel repeatedmeasures and logistic regression models were used to analyze continuous variables and categorical variables, respectively; linear extrapolation was used for imputation of missing data(maximum of 1 year). Results 82.6% (2125/2573) of patients entered long-term extension study. Among DMARD-naive patients, those on initial BARI monotherapy or in combination with MTX had significantly slower radiographic progression(ΔmTSS) versus those on initial MTX at Years 3, 4, 5 (p ≤ 0.05). They had significantly fewer erosions at these time points (p ≤ 0.05). A greater proportion of patients who received initial BARI therapy and BARI+MTX had no radiographic progression versus initial MTX monotherapy using thresholds of 0.5 (p ≤ 0.05). Among MTX-IR patients, those on initial BARI treatment had slower radiographic progression compared to PBO and results were comparable to those on initial ADA treatment at Years 3, 4, 5. A greater proportion of patients who received initial BARI therapy had no radiographic progression versus initial PBO using thresholds of SDC (p ≤ 0.05). Among csDMARD-IR patients, although differences between groups were small, patients on initial BARI 4mg had slowest radiographic progression compared to initial PBO and initial BARI 2mg. At least 74% of the structure data used in the analyses are based on observed data. Conclusion Treatment with once-daily oral BARI maintained low rates of radiographic progression for up to 5 years in different patient populations with RA. Disclosure D.M.F.M. van der Heijde: Consultancies; AbbVie, Amgen, Astellas, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Cyxone, Daiichi Sankyo, Eli Lilly and Company, Galapagos NV, Gilead Sciences, Janssen, Merck Sharp &amp; Dohme, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, and UCB Pharma. C.E. Kartman: Shareholder/stock ownership; Eli Lilly and Company. L. Xie: Shareholder/stock ownership; Eli Lilly and Company. S. Beattie: Shareholder/stock ownership; Eli Lilly and Company. D.E. Schlichting: Shareholder/stock ownership; Eli Lilly and Company. P. Durez: Member of speakers’ bureau; Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, and Sanofi. Y. Tanaka: Member of speakers’ bureau; AbbVie, Asahi-kasei, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly and Company, GlaxoSmithKline, Janssen, Mitsubishi-Tanabe, Novartis, Pfizer, Sanofi, Takeda, UCB, and YL Biologics. Grants/research support; AbbVie, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi-Tanabe, MSD, Ono, and Taisho-Toyama and Takeda. R. Fleischmann: Consultancies; AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Janssen, Novartis, Pfizer, Roche, Sanofi-Aventis, and UCB.

O09 Safety profile of baricitinib for the treatment of RA up to 8.4 years: an updated integrated safety analysis

Abstract Background/Aims Baricitinib (BARI) is an oral selective inhibitor of Janus kinase (JAK)1/2, approved for treatment of moderate-to-severe- rheumatoid arthritis (RA) in adults. Here, we update the drug’s safety profile with data up to 8.4 years of treatment. Methods Long-term safety of BARI was assessed from 9 completed randomized trials(5 Ph3, 3 Ph2, 1 Ph 1b) and 1 ongoing long-term extension(LTE) study. Incidence rates(IRs) per 100 patient-years (PY) were calculated for all RA patients treated with ≥1 dose of BARI through 1-Sep-2019(All-BARI-RA set). IRs for deep vein thrombosis(DVT), pulmonary embolism(PE), and DVT and/or PE(DVT/PE) were also calculated for groups of patients while receiving BARI 2mg/4mg within All-BARI-RA. Major adverse cardiovascular events(MACE) were adjudicated in 5 Ph3 studies and the LTE. Results 3770 pts received BARI for 13,148 PY, with median and maximum exposure: 4.2 and 8.4 years, respectively. Overall IRs per 100 PY were: for any treatment-emergent adverse event (AE)(25.8); serious AE (including death)(7.2); temporary interruption due to AE (9.5); permanent discontinuation due to AE (4.8); death (0.52); serious infection (2.7); opportunistic infection (0.46)(excluding tuberculosis [TB], including multidermatomal herpes zoster [HZ]); TB (0.15); HZ (3.0); MACE (0.50); DVT (0.31); PE (0.24); DVT/PE (0.46); malignancies excluding non-melanoma skin cancer (NMSC)(0.91); NMSC (0.33); lymphoma (0.07); and gastrointestinal perforation (0.04). (IRs)[95% confidence intervals] for patients while receiving BARI 2mg (N = 1077) and BARI 4mg (N = 3400) were DVT 2mg (0.38)[0.18, 0.73] and 4mg (0.30)[0.21, 0.43]; PE 2mg (0.26)[0.09, 0.56] and 4mg (0.25)[0.16, 0.36]; and DVT/PE 2mg (0.47)[0.23, 0.84] and 4mg (0.46)[0.34, 0.61]. IRs for death tended to increase in later time intervals (beyond 192 weeks). No particular cause of death contributed to this increase. For all other safety topics of interest, across 48-week treatment intervals, IRs remained stable over time. Across safety topics, IRs were consistent with previous analyses. Conclusion In this update, with 3021 additional PY of exposure, BARI maintained a safety profile similar to that previously reported, with no increase of IRs across safety topics through exposures up to 8.4 years. Disclosure K.L. Winthrop: Consultancies; AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly and Company, Pfizer, and UCB Pharma. Grants/research support; Bristol Myers Squibb and Pfizer. T. Takeuchi: Consultancies; AbbVie, Asahi Kasei Medical, Astellas, AstraZeneca, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly and Company, GlaxoSmithKline, Janssen, Mitsubishi Tanabe Pharma, Nippon Kayaku, Novartis, Pfizer Japan, Taiho Pharmaceutical, Taiho Toyama Pharmaceutical, Takeda, and UCB Japan. G. Burmester: Consultancies; Eli Lilly and Company, Janssen, Novartis, and Pfizer. Grants/research support; Eli Lilly and Company. W. Deberdt: Shareholder/stock ownership; Eli Lilly and Company. D. Schlichting: Shareholder/stock ownership; Eli Lilly and Company. D. Mo: Shareholder/stock ownership; Eli Lilly and Company. C. Walls: Shareholder/stock ownership; Eli Lilly and Company. J.S. Smolen: Consultancies; AbbVie, Amgen, AstraZeneca, Astro Pharma, Bristol Myers Squibb, Celgene, Celltrion, Chugai, Eli Lilly and Company, Gilead Sciences, ILTOO Pharma, Janssen, MedImmune, Merck Sharp &amp; Dohme, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi-Aventis, and UCB Pharma. Grants/research support; AbbVie, Eli Lilly and Company, Janssen, Merck Sharp &amp; Dohme, Novartis, Pfizer, and Roche.

Managing the Impact of Immunogenicity in an Era of Immunotherapy: From Bench to Bedside.

Biotherapeutics have revolutionized our ability to treat life-threatening diseases. Despite clinical success, the use of biotherapeutics has sometimes been limited by the immune response mounted against them in the form of anti-drug antibodies (ADAs). The multifactorial nature of immunogenicity has prevented a standardized approach for assessing this and each of the assessment methods developed so far does not exhibit high enough reliability to be used alone, due to limited predictiveness. This prompted the Roche Pharma Research and Early Development (pRED) Immunogenicity Working Group to establish an internal preclinical immunogenicity toolbox of in vitro/in vivo approaches and accompanying guidelines for a harmonized assessment and management of immunogenicity in early development. In this article, the complex factors influencing immunogenicity and their associated clinical ramifications are discussed to highlight the importance of an end-to-end approach conducted from lead optimization to clinical candidate selection. We then examine the impact of the resulting lead candidate categorization on the design and implementation of a multi-tiered ADA/immunogenicity assay strategy prior to phase I (entry into human) through early clinical development. Ultimately, the Immunogenicity Toolbox ensures that Roche pRED teams are equipped to address immunogenicity in a standardized manner, paving the way for lifesaving products with improved safety and efficacy.

Rapid Steroid Withdrawal after Renal Transplantation Reduces Mortality: Five Year Follow-Up of a Randomized Controlled Trial (Harmony Study) Confirms Long Term Efficacy and Safety

Background: We previously reported excellent efficacy and improved safety aspects of rapid steroid withdrawal (RSWD) in the randomized controlled one year “Harmony” trial, in which 587 predominantly deceased-donor kidney transplant recipients were randomized either to basiliximab or rabbit ATG induction therapy and compared to standard immunosuppressive therapy consisting of basiliximab, low tacrolimus once daily, mycophenolate mofetil, and corticosteroids. Methods: Following the end of the original one-year study period, patients were asked to participate in the observational follow-up (FU) study examining most of the end points of the original study. Hereby, de novo incidences between year one and three as well as year three and five were assessed at the three-/five-year visits, respectively. Findings: Biopsy-proven acute rejection and death-censored graft survival rates remained low and independent of RSWD. RSWD was an independent positive factor for patient survival (adjusted hazard ratio 0·554, 95% confidence interval 0·314 to 0·976; p=0·041). Survival rate was increased with 89·4 % or 90·4 % in RSWD patients (basiliximab or rabbit ATG) compared to 84·7 % in control patients (p = 0·064). The reduced incidence of post-transplantation diabetes mellitus in RSWD patients during the original one-year study period was not compensated by later incidences during FU. Also, incidences of other important outcome parameters such as opportunistic infections, malignancies, cardiovascular morbidity/risk factors, donor specific antibody formation, or kidney function did not differ during FU period. Unexpectedly, patient incidences of bacterial infections requiring hospitalization was reduced in the rabbit ATG group. Interpretation: The Harmony FU trial confirms excellent efficacy and beneficial safety aspects of RSWD under modern immunosuppressive therapy. This is the first randomized study demonstrating increased patient survival in RSWD patients. The results shown here support that RSWD should become the new gold standard approach in an immunologically low-risk, elderly, and severely diseased population of Caucasian kidney transplant recipients. Trial Registration: Follow-up study DRK5786; Original trial NCT 00724022). Funding: The FU trial was designed and run by the first and last author who received financial support from Astellas Pharma GmbH and Sanofi (Investigator Initiated Trial (NCT 00724022, follow up study DRK5786). Neither of the funders had any role in data collection, data analysis, data interpretation, or writing of the manuscript. An independent contract research organization (Coordination Center for Clinical Studies of the Technical University of Dresden, Dresden, Germany) was responsible for data collection, monitoring and statistical analyses. Declaration of Interest: CH received grant support, consulting fees, and lecture fees from Astellas, Sanofi, Genzyme, Roche Pharma, Novartis, and Wyeth/Pfizer. CK received consulting fees and lecture fees from Astellas, Chiesi, Novartis, Sanofi-Genzyme. JWM received grant support, consulting fees, and lecture fees from Vifor, GSK, Novartis, Astra-Zeneca and Boehringer Ingelheim. OW has received research grants for clinical studies, speaker’s fees, honoraria and travel expenses from Amgen, Alexion, Astellas, Basilea, Biotest, Bristol-Myers Squibb, Correvio, Chiesi, Gilead, Hexal, Janssen, Dr. F. Kohler Chemie, MSD, Novartis, Roche, Pfizer, Sanofi, Takeda, TEVA and UCB. BB received grant support, consulting fees and lecture fees from Astellas, Bayer, Chiesi and Novartis. All other authors declare no competing interests. Ethical Approval: The study was approved by the institutional review boards of all sites participating in the follow-up period.

Pirfenidone in patients with progressive fibrotic interstitial lung diseases other than idiopathic pulmonary fibrosis (RELIEF): a double-blind, randomised, placebo-controlled, phase 2b trial

Pirfenidone has been shown to slow disease progression in patients with idiopathic pulmonary fibrosis (IPF). However, there are few treatment options for progressive fibrotic interstitial lung diseases (ILDs)) other than IPF. In view of the pathomechanistic and clinical similarities between IPF and other progressive fibrotic ILDs, we aimed to assess the efficacy and safety of pirfenidone in patients with four non-IPF progressive fibrotic ILDs. We did a multicentre, double-blind, randomised, placebo-controlled, parallel phase 2b trial (RELIEF) in 17 centres with expertise in ILD in Germany. Eligible participants were patients aged 18-80 years with progressive fibrotic ILD due to four diagnoses: collagen or vascular diseases (ie, connective tissue disease-associated ILDs), fibrotic non-specific interstitial pneumonia, chronic hypersensitivity pneumonitis, or asbestos-induced lung fibrosis. Other eligibility criteria included a forced vital capacity (FVC) of 40-90% predicted, a diffusing capacity of the lung for carbon monoxide of 10-90% predicted, and an annual decline of FVC of at least 5% predicted despite conventional therapy, based on at least three measurements within 6-24 months before enrolment. Patients who had received any previous antifibrotic therapy were excluded. We randomly assigned patients (1:1) to either oral pirfenidone (267 mg three times per day in week 1, 534 mg three times per day in week 2, and 801 mg three times per day thereafter) or matched placebo, added to their ongoing medication. Randomisation was done centrally using permuted block randomisation with varying block sizes stratified by the four diagnostic groups. Patients, investigators, statisticians, monitors, and the study coordinator were masked to treatment assignment until database closure. The placebo-controlled study period was 48 weeks (including up-titration). The primary endpoint was absolute change in percentage of predicted FVC (FVC % predicted) from baseline to week 48 in the intention-to-treat population, with imputation of missing data by the smallest sum of squared differences and attribution of deceased patients to the lowest rank in a rank ANCOVA model. Additionally, we did linear mixed-model repeated measures slope analyses of FVC % predicted longitudinal data over the course of the study as a prespecified sensitivity analysis and post-hoc sensitivity analyses of the primary endpoint in the intention-to-treat population using imputation methods of last observation carried forward [LOCF] and a regression-based multiple imputation procedure. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered with EudraCT 2014-000861-32; DRKS00009822 and is no longer recruiting. Between April 5, 2016, and Oct 4, 2018, we randomly assigned 127 patients to treatment: 64 to pirfenidone, 63 to placebo. After 127 patients had been randomised, the study was prematurely terminated on the basis of an interim analysis for futility triggered by slow recruitment. After 48 weeks and in the overall population of 127 patients, rank ANCOVA with diagnostic group included as a factor showed a significantly lower decline in FVC % predicted in the pirfenidone group compared with placebo (p=0·043); the result was similar when the model was stratified by diagnostic group (p=0·042). A significant treatment effect was also observed when applying the LOCF and multiple imputation methods to analyses of the primary endpoint. The median difference (Hodges-Lehmann estimate) between pirfenidone and placebo groups for the primary endpoint was 1·69 FVC % predicted (95% CI -0·65 to 4·03). In the linear mixed-model repeated measures slope analysis of FVC % predicted, the estimated difference between treatment and placebo groups from baseline to week 48 was 3·53 FVC % predicted (95% CI 0·21 to 6·86) with imputation of deaths as prespecified, or 2·79 FVC % predicted (95% CI 0·03 to 5·54) without imputation. One death (non-respiratory) occurred in the pirfenidone group (2%) and five deaths (three of which were respiratory) occurred in the placebo group (8%). The most frequent serious adverse events in both groups were infections and infestations (five [8%] in the pirfenidone group, ten [16%] in the placebo group); general disorders including disease worsening (two [3%] in the pirfenidone group, seven [11%] in the placebo group); and cardiac disorders (one ([2%] in the pirfenidone group, 5 [8%] in the placebo group). Adverse events (grade 3-4) of nausea (two patients on pirfenidone, two on placebo), dyspnoea (one patient on pirfenidone, one on placebo), and diarrhoea (one patient on pirfenidone) were also observed. In view of the premature study termination, results should be interpreted with care. Nevertheless, our data suggest that in patients with fibrotic ILDs other than IPF who deteriorate despite conventional therapy, adding pirfenidone to existing treatment might attenuate disease progression as measured by decline in FVC. German Center for Lung Research, Roche Pharma.

Corrigendum: Combination of T-Cell Bispecific Antibodies With PD-L1 Checkpoint Inhibition Elicits Superior Anti-Tumor Activity

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Phase 1 Study of CD19 Targeted 4-1BBL Costimulatory Agonist to Enhance T Cell (Glofitamab Combination) or NK Cell Effector Function (Obinutuzumab Combination) in Relapsed/Refractory B Cell Lymphoma

Phase 1 Study of CD19 Targeted 4-1BBL Costimulatory Agonist to Enhance T Cell (Glofitamab Combination) or NK Cell Effector Function (Obinutuzumab Combination) in Relapsed/Refractory B Cell Lymphoma