Bristol-Myers Research Articles

83-OR: Metabolic Dysfunction–Associated Steatotic Liver Disease and Nonalcoholic Fatty Liver Disease Have Similar Clinical Profiles and Mortality

Introduction & Objective: Metabolic dysfunction associated steatotic liver disease (MASLD) has recently replaced the term nonalcoholic fatty liver disease (NAFLD). Concern remains whether evidence generated under NAFLD definition is fully applicable to MASLD. We compared the clinical profile and outcomes of NAFLD to MASLD using population-based data. Methods: National Health and Nutrition Examination Survey (NHANES-III) with the linked Mortality file (through 2019) were used to compare groups defined as NAFLD and MASLD. Hazard ratios (HRs) of MASLD/NAFLD on all-cause mortality were calculated by cox-regression models. Results: Among 2,736 NHANES participants with NAFLD (age 47.80 years, 52.48% male, 47.66% obese, 18.26% T2D, 94.71% ≥ 1 cardiometabolic criteria), only 5.29% patients did not meet MASLD criteria. The clinical profile of MASLD was similar except for age (48.56 years) and presence of cardiometabolic risks (50.32% obese, 19.28% T2D, 100% ≥ 1 cardiometabolic criteria). There was excellent concordance between NAFLD and MASLD definitions (Cohen’s kappa coefficient=0.968 [95% CI: 0.962-0.973]). After a median follow-up of 22.83 years, there were no mortality rate differences between MASLD and NAFLD (p-values ≥ 0.05). Adjusting for socio-demographic factors, lack of healthy eating and physical activity, MASLD had a higher all-cause mortality risk (Hazard Ratio (HR)=1.15 [1.05-1.25]). However, after further adjustment for cardiometabolic risks, MASLD was not associated with increased all-cause mortality (p-value>0.80). Conclusions: NAFLD and MASLD are similar except MASLD subjects are older with slightly higher mortality risk, potentially due to the inclusion of cardiometabolic risk factors. These data provide evidence that NAFLD and MASLD can be used interchangeably. Disclosure Z. Younossi: Consultant; Gilead Sciences, Inc., Bainan Biotech, AbbVie Inc., Bristol-Myers Squibb Company, Abbott, Novo Nordisk, Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Siemens Healthcare Diagnostics, Intercept Pharmaceuticals, Inc. J.M. Paik: None. P. Golabi: None. J. Ong: None. L. Henry: None. S. Alqahtani: Consultant; AbbVie Inc., Bristol-Myers Squibb Company, Merck & Co., Inc., Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc. F. Nader: None.

P107 Real world clinical outcomes of patients with moderate-to-severe rheumatoid arthritis initiating upadacitinib in the United Kingdom: Interim analysis from a prospective observational cohort study (ENDEAVOUR)

Abstract Background/Aims Upadacitinib (UPA) 15 mg, a once-daily Janus kinase inhibitor (JAKi), is approved by NICE for treating adults with moderate-to-severe rheumatoid arthritis (RA) unresponsive to conventional Disease Modifying Antirheumatic Drugs (DMARDs). This study aims to evaluate UPA's real-world effectiveness in the UK. Methods ENDEAVOUR is a prospective observational cohort study which recruited 97 patients with moderate to severe RA whom the managing health care professional has decided to treat with UPA in line with marketing authorisation across 14 sites in the UK. Patient demographics, comorbidities, concomitant therapies and patient reported disease activity were collected at baseline, three months, and six months. Patient Reported Outcomes (PROs) were collected using an app hosted by UMotif. Primary objective was the proportion of patients achieving clinical remission (defined as DAS28<2.6) with upadacitinib at six months. The study is ongoing and therefore not all patients have completed study visits at three and six months yet however this interim analysis reports the baseline demographics of 77 patients whose data has been cleaned thus far and clinical outcomes and safety of UPA 47 adult patients at three months. Data are as observed. Results Data were available for 77 adults at baseline: 42% had moderate and 58% had severe RA based on DAS28-CRP scores. Patients' average age was 55 years, 64 (83%) were female, and most had at least one comorbidity, such as hypertension (16,21%) or asthma (12,16%). 32 (42%) had prior biologic therapy, with treatment failure the most commonly reported reason for switch (26/33, 79%). Of the 47 participants with three-month data, 18 (38%) achieved DAS28 remission. The proportion of patients with high disease activity decreased markedly from 45 (58%) at baseline to three (6%) at three months and moderate disease activity from 32 (42%) at baseline to 14 (30% at three months). Concurrent corticosteroid use declined, from 13 (17%) patients at baseline to just three (5%) by three months. The mean exposure time was six months (IQR five to seven). Nine patients (9%) stopped UPA during the study period, (5/9 due to adverse events, 4/9 due to patient or physician choice). One case of shingles occurred, with temporary treatment interruption. Reports of serious adverse events were low (4% patients of events reported) with cases of serious and opportunistic infections reported most frequently (three cases). There were no reports of MACE or venous thromboembolic events. 1 report of malignancy (extranodal marginal zone B-cell lymphoma) was considered unrelated to treatment. Conclusion This preliminary analysis of an observational study provides valuable insights into the real-world effectiveness of UPA for treatment of moderate to severe RA with similar early efficacy to that observed in clinical trials. 38% of patients achieved clinical remission by 3 months, and adverse events were infrequent. Disclosure J. Taylor: None. S. Srirangan: None. M. Bukhari: Honoraria; M.B has received honoraria for speaking and attended advisory boards with Bristol-Myers Squib, UCB celltech, Roche/Chugai, Pfizer, AbbVie, Merck, Mennarini, Sanofi-aventis, Eli-Lilly, Janssen, Amgen, Novartis and Gilead. Other; M.B. has been sponsored to attend regional, national and international meetings by UCB celltech, Roche/Chugai, Pfizer, Abbvie, Merck, Mennarini, Janssen, Bristol-Myers Squib, Novartis and Eli-lilly. S. Bilgrami: Other; S.B. has received professional and financial support from Eli Lilly, UCB & Pfizer. M.K. Nisar: Other; M.K.N undertakes clinical trials and received support (including attendance at conferences, speaker fees and honoraria) from Roche, Chugai, MSD, AbbVie, Pfizer, BMS, Novartis, Celgene, UCB and, Lilly. S. McDonald: None. N. Goodson: None. A. Allard: Other; A.A. has received payment for services, sponsorship, funding, grants or worked on clinical trials for AbbVie, Eli Lilly, Pfizer, Novartis, BMS, Roche. A. Kinder: None. M. Green: None. L. Hunt: None. S. Raizada: Honoraria; S.R. has received honoraria from AbbVie. B. Kirkham: Consultancies; B.K. has received consultant/speaker fees from AbbVie, Eli Lilly, Galapagos, Janssen, Novartis, Pfizer and UCB. Grants/research support; B.K. has received research support from Eli Lilly and Novartis. E. Thomas: Other; E.T. has been on advisory boards for Janssen and Galapagos. R. Horsfall: None. S. Bartlett: None. R. Millward: None. V. Burton: None. J. Galloway: Consultancies; J.G. has received speaker/consultancy for AbbVie, Galapagos, Janssen, Lilly, Pfizer, UCB and Vifor. Grants/research support; He has received research grants for AbbVie, Galapagos, GSK, Janssen, Lilly, Pfizer.

OA28 The use of ACE and sIL2-R in a large tertiary cohort of patients with multi-system sarcoidosis

Abstract Background/Aims Sarcoidosis is a systemic inflammatory disorder characterised by the formation of non-caseating granulomas, and can affect almost any organ, ranging from self-limiting to a chronic and progressive disease. There are no validated biomarkers that help establish diagnosis or monitor disease progression. Serum Angiotensin-Converting Enzyme (ACE) is used in clinical practice despite some studies reporting a poor reflection of disease activity. Soluble interleukin 2 receptor (sIL-2R) is being used with increasing frequency and may be a useful tool in establishing diagnosis and monitoring disease progression. Our objectives were to evaluate the use of ACE and sIL2-R in a large tertiary cohort of patients with multisystem sarcoidosis. Methods This was an observational cohort study. Patients with a confirmed diagnosis of sarcoidosis at King’s College Hospital between 2013 and 2023 were identified. Demographics, symptoms onset, clinical features, ACE, sIL2-R, high-resolution computed tomography (HRCT), Positron emission tomography-computed tomography (PET-CT), histology and immunomodulating therapy were extracted from electronic health records. Cross sectional correlations between ACE and sIL2-R was assessed by Spearman’s correlation coefficient (rs). Results Data were extracted for 196 individuals diagnosed with sarcoidosis. The mean age was 55 (SD 16) with a female and black predominance (table 1). A prior exposure risk of silica or dust was identified in 5 individuals. At diagnosis the most frequently reported organ involvement was lung (65%), eye (20%), musculoskeletal (13%) and skin (12%). Organ involvement on PET-CT was seen in 77%. 22% had interstitial lung disease (ILD) confirmed on HRCT and 3% had myocarditis on cardiac MRI. Steroids were commenced in 56%, with a mean dose of 19mg (SD 13mg). The mean duration of follow up was 7 years (IQR 2.9-14.4), 11% developed symptoms suggestive of new organ involvement, 7% had PET-CT evidence of new organ involvement, 4% had evidence of ILD progression and 14% underwent re-initiation or escalation of steroid therapy. 42% (n = 82) had results for both sIL2-R and ACE biomarkers. The median ACE was 55u/L (IQR 40-83) and sIL2-R 1781ng/L (IQR 1328-2436). 50% (41/82) had a sIL2-R >1800ng/L and 59% (48/82) had an ACE >50u/L. Interestingly, 32% (13/41) with a sIL2-R >1800 had a normal ACE and 42% (20/41) with an ACE >50 had a normal sIL2-R results. sIL2-R correlated with ACE (rs = 0.34, p = 0.0018). There was no significant difference in ACE levels in those taking ACE inhibitors (n = 9) compared to those (n = 73) not: 55u/L (IQR 41-83) versus 39u/L (IQR 30-65) p = 0.30. Conclusion sIL2-R significantly correlated with serum ACE, although the rs value is not particularly strong, suggesting other factors may be influencing the relationship. These biomarkers represent different aspects of the disease; serum ACE reflects granulomatous inflammation whilst sIL2-R implies immune system activation and T-cell involvement, which may explain our findings. Disclosure M. Hughes: None. K. Bechman: Honoraria; UCB, Viforpharma. Grants/research support; NIHR, Versus Arthritis/Pfizer. R. Roy: None. M. Omar: None. D. Mehta: None. D. Nagra: None. S. Walsh: None. S.S. Birring: None. D.M. Sado: None. P.A. Brex: None. J. Galloway: Honoraria; Abbvie, Biovitrum, Bristol Myers Squib (BMS), Celgene, Chugai, Gilead, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi, Sobi, UCB.

E066 Baseline characteristics of patients initiating ixekizumab, secukinumab or a tumour necrosis factor inhibitor by country in the 24-month Prospective Psoriatic Arthritis Observational Study of Persistence of Treatment - PRO-SPIRIT

Abstract Background/Aims The Psoriatic Arthritis Observational Study of Persistence of Treatment (PRO-SPIRIT) is the first large-sample, multinational, prospective, observational study to provide real-world evidence for ixekizumab (IXE) in patients with psoriatic arthritis (PsA) who start a new biologic/targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD), with a primary end point of persistence at 24 months. Aims: To describe baseline characteristics of PRO-SPIRIT patients initiating or switching to IXE, secukinumab (SEC) or a tumour necrosis factor inhibitor (TNFi) in Canada (CA), France (FR), Germany (DE), Italy (IT), Spain (ES) and the United Kingdom (UK). Methods PRO-SPIRIT enrolled adults diagnosed with PsA (≥6 months) between December 2019 and June 2022 to be initiated or switched to a new b/tsDMARD, locally approved for the management of PsA. Baseline characteristics, including patient demographics, therapy and disease activity measures, are described here by country for patients initiating IXE, SEC (both IL-17A inhibitors) or a TNFi (adalimumab, etanercept, infliximab or biosimilar) only. Results This analysis included 943 patients (Table 1). The overall proportion of patients with BMI ≥30 mg/kg2 was highest in CA (67.2%) and lowest in IT (24.5%); across countries, higher proportions of patients initiating an IL-17A vs a TNFi had BMI ≥30 mg/kg2 (except IXE groups in IT, ES and UK). Higher proportions of patients initiating an IL-17A vs a TNFi were diagnosed with PsA ≥3 years before baseline (except SEC groups in DE and ES). The highest proportions of b/tsDMARD-naïve patients were observed in the TNFi groups in all countries (range 46.2% [CA] to 81.9% [UK]). Patients in the IL-17A groups were more likely to be on monotherapy than patients in the TNFi groups (except in FR). There were no clear trends in baseline disease activity for patients initiating IL-17As or TNFis, although country-specific differences were observed. Conclusion The PRO-SPIRIT baseline characteristics described offer important insights into country-specific patient demographics and treatment patterns when initiating or switching to a new b/tsDMARD in a real-world setting. Between-country variations observed in PRO-SPIRIT baseline characteristics may be due to differences in healthcare systems and/or the evolution of treatment options for patients with PsA in each country. Disclosure N. Gullick: Consultancies; AbbVie,Novartis, UCB. Honoraria; AbbVie, Eli Lilly, Janssen, Novartis, UCB. Grants/research support; AbbVie, Astra Zeneca, Eli Lilly, Novartis. M. Sheesh: Corporate appointments; Eli Lilly and Company. Shareholder/stock ownership; Eli Lilly and Company. C. Laedermann: Corporate appointments; Eli Lilly and Company. Shareholder/stock ownership; Eli Lilly and Company. M. Ngantcha: Corporate appointments; Eli Lilly and Company. Shareholder/stock ownership; Eli Lilly and Company. B. Gittens: Corporate appointments; Eli Lilly and Company. K. Ng: Corporate appointments; Eli Lilly and Company. Shareholder/stock ownership; Eli Lilly and Company. W. Tillett: Consultancies; Abbvie, Amgen, Eli Lilly and Company, GSK, Janssen, Novartis, Ono Pharma, Pfizer, UCB. Member of speakers’ bureau; AbbVie, Amgen, Eli Lilly and Company, GSK, Janssen, Novartis, Pfizer, UCB. Grants/research support; Janssen, UCB, Pfizer, Eli Lilly and Company. J. Morel: Consultancies; Pfizer, AbbVie, Boerhinger Ingelheim, Galapagos, GSK. Member of speakers’ bureau; Biogen, Amgen, Bristol Myers Squib, Eli Lilly and Company, Novartis, Sanofi, MSD, Mylan, Fresenius Kabi, Roche, Union Chimique Belge, Janssen, Medac, Nordic Pharma. Grants/research support; Fresenius Kabi. E. Lubrano: Member of speakers’ bureau; Abbvie, Janssen Cilag, Lilly, UCB, Pfizer, Novartis. R. Alten: Consultancies; AbbVie, BMS, Celltrion, Galapagos, Eli Lilly and Company, Novartis, Pfizer, Roche, UC. Member of speakers’ bureau; AbbVie, BMS, Celltrion, Galapagos, Eli Lilly and Company, Novartis, Pfizer, Roche, UCB. L. Kristensen: Consultancies; Pfizer, AbbVie, Amgen, UCB, Gilead, Biogen, BMS, MSD, Novartis, Eli Lilly and Company, Janssen. Member of speakers’ bureau; Pfizer, AbbVie, Amgen, UCB, Gilead, Biogen, BMS, MSD, Novartis, Eli Lilly and Company, Janssen. Grants/research support; Pfizer, Abb- Vie, UCB, Gilead, Biogen, Novartis, Eli Lilly and Company, Janssen. V. Chandran: Consultancies; AbbVie, Eli Lilly, Novartis, Amgen, Janssen. Grants/research support; AbbVie. A. Martinez-Ferrer: Grants/research support; Eli Lilly and Company. B. Kirkham: Consultancies; Abbvie, Eli Lilly and Company, Galapagos, Novartis. Member of speakers’ bureau; Abbvie, Eli Lilly and Company, Galapagos, Janssen, Novartis, Pfizer, UCB. Grants/research support; Eli Lilly and Company, Novartis.

OA20 Serious infections hospital admissions and mortality in patients with early inflammatory arthritis: results from the National Early Inflammatory Arthritis Audit

Abstract Background/Aims To identify the risk of serious infections (SI) according to initial treatment strategy, using conventional synthetic disease modifying anti-rheumatic drugs (csDMARD) and corticosteroids, in patients recruited to the National Early Inflammatory Arthritis Audit (NEIAA). Methods An observational cohort study design was used. The population included adults in England with a new onset rheumatoid arthritis (RA), fulfilling ACR/EULAR 2010 criteria, between April 2018-March 2021. Outcomes studied were SI, defined by infections requiring hospitalisation (primary admission diagnosis/nosocomial acquisition) or death (SI stated on death certificate), identified using NHS Digital linkage. Patients' characteristics were tabulated by treatment strategies. Hazard ratios (HR) were calculated using single failure Cox proportional-hazards models, with confounders-adjusted models (age, gender, smoking status, comorbidities, social deprivation) and fully-adjusted models including disease factors (seropositivity, DAS28). Individuals were considered at risk from the date of RA diagnosis, and censored at SI event, death, or March 2021 (whichever was earliest). Results 20,060 patients with RA were included. Initial DMARD therapy was known for 19,572 patients, of whom 11,966 were on methotrexate/MTX based strategies (mono or combo), 5,059 on csDMARD combination strategies (other than MTX) and 2,547 on no DMARD strategy. 15,319 patients were on corticosteroids at baseline. Mean age 59.5 years (+/-15); 63% female; smoking status (20% current; 30% ex-smokers); comorbidities (21% hypertension; 10% diabetes; and 12% lung disease). Rheumatoid Factor/CCP antibodies were positive in 68%. At presentation, median disease scores were 5.1 (interquartile range [IQR]: 4.0-5.9) for DAS28, 1.1 (IQR: 0.6-1.7) for health assessment questionnaire (HAQ) and 24 (IQR: 16.0-33.0) for musculoskeletal health questionnaire (MSKHQ).There were 519 SI admissions and 17 SI deaths, corresponding to incidence rates per 100 person-years for admissions: 3.19 (95% CI: 2.93-3.48) and deaths: 0.10 (95% CI: 0.06-0.16). In fully-adjusted models, increasing age predicted both SI admissions and deaths. Being a smoker, having a comorbidity, higher disease activity (DAS28), symptom burden (MSKHQ) and disability (HAQ) at presentation associated with more SI admissions. For each 1 unit increase in DAS28, the risk of SI increased by 8% (HR 1.08 [95% CI:1.01-1.16]). Seropositivity did not associate with SI. MTX-based strategies 0.75 (95% CI:0.62-0.91) and csDMARD combination therapy 0.70 (95% CI:0.53-0.94) associated with fewer SI admissions compared to no DMARD. In unadjusted models, corticosteroid associated with more SI admissions 1.29 (95% CI:1.10 -1.62); however, in fully-adjusted models this association was no longer statistically significant. csDMARD strategies did not associated with SI deaths in any of the models. Conclusion Patient and disease factors at diagnosis appear to be important predictors of admissions and mortality for serious infections. Infection risk appears to be greatest in those with higher RA disease activity. An important limitation is that NEIAA does not capture data on treatment changes over time and steroid use beyond baseline. Disclosure M. Adas: None. K. Bechman: None. M. Russell: Honoraria; Lilly and Menarini. Other; upport for attending conferences from Lilly, Pfizer, Janssen, and UCB, and advisory board fees from Biogen.. I. Karafotias: None. D. Nagra: None. S. Patel: None. S. Gallagher: None. E. Price: None. M. Garton: None. A. Rutherford: None. A. Cope: None. S. Norton: None. J. Galloway: Honoraria; from Abbvie, Biovitrum, Bristol Myers Squib (BMS), Celgene, Chugai, Gilead, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi, Sobi, and UCB.

Repotrectinib: First Approval.

Repotrectinib (AUGTYRO™) is a next-generation, oral, small-molecule kinase inhibitor of proto-oncogene tyrosine-protein kinase ROS1 (ROS1) and tropomyosin receptor tyrosine kinases (TRKs) TRKA, TRKB, and TRKC. It is being developed by Turning Point Therapeutics, a wholly owned subsidiary of Bristol-Myers Squibb (BMS), for the treatment of locally advanced or metastatic solid tumours, including non-small cell lung cancer (NSCLC). Repotrectinib is a next-generation tyrosine kinase inhibitor rationally designed to inhibit ROS1 and TRK fusion, including in the presence of resistance mutations such as solvent-front mutations. In November 2023, repotrectinib received its first approval in the USA for the treatment of adults with locally advanced or metastatic ROS1-positive NSCLC. Repotrectinib is under regulatory review in China and the EU for NSCLC. Clinical studies of repotrectinib are ongoing in several countries in patients with NSCLC and other solid tumours (including primary central nervous system cancer) across both adult and paediatric patient populations. In addition, preclinical investigation of repotrectinib in multiple myeloma is underway in the USA. This article summarizes the milestones in the development of repotrectinib leading to this first approval for the treatment of locally advanced or metastatic ROS1-positive NSCLC.

Multiple Myeloma in Zimbabwe. Knowledge Levels, Age and Sex as Risky Factors. Insights from Zimbabwe Multiple Myeloma Consortium

Multiple myeloma is a serious cancer of the blood affecting millions of people across the world and is the second most prevalent hematological disease accounting for 10% of hematological disease cases while representing 1% of all serious diseases in the world. Multiple myeloma is also a major threat in Sub-Saharan Africa as revealed by the statistics provided by the Ríos-Tamayo, Rodríguez, Chang-Chan, & Pérez (2018) . On average, according to Globocan (2020), 3.2 per 100 000 have MM in Southern Africa, while there are 0.98 and 0.83 per 100 000 people with MM in Eastern Africa and Western Africa respectively. This indicates that Southern Africa is disproportionately affected by multiple myeloma. This is particularly the cases with Zimbabwe in which the number of people with MM is estimated to be 2.69 per 100 000 people along with a 5-year prevalence of 400 new cases every year (Globocan, 2020). It is from this background that, the Zimbabwe multiple myeloma consortium funded by the Bristol Myers Squib Foundation implemented the multiple myeloma project in Zimbabwe since April 2022. Objectives of the project include the need to improve patients’ quality of life, to improve multiple myeloma service delivery systems and effects of multiple myeloma, where patients efficiently and effectively get diagnostic and palliative care services as well as increasing multiple myeloma awareness and knowledge levels among the general population and health workers of Zimbabwe. This article provides statistics to give insights of multiple myeloma in Zimbabwe in terms of case findings conducted to date as well as number of MM patients identified. Mixed method was employed where data was collected and captured using Qualtrics system integrating both qualitative and quantitative. Thematic analysis was incorporated to analyse qualitative data using 5 different steps namely: familiarization, generating initial codes, search for themes, reviewing of themes and write up. Participants for this research were drawn from a caseload of 181 patients. These patients received their services from Parirenyatwa Group of Hospitals, Gweru Provincial Hospital and Mpilo Hospital in Bulawayo. Findings of this research indicated that, there is deaths of multiple myeloma information among health care workers, professionals such as physicians and orthopaedics as well as general population. Late diagnosis has seen to be a cause for concern among mm patients. Males are the most vulnerable population to be affected by the disease and again ageing is a contributing factor. Recommendations made include but not limited to; targeted sensitisation reaching out to oncologists, physicians, orthopaedics health care workers, workplaces and tertiary institutions. This will translate to early diagnoses thereby improving quality of life. More funding is needed to support treatment of mm patients and as enablers to conduct home visits in relation to palliation activities by service providers. Social media engagement to be an ongoing endeavour packaged with mm risk factors, signs and symptoms related information.

Pharmacodynamic Biomarkers and CtDNA Support the Mechanism of Action and Clinical Efficacy of Golcadomide (CC-99282) Combined with R-CHOP in Previously Untreated Aggressive B-Cell Lymphoma

Introduction Golcadomide (GOLCA, CC-99282) is an orally available cereblon E3 ligase modulator (CELMoD ®) that potently degrades target proteins Ikaros and Aiolos, enhancing antiproliferative, apoptotic, and immunomodulatory activity and preferentially distributing to lymphoid organs. In a phase 1 study, GOLCA monotherapy previously demonstrated a manageable safety profile with promising clinical activity in relapsed/refractory non-Hodgkin lymphoma (Michot Blood 2021). In the ongoing CC-220-DLBCL-001 study (NCT04884035), GOLCA dose finding is underway in patients with previously untreated aggressive B-cell lymphoma (BCL), in combination with R-CHOP in 21-day (D) cycles (C), at a variety of GOLCA dose levels (DLs) and schedules: DL-1 = 0.2 mg D1-7, DL1 = 0.4 mg D1-7, and DL2 = 0.4 mg D1-10. Here, we report Ikaros degradation, immune modulation, circulating tumor DNA (ctDNA) assessment, and baseline tumor genomics. Methods Peripheral blood was collected to analyze Ikaros and Aiolos levels in T cells by flow cytometry (C1D1, C1D7, and C2D1). Immune phenotyping of T and natural killer (NK) cells was performed by flow cytometry (C1D1, C1D15, C2D1, and C3D1). ctDNA levels were analyzed by the PhasED-Seq assay (timepoints C1D1, C2D1, C3D1, and end of treatment [EOT]; Kurtz Nat Biotechnol 2021); somatic variants were filtered by performing PhasED-seq on buffy coats. Pretreatment biopsies were analyzed by whole genome sequencing and whole transcriptome sequencing. DL1 (0.4 mg D1-7) and DL2 (0.4 mg D1-10) data were pooled. Results Ikaros levels in T cells at 5 hours after the first dose had a 1.1% median increase with 0.2 mg and 44% median decrease with 0.4 mg; by C1D7 pretreatment, Ikaros substantially decreased with both DLs (median: 0.2 mg, 87% decrease; 0.4 mg, 83% decrease). Ikaros differences between 0.2 mg and 0.4 mg were not substantial. By C2D1, Ikaros levels recovered to baseline. Based on preclinical benchmarks, steady-state Ikaros degradation in T cells suggested that direct tumor cell killing by GOLCA was achieved. Changes in T and NK cell phenotypes in peripheral blood included activation, increased proliferation, increased T effector memory and regulatory cell levels, and decrease in naive T cells. Changes were seen by C1D15 and maintained at C2D1 and C3D1. Overall, immune changes between 0.2 mg and 0.4 mg dose levels were not substantially different. Phased variant data from ctDNA and buffy coats were evaluable for 34 patients (0.2 mg, n =15; 0.4 mg, n = 19). Baseline ctDNA levels were similar between the 0.2 mg and 0.4 mg cohorts and, consistent with prior studies, correlated with International Prognostic Index and cell of origin. Previously reported landmarks such as early molecular response (EMR; ≥ 2 log decrease) at C2D1 and major molecular response (MMR; ≥ 2.5 log decrease) at C3D1 were assessed (Kurtz J Clin Oncol 2018) . A high fraction of patients designated high risk by pretreatment ctDNA (≥ 2.5 log haploid genome equivalents [HGE]/mL; Kurtz J Clin Oncol 2018) were clinical responders. Patients who achieved minimal residual disease (MRD) negativity on treatment generally remained MRD negative at subsequent timepoints. At C2D1, the EMR and MRD negativity rates for 0.2 mg were 73% (11/15) and 20% (3/15), respectively; for 0.4 mg these rates were 83% (15/18) and 44% (8/18). At C3D1, the MMR and MRD negativity rates for 0.2 mg were 83% (10/12) and 42% (5/12), respectively; for 0.4 mg these were 83% (10/12) and 58% (7/12). Although ctDNA differences between 0.2 mg and 0.4 mg were not substantial, numerically greater ctDNA changes were seen with 0.4 mg GOLCA + R-CHOP vs 0.2 mg GOLCA + R-CHOP and vs R-CHOP and R-CHOP-like regimens from other cohorts ( Figure). Insufficient samples were available to draw conclusions about EOT, but additional ctDNA data will be presented. Whole genome and transcriptome sequencing data from GOLCA + R-CHOP-treated patients will be shown. Conclusions Pharmacodynamic biomarkers and ctDNA levels indicate that both tumor-intrinsic and immune-modulating mechanisms of action of GOLCA remain relevant in combination with R-CHOP in previously untreated aggressive BCL. ctDNA data during treatment are consistent with the efficacy noted on clinical restaging. Translational data demonstrate the potency of GOLCA and will support future frontline clinical trial designs in patients with untreated aggressive BCL. Study support: Celgene, a Bristol-Myers Squibb Company

Idecabtagene Vicleucel (ide-cel) Versus Standard (std) Regimens in Patients (pts) with Triple-Class-Exposed (TCE) Relapsed and Refractory Multiple Myeloma (RRMM): Updated Analysis from KarMMa-3

Introduction A single ide-cel infusion showed significantly longer median progression-free survival (PFS) vs std regimens (13.3 vs 4.4 months [mo], HR 0.49, 95% CI 0.38-0.65, P < 0.001) with deep, durable responses in heavily pretreated TCE RRMM at an interim analysis (IA) of KarMMa-3 (NCT03651128); safety data were consistent with prior studies (Rodríguez-Otero et al. NEJM 2023). Ide-cel benefits were consistent across pts in high-risk subgroups and across 2-4 prior lines of therapy (Tx). Results of the preplanned final PFS analysis of KarMMa-3 with 12.3 mo additional follow-up are reported. Methods In the phase 3 KarMMa-3 trial, pts with RRMM who received 2-4 prior regimens, including an immunomodulatory agent, proteasome inhibitor, and daratumumab, and were refractory to last regimen were randomized 2:1 to ide-cel or a std regimen (DPd, DVd, IRd, Kd, or EPd). In the ide-cel arm, pts could receive ≤ 1 cycle of optional bridging Tx for disease control. Pts in the std regimens arm could receive ide-cel after confirmed disease progression (PD). The primary endpoint was IRC-assessed PFS in the ITT population; final PFS was planned to be analyzed with ~289 events. Key secondary endpoints were IRC-assessed overall response rate (ORR) and overall survival (OS); other secondary endpoints included complete response rate (CRR), duration of response (DOR), minimal residual disease (MRD) status, time to next anti-myeloma Tx (TTNT; time from randomization to next anti-myeloma Tx [MTx]), event-free survival (EFS; time from randomization to first PD, next MTx or any-cause death, whichever is first), PFS2 (time from randomization to second objective PD or any-cause death, whichever is first), safety, and health-related quality of life (QOL). Results Of 386 randomized pts (ide-cel, n = 254; std regimens, n = 132), 225 received ide-cel and 126 received a std regimen. Baseline characteristics were generally balanced. Median follow-up from randomization to data cutoff (April 28, 2023) was 30.9 mo (range 12.7-47.8). Ide-cel significantly improved median PFS (95% CI) vs std regimens (13.8 [11.8-16.1] vs 4.4 [3.4-5.8] mo), representing a 51% reduced risk of PD or death (HR 0.49, 95% CI 0.38-0.63; Figure); 18 mo PFS rates were 41% vs 19%, respectively. Ide-cel significantly improved ORR vs std regimens (71% vs 42%) with deeper (CRR 44% vs 5%; ≥CR and MRD negative status [sensitivity level 10 -5], 22% vs 1%), more durable responses (median DOR 16.6 vs 9.7 mo; Table). PFS and ORR benefits of ide-cel vs std regimens were consistent with the IA. Interim OS will be included in the presentation. In pts who received ide-cel (n = 225) or a std regimen (n = 126), median PFS (95% CI) was 15.7 (12.5-18.9) vs 4.4 (3.4-5.8) mo, respectively. In the ITT population, median TTNT, EFS, and PFS2 were numerically longer with ide-cel vs std regimens. Median (range) TTNT was 20.9 (16.6-24.2) vs 7.0 (5.3-8.5) mo. Median (95% CI) EFS was 13.3 (11.3-15.7) vs 3.9 (3.0-5.3) mo. Median PFS2 (95% CI) was 23.5 (18.4-27.9) vs 16.7 (12.2-20.3) mo; ide-cel was next MTx in 70 (53%) pts in the std regimens arm. In the treated population, grade (gr) 3/4 infections occurred in 66/249 (27%) pts in the ide-cel arm vs 25/126 (20%) in the std regimens arm. In the ide-cel safety population, any gr cytokine release syndrome occurred in 197/225 (88%) pts, gr ≥ 3 in 11 (5%); median time to first onset was 1 d (1-14), median duration was 4 d (1-51). Any gr investigator-identified neurotoxicity occurred in 34/225 (15%) pts, gr ≥ 3 in 7 (3%); median time to onset was 3 d (range 1-317); median duration was 2.5 d (range 1-252). Ide-cel continued to demonstrate durable, clinically meaningful improvements in pt-reported outcomes, including symptoms, functioning, and QOL vs std regimens. Conclusions In this final PFS analysis of KarMMa-3, significantly longer PFS was maintained with ide-cel; PD or death risk reduced by 51%; responses were deeper and more durable vs std regimens. CRR with ide-cel increased since the IA, indicating a deepening response, but were unchanged with std regimens. A single ide-cel infusion vs continuous treatment with std regimens resulted in longer median TTNT and PFS2, indicating improved long-term disease control. The ide-cel safety profile was consistent with previous reports, with no parkinsonism or Guillain-Barré syndrome reported. These data continue to support use of ide-cel in pts with TCE RRMM. Study support 2seventy bio and Celgene, a Bristol-Myers Squibb Company.

Efficacy and Safety of Idecabtagene Vicleucel (ide-cel) in Patients with Clinical High-Risk Newly Diagnosed Multiple Myeloma (NDMM) with an Inadequate Response to Frontline Autologous Stem Cell Transplantation (ASCT): KarMMa-2 Cohort 2c Extended Follow-up

Introduction Patients (pts) with multiple myeloma (MM) have a higher risk of progression/death following an inadequate response to frontline ASCT (van de Velde Eur J Haematol 2017). Therapies (Tx) with novel mechanisms of action may further improve response outcomes. Ide-cel previously demonstrated frequent, deep, and durable responses in KarMMa (Munshi N Engl J Med 2021) and significantly improved median progression-free survival (PFS) and overall response rate (ORR) versus standard regimens in KarMMa-3 (Rodríguez-Otero N Engl J Med 2023) in pts with triple-class-exposed relapsed and refractory MM. KarMMa-2 (NCT03601078) is a multicohort, phase 2, multicenter trial evaluating the efficacy and safety of ide-cel in pts with MM; cohort 2c included pts with NDMM who had an inadequate response to frontline Tx with ASCT. In cohort 2c, with a median follow-up of 27.9 months, ide-cel demonstrated deep and durable responses; complete response (CR) rate was 74.2% (ORR, 87.1%), with a 24-month PFS rate of 83.1% (Dhodapkar Blood 2022). Here, we report results with an additional 11.5 months of median follow-up for updated efficacy and safety data, and health-related quality of life (HRQoL) outcomes in cohort 2c. Methods Eligible pts had NDMM, received ≥ 3 cycles of induction Tx (including a proteasome inhibitor, an immunomodulatory agent, and dexamethasone), had < very good partial response (VGPR) 70-110 days after ASCT (single/tandem), and had Eastern Cooperative Oncology Group performance status ≤ 1. Pts received a single infusion of ide-cel (dose range: 150-450 × 10 6 CAR+ T cells) after lymphodepletion and could receive maintenance Tx post-infusion at investigator's discretion. The primary endpoint CR rate and secondary endpoints ORR, duration of response (DOR), PFS, overall survival (OS), safety, and patient-reported outcomes on HRQoL, assessed via European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core 30 Questionnaire (QLQ-C30) and EORTC Quality of Life Multiple Myeloma Module 20 Questionnaire (QLQ-MY20), are reported. The exploratory endpoint of minimal residual disease (MRD) negativity (sensitivity, 10 -5) is also reported. Results At data cutoff (May 3, 2023), with a median follow-up of 39.4 (range, 31.6-44.7) months, all 31 pts who were infused with ide-cel were alive; 28 (90.3%) remained in follow-up, with 3 (9.7%) having discontinued due to disease progression. The ORR and CR rates were 87.1% and 77.4%, respectively ( Table); best overall response in 1 pt improved from VGPR to stringent CR. The median DOR was not reached (NR; 95% CI, NR-NR), neither was median PFS (95% CI, 38.0-NR) or median OS (95% CI, NR-NR); the 36-month event-free rates were 80.9%, 76.8%, and 100.0%, respectively. In pts who did not receive lenalidomide (LEN) maintenance, 9 (29.0%) had disease progression; of the 8 pts who received LEN maintenance post ide-cel infusion, none experienced disease progression. At 36 months, MRD negativity was confirmed in 9/14 (64.3%) evaluable pts; all 9 achieved ≥ CR. In this extended follow-up, safety results were generally consistent with the previous data cutoff. All pts experienced ≥ 1 any-grade adverse event (AE), most commonly hematologic, including neutropenia (80.6%), anemia (38.7%), leukopenia (32.3%), and thrombocytopenia (29.0%); infection and infestation AEs occurred in 74.2% of pts. No grade 5 AEs were reported. Incidence of any-grade cytokine release syndrome (58.1%; no grade ≥ 3) was unchanged and there were no additional reports of parkinsonism since the previous report. Overall, HRQoL improved ( Figure) and MM disease symptoms were stable over time based on the EORTC QLQ-C30 and QLQ-MY20, respectively, following ide-cel treatment; by month 3, > 75% of pts had improved or stable global health status/QoL. Conclusions Ide-cel continued to demonstrate deep, durable responses in pts with an inadequate response to frontline ASCT, no new safety signals were observed with extended follow-up, and no deaths were reported. No pts who received LEN maintenance post ide-cel experienced disease progression. Ide-cel treatment resulted in stable or improved HRQoL. Overall, ide-cel continued to demonstrate a favorable clinical benefit-risk profile in NDMM after ASCT. Study support 2seventy bio and Celgene, a Bristol-Myers Squibb Company.

Idecabtagene Vicleucel (ide-cel) Versus Standard (std) Regimens in Patients (pts) with Triple-Class-Exposed (TCE) Relapsed and Refractory Multiple Myeloma (RRMM): Analysis of Cytopenias and Infections in Pts from KarMMa-3

Introduction In the KarMMa-3 trial (NCT03651128), ide-cel, a BCMA-directed CAR T cell therapy (Tx), significantly improved median progression-free survival (13.3 vs 4.4 mo, HR 0.49, P < 0.001) and overall response rate (71% vs 42%, P < 0.001) vs std regimens in pts with RRMM who were TCE to immunomodulatory (IMiD ®) agents, proteasome inhibitors (PIs), and daratumumab (Rodríguez-Otero NEJM 2023). Early high-grade (gr) cytopenias and severe infections have been reported post-CAR T cell infusion (Logue Blood 2022, Thibaud Blood 2022), and persistent cytopenias and infections can pose clinical challenges in pt care. In this safety analysis of KarMMa-3, we report frequency, kinetics of occurrence, and management of cytopenias and infections post-Tx with ide-cel or std regimens. Methods This international, randomized, multicenter phase 3 trial enrolled pts with RRMM who received 2-4 prior Txs (an IMiD agent, a PI, and daratumumab) and were refractory to the last Tx. Pts were randomized 2:1 to ide-cel or a std regimen (DPd, DVd, IRd, Kd, or EPd) selected by investigator based on prior anti-MM Tx. In the ide-cel arm, pts could have ≤ 1 cycle of optional bridging Tx (BTx) for disease control. Treated population (pop; ide-cel: pts who received leukapheresis [LA], BTx, lymphodepleting chemotherapy, or ide-cel; std regimens: pts who received any dose of study Tx) was used to assess adverse events (AEs), gr 3/4 AEs, and serious AEs. Safety pop (pts who received ide-cel or any dose of std regimens) was used to assess treatment-emergent AEs, AEs of special interest, investigator-identified neurotoxicity/cytokine release syndrome and others. In pts who had documented disease progression on std regimens and then underwent LA to receive ide-cel, only AEs before LA were included. In this analysis, incidence of cytopenias and infections at various time intervals and management, types of infections, and incidence of hypogammaglobulinemia (HGG) were assessed. Results At data cutoff (Oct 3, 2022), median follow-up was 24.1 (range 5.9−41.0) mo in the 386 randomized pts. In the treated pop, 248/249 (99.6%) vs 124/126 (98.4%) pts had any-gr AEs, 234 (94.0%) vs 96 (76.2%) had gr 3/4, and 36 (14.5%) vs 9 (7.1%) had gr 5 in ide-cel vs std regimens arms, respectively. Of the gr 5 AEs, 18/36 and 3/9 had verbatim terms consistent with progressive disease. In the safety pop, incidence of gr 3/4 cytopenias with ide-cel were higher early after infusion but generally resolved over time (196 [87.1%] pts at < 3 mo, 52 [24.1%] pts at 3−< 6 mo, 30 [14.7%] pts at ≥ 6 mo; Table 1) vs std regimens, which showed lower rate of resolution over time. More pts in the ide-cel (16 [7.1%]) vs std regimens arms (3 [2.4%]) had any-gr febrile neutropenia. Cytopenias were mainly managed using colony-stimulating factor in both arms (55.5% and 58.7%, respectively); RBC (48%) and platelet transfusions (32%) were more common in the ide-cel arm. Overall, incidence of gr 3/4 infections was high at < 3 mo and remained consistent over time in both arms (ide-cel: 17 [7.6%] pts at < 3 mo, 18 [8.3%] pts at 3−< 6 mo, 13 [6.4%] pts at ≥ 6 mo; Table 2). Any-gr bacterial infections were more common in the ide-cel vs std regimens arms with higher incidence at < 3 mo (10% vs 6%) but lowered at later timepoints. Incidence of gr ≥ 3 viral infections remained low and consistent with time; fungal infections were uncommon. Deaths due to infections occurred in 3 (1.3%) vs 1 (0.8%) pts at < 3 mo, 0 pts at 3−< 6 mo, and 7 (3.4%) vs 2 (2.6%) pts at ≥ 6 mo in the ide-cel vs std regimens arms, respectively. Indence of any-gr new HGG was higher in the ide-cel vs std regimens arms but decreased over time: 15 (6.7%) vs 2 (1.6%) pts at < 3 mo, 3 (1.4%) vs 1 (0.9%) at 3−< 6 mo, and 5 (2.5%) vs 0 at ≥ 6 mo, respectively; of these, 13 (5.8%) vs 1 (0.8%), 2 (0.9%) vs 1 (0.9%), and 5 (2.5%) vs 0 pts received IV immunoglobulin replacement Tx at the respective time intervals. Incidence rate (% per 100 pt-years, 95% CI) of second primary malignancies remained low and similar between arms (ide-cel, 4.0 [2.4−6.7]; std regimens, 4.4 [1.9−10.7]). Conclusion In KarMMa-3, most severe cytopenias associated with ide-cel occurred early, with a low incidence of prolonged cytopenias; all were largely manageable. Any-gr bacterial infections decreased over time while viral infections remained the same. No new safety concerns were identified for ide-cel; safety profile was consistent with previous reports. Study support 2seventy bio and Celgene, a Bristol-Myers Squibb Company.

Operationalization of decentralized clinical trials: The BrUOG354 experience.

100 Background: Decentralized clinical trials (DCT) aim to bring a trial’s activities to the patient. However, to date there is little practical experience about conducting them in the therapeutic arena. Due to the COVID-19 pandemic, and in partnership with Bristol Myers Squibb (BMS), we modified our Investigator-Initiated study, BrUOG354 (ClinicalTrials.gov ID: NCT03355976), a phase II trial on the role of Nivolumab and Ipilimumab in extra-renal clear cell carcinoma. This allowed for the shipment of investigational product (IP) to the patient for local administration without trial site activation. Here we report the experience and lessons learned. Methods: The administrative process to facilitate decentralization on BrUOG-354 required FDA guidance, BMS agreement, and Lifespan IRB approval. Brown University Oncology Group (BrUOG) databases were mined for all communications with local sites and providers. We report on enrollment figures per quarter pre- and during/post-pandemic, the number of off-study sites approached, and agreements reached. The reasons for not moving forward at the local site were characterized by two authors (DD, RW). Results: This study was initiated at two Providence health systems initially and activated a third site at the University of Illinois at Chicago in 2021. In total, 46 volunteers were consented to this trial between April 2018 and April 2023, with 16 (34.8%) registered prior to the lockdown in March 2020 and 30 (65.2%) after. Among 34 patients treated at the PI’s institution, seven travelled from out of state for treatment. Two who started treatment pre-lockdown were successfully transitioned so that protocol therapy was administer locally, and both remain on study. Five people were registered during the pandemic and six institutions were approached; three accommodated the request. Reasons provided for not allowing local administration of IP including: unavailability of a research pharmacy (1), blanket institutional prohibition (1) and lack of indemnification language (1). Conclusions: The experience with BrUOG354 exemplifies the potential of DCTs in an oncological setting while simultaneously highlighting barriers to implementation. Therapeutic DCTs are feasible and heightened capacity for future patient-centric trial designs is an exciting prospect. For these to succeed, the ability to conduct study visits by telehealth, especially for out of state residents, is critical. While not originally designed to be decentralized, adopting this approach enabled us to complete enrollment in a rare tumor during the pandemic. By shifting to a patient-centric model, DCTs may improve patient access and options for clinical trials in particular for less common malignancies, while preserving quality of life, addressing financial toxicity, and foster a more diverse trial population. Clinical trial information: NCT03355976 .

189-LB: LDL Cholesterol Reduction and Cardiovascular Outcomes in High-Risk Primary Prevention Patients

Background: Current guidelines recommend reducing LDL cholesterol in patients at high risk for a first major adverse cardiovascular event (primary prevention). However, these recommendations are predominately based on clinical trials conducted many years ago. Most contemporary trials of LDL-cholesterol lowering therapies have enrolled only secondary prevention patients. Some authorities have questioned whether the benefits of cholesterol lowering exceed the harms in primary prevention patients. Currently, lipid-lowering therapies are underutilized in high-risk patients without a prior event, particularly in women and patients with diabetes. More than half of eligible patients are not currently receiving LDL-cholesterol lowering therapies. Methods: The CLEAR Outcomes trial reported cardiovascular outcomes for bempedoic acid treatment compared with placebo in a mixed population of primary and secondary prevention patients unable or unwilling to take guideline-recommended doses of statins (N=13,970). The primary end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction (MI), nonfatal stroke, or coronary revascularization. The results of the CLEAR OUTCOMES trial were presented and simultaneously published in the NEJM on March 4. The hazard ratio for the primary end point for the full population was 0.87 (95% CI 0.79-0.96), P=0.004. Results: In the CLEAR Outcomes trial, 4206 patients (30%) met high risk primary prevention entry criteria, two thirds with diabetes. The HR in these primary prevention patients was lower than the HR for secondary prevention patients, 0.68 (95% CI 0.53-0.87), with a significant interaction P value (0.03). The current Late Breaking Trial will report detailed results for the primary and all key secondary endpoints for the 4206 patients enrolled based on high risk primary prevention criteria. Full results will be available in mid-April for simultaneous presentation and publication during the ADA meeting. Disclosure S. Nissen: Research Support; Eli Lilly and Company, AbbVie Inc., AstraZeneca, Bristol-Myers Squibb Company, ESPERION Therapeutics, Inc., New Amsterdam Pharma, Novartis, Patient-Centered Outcomes Research Institute, Silence Therapeutics. For the clear outcomes trial investigators: n/a. Funding National Heart, Lung, and Blood Institute (K23HL153774 to J.E.T.); University of Toronto (to B.R.S.)

836-P: Glucose-Dependent Insulin Production and Insulin-Independence in Type 1 Diabetes from Stem Cell–Derived, Fully Differentiated Islet Cells—Updated Data from the VX-880 Clinical Trial

VX-880 is an investigational allogeneic stem cell-derived, fully differentiated, pancreatic islet cell replacement therapy being evaluated in a phase 1/2 clinical trial in patients with T1D and impaired hypoglycemic awareness and severe hypoglycemia. The phase 1/2 trial has three parts: Part A in which 2 patients are enrolled sequentially and receive half the target dose (presented at ADA 2022), Part B in which 5 patients are enrolled sequentially and receive the target (full) dose, and Part C where 10 patients are enrolled concurrently and receive the target (full) dose. The first two patients infused with VX-880 at half the target dose (in Part A) had restored insulin production and glucose control. One of these patients achieved and has maintained insulin independence, defined as at least one week off exogenous insulin, HbA1C ≤7%, post-prandial serum glucose at 90 minutes ≤180 mg/dL, fasting serum glucose ≤126 mg/dL, and fasting or stimulated C-peptide ≥166 pmol/L (latter 3 measured during mixed-meal tolerance test). The safety profile was consistent with the immunosuppressive regimen used in the study and the perioperative period. Part B is now fully enrolled and multiple patients have been dosed with the full (target) dose. Longer-term data on both patients in Part A and new data on patients who received the full (target) dose in Part B will be provided in the presentation. These results are the first from a clinical trial of allogeneic, fully differentiated, insulin producing, stem cell-derived islets which has demonstrated the potential to restore insulin production and glycemic control and provide insulin independence in patients with T1D. Disclosure T.W.Reichman: Consultant; Sernova, Corp., Research Support; Vertex Pharmaceuticals Incorporated. J.L.Shih: Employee; Vertex Pharmaceuticals Incorporated. C.Wang: Employee; Vertex Pharmaceuticals Incorporated. D.Melton: None. F.Pagliuca: Employee; Vertex Pharmaceuticals Incorporated, Stock/Shareholder; Vertex Pharmaceuticals Incorporated. B.Sanna: Employee; Vertex Pharmaceuticals Incorporated. L.S.Kean: Advisory Panel; HiFiBio, Mammoth Biosciences, Consultant; Vertex Pharmaceuticals Incorporated, Other Relationship; Bristol-Myers Squibb Company, Research Support; Bristol-Myers Squibb Company, Adaptive Biotechnologies, Merck & Co., Inc., Tessera, Novartis. A.L.Peters: Advisory Panel; Abbott Diabetes, Medscape, Novo Nordisk, Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S, Research Support; Abbott Diabetes, Dexcom, Inc., Insulet Corporation, Stock/Shareholder; Omada Health, Inc., Livongo. P.Witkowski: Advisory Panel; Vertex Pharmaceuticals Incorporated, Novartis. M.R.Rickels: Consultant; Sernova, Corp., Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S, Research Support; Dompé. C.Ricordi: Advisory Panel; Vertex Pharmaceuticals Incorporated. A.Naji: None. J.F.Markmann: None. B.A.Perkins: Advisory Panel; Dexcom, Inc., Insulet Corporation, Novo Nordisk, Sanofi, Vertex Pharmaceuticals Incorporated, Other Relationship; Abbott, Medtronic, Sanofi, Research Support; Novo Nordisk, Bank of Montreal (BMO). M.Wijkstrom: None. S.Paraskevas: None. B.Bruinsma: Employee; Vertex Pharmaceuticals Incorporated. G.Marigowda: Employee; Vertex Pharmaceuticals Incorporated.

178-OR: Better Glycemic Control with Once-Weekly Insulin Icodec vs. Once-Daily Insulin Degludec in Insulin-Naïve Type 2 Diabetes (ONWARDS 3)

Efficacy and safety of once-weekly insulin icodec (icodec) vs once-daily insulin degludec (degludec) in insulin-naïve adults with T2D were examined in ONWARDS 3 (NCT04795531), a 26-week, randomized, double blind, double dummy, treat-to-target, phase 3a trial. Participants (n=588) were randomized 1:1 to icodec or degludec. Key outcomes are shown in the table. The primary endpoint was A1C change from baseline (BL) to week 26. Estimated mean A1C change was greater with icodec (−1.57%; BL: 8.55%) vs degludec (−1.36%; BL: 8.48%); estimated treatment difference −0.21%-points (95% CI −0.34, −0.08), confirming non-inferiority (p<0.0001) and superiority (p=0.0016). Level 2 or 3 hypoglycemia rates were numerically but not statistically significantly higher with icodec vs degludec in the on-treatment period. Odds of achieving A1C <7% without level 2 or 3 hypoglycemia were statistically significantly higher with icodec vs degludec. There were no significant differences in weekly insulin dose from week 24 to 26 or body weight change from BL to week 26 between arms. No unexpected safety findings were observed. Overall, once-weekly icodec demonstrated superior A1C reduction vs once-daily degludec with low level 2 or 3 hypoglycemia rates in both arms. Icodec may facilitate insulin treatment acceptance and adherence by reducing basal insulin injections from ≥365 to 52 per year. Disclosure I.Lingvay: Advisory Panel; Novo Nordisk A/S, Lilly Diabetes, Boehringer-Ingelheim, Sanofi, Consultant; Carmot Therapeutics, Inc., Merck Sharp & Dohme Corp., Janssen Scientific Affairs, LLC, Pfizer Inc., Intercept, Intarcia, Valeritas, TargetRWE, Shionogi, Zealand Pharma, Structure, Bayer, Research Support; Novo Nordisk A/S, Boehringer-Ingelheim. M.Asong: Employee; Novo Nordisk. C.Desouza: Advisory Panel; Novo Nordisk A/S, Bayer Inc., Consultant; Asahi Kasei Corporation, Research Support; Eli Lilly and Company. P.Gourdy: Advisory Panel; Novo Nordisk, Eli Lilly and Company, Sanofi, Bayer Inc., Merck Sharp & Dohme Corp., Novartis, Intercept Pharmaceuticals, Inc., Research Support; Novo Nordisk, Speaker's Bureau; Novo Nordisk, Eli Lilly and Company, Sanofi, Abbott, AstraZeneca, Boehringer-Ingelheim. S.Kar: None. A.G.Vianna: Advisory Panel; AstraZeneca, Board Member; Abbott Diabetes, Novo Nordisk, Medtronic, Research Support; Novo Nordisk, Anji Pharmaceuticals, Lilly, Speaker's Bureau; AstraZeneca, Novo Nordisk, Medtronic. T.Vilsbøll: Consultant; AstraZeneca, Boehringer Ingelheim Inc., Gilead Sciences, Inc., Eli Lilly and Company, Mundipharma, Merck & Co., Inc., Novo Nordisk A/S, Sanofi, Sun Pharmaceutical Industries Ltd., Bristol-Myers Squibb Company. S.M.Vinther: Employee; Novo Nordisk. Y.Mu: Speaker's Bureau; Abbott Diabetes, Boehringer Ingelheim Inc., Novo Nordisk (China), Sanifit. Funding Novo Nordisk A/S

1361-P: Patients with Severe Nonalcoholic Steatohepatitis (NASH) Have Profound Insulin Resistance and Lipotoxicity

NASH is the more severe form of nonalcoholic fatty liver disease (NAFLD), prone to advanced fibrosis/cirrhosis. However, the metabolic profile of such patients is not well characterized. The aim of this study was to assess the cardiometabolic features of patients with NASH matched for major variables (age, gender, BMI, A1c), to people with less severe disease activity and without NAFLD. To this end, we recruited 46 patients (age: 57±1.5 years; BMI: 36.2±0.8 kg/m2; A1c: 6.8±0.2%; T2DM: 70%), from our outpatient endocrine and PCP clinics and measured liver disease activity/severity by magnetic resonance (MR) iron corrected T1 imaging (cT1). Patients were grouped based on disease activity (cT1) into those without NAFLD (non-NAFLD; n = 8; cT1 <800 ms), mild-to-moderate NASH (mNASH; n = 16; cT1 ≥800 to ≤875 ms), and severe/high-risk steatohepatitis (sNASH; n = 22; cT1 >875 ms). Insulin resistance increased with the severity of NASH (HOMA-IR: non-NAFLD: 3.6±0.9 vs. mNASH: 4.3±0.7 vs. sNASH: 5.5±0.7), and so did adipose tissue IR (adipo-IR [fasting FFA x insulin]: 3.5±0.5 vs. 5.5±1.0 vs. 8.2±1.0; respectively, p=0.03). Dysfunctional adipose tissue/lipotoxicity was also evident from lower adiponectin levels (non-NAFLD: 7.4±2.4 vs. mNASH: 3.9±0.7 vs. sNASH: 3.7±0.3 µg/mL; p=0.04) and a 2-fold increase in ectopic fat/liver steatosis by MR-PDFF (mNASH: 11.2±0.9 vs. sNASH: 20.3±1.6; p<0.001). Plasma CK-18, a marker of hepatocyte apoptosis, increased with NASH severity (105±13 vs. 220±44 vs. 361±57 U/L; respectively p=0.02) and correlated with the severity of NASH by cT1 (r=0.46; p<0.01). Liver steatosis (r=0.73; p<0.01) and adipo-IR (r=0.32; p=0.1) were also associated with cT1. Conclusion: Increased hepatic disease activity (cT1) in patients with NASH is a strong indicator of insulin resistance and an unfavorable cardiometabolic profile. Its use in the clinic may identify patients with a greater risk of adverse liver and cardiovascular outcomes. Disclosure S.A.Marangi: None. S.Shrestha: None. L.Mansour: None. S.S.Shetty: None. M.M.Calvet: None. R.Lomonaco: None. D.Barb: None. K.Cusi: Consultant; Poxel SA, Altimmune, Arrowhead Pharmaceuticals, Inc., AstraZeneca, 89bio, Inc., Bristol-Myers Squibb Company, Lilly, Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Medscape, Myovant, Novo Nordisk, ProSciento, Quest Diagnostics, Sagimet, Sonic Incytes, Terns, Research Support; Echosens, Inventiva, LabCorp, Zydus. S.Kalavalapalli: None. E.Godinez leiva: None. H.B.Thomaides-brears: Employee; Perspectum Ltd., Stock/Shareholder; Perspectum Ltd. C.Diamond: Employee; Perspectum Ltd. Y.Mohseni: None. M.A.Gonzalez: None. A.Ortiz rocha: None. E.Valdez saenz: None. Funding National Institutes of Health (R01120331-01A1)

1440-P: Single Islet Antigen 2 Antibody–Positive (IA2A Ab+) Children Exhibit Significant Metabolic Abnormalities and 5-Year Type 1 Diabetes (T1D) Risk

Current T1D staging defines multiple Ab+ as the start of T1D (Stage 1 or 2 depending on presence of dysglycemia). However, single Ab+ individuals are considered low-risk and are typically not considered for inclusion in prevention trials. We hypothesized that single IA2A+ children exhibit metabolic compromise with appreciable Stage 3 (clinical diabetes) risk. To test this, we evaluated 2163 confirmed single Ab+ children (IA2A, glutamic acid decarboxylase [GADA], or insulin [IAA]) with available OGTT data in the TrialNet natural history study. With and without age and BMI adjustment (Table), IA2A+ children had higher area under the curve (AUC) glucose, lower AUC C-peptide, and higher diabetes risk indices (Diabetes Prevention Trial Type 1 Risk Score [DPTRS] and Index60). Cox regression demonstrated that IA2A+ children were most likely to have progressed to Stage 3 (50.9% vs. 12.0% or 9.6% over 5 years). Of single Ab+ children who did not progress to Stage 3, GADA+ most frequently progressed to multiple Ab+ (34.0% over 5 years). In conclusion, amongst single Ab+ children, IA2A+ children have greater metabolic dysfunction and rates of progression to Stage 3. These findings suggest that single IA2A+ children exhibit substantial T1D risk, should also be considered as having Stage 1 T1D, and be considered for eligibility in prevention studies. Disclosure E.K.Sims: Speaker's Bureau; Medscape, American Diabetes Association. D.D.Cuthbertson: None. E.Bosi: None. C.Evans-molina: Advisory Panel; Provention Bio, Inc., DiogenX, Avotres Inc., Neurodon, MaiCell Therapeutics, Other Relationship; Isla Technology, Bristol-Myers Squibb Company, Nimbus Therapeutics, Research Support; Lilly, Astellas Pharma Inc. M.J.Redondo: None. B.M.Nathan: None. H.M.Ismail: Consultant; Rise Therapeutics. L.M.Jacobsen: None. J.Sosenko: None.

1096-P: Plasma Metabolites Predict Loss of Glycemic Control in Youth with Type 2 Diabetes (T2D)

We aimed to identify metabolites that predict the loss of glycemic control in youth-onset T2D (Y-T2D), a disease characterized by more rapid decline in β-cell function than adults-onset T2D. The increasing incidence of Y-T2D highlights the need to understand its pathophysiology and develop appropriate interventions. We measured 40 plasma metabolites in 374 baseline and 10-year follow-up samples from the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study, using mass spectrometry with a targeted ZipChip based assay. Loss of glycemic control was defined as HbA1c ≥8% for 6 months or inability to wean from temporary insulin after acute metabolic decompensation. We evaluated associations with time to loss of glycemic control in Cox proportional hazards models adjusted for HbA1c, triglycerides, systolic blood pressure, and estimated insulin sensitivity. Participants were 14±2 years of age, 63% female; 72% experienced loss of glycemic control. Five baseline plasma metabolites (threonine, asparagine, glycine, glutamine, L-alpha-aminobutyrate) associated with lower risk of loss of glycemic control, and one baseline plasma metabolite (citrate) associated with higher risk of loss of glycemic control. After multivariable adjustments, only plasma citrate remained statistically significant (HR: 1.16 per 1 SD [95% CI 1.04, 1.30]). At 10-year follow-up, of these plasma metabolites only threonine (logFC: -0.28, p=3.8×10-11) and glycine (logFC: -0.17, p=5.7×10-5) were significantly lower. Plasma metabolites, such as citrate that might originate from an excess of fatty acids, predicted loss of glycemic control in youth with T2D. Future work should validate these findings and investigate their response to promising therapies. Disclosure P.Bjornstad: Advisory Panel; AstraZeneca, Novo Nordisk, Lilly, Horizon Therapeutics plc, Boehringer Ingelheim (Canada) Ltd., LG Chem, Consultant; Bayer Inc., Bristol-Myers Squibb Company. R.Gubitosi-klug: None. K.Drews: None. K.L.Tommerdahl: None. J.B.Tryggestad: None. E.M.Isganaitis: None. F.Bacha: Other Relationship; Takeda Pharmaceutical Co., Ltd., AstraZeneca. L.Pyle: None. K.Sharma: Advisory Panel; Reata Pharmaceuticals, Inc., Otsuka America Pharmaceutical, Inc. T.B.Vigers: None. I.De boer: Advisory Panel; AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, Boehringer Ingelheim International GmbH, Otsuka America Pharmaceutical, Inc., Bayer Inc., Consultant; George Clinical, Gilead Sciences, Inc., Medscape, Research Support; Dexcom, Inc. L.El ghormli: None. H.L.Heerspink: Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Bayer Inc., Eli Lilly and Company, Chinook Therapeutics Inc., CSL Behring, Gilead Sciences, Inc., George Clinical, Merck & Co., Inc., Janssen Research & Development, LLC, Traveere Pharmaceuticals, Novo Nordisk. L.M.Laffel: Advisory Panel; Medtronic, Lilly Diabetes, Novo Nordisk, Vertex Pharmaceuticals Incorporated, Roche Diagnostics, Provention Bio, Inc., Consultant; Dexcom, Inc., Janssen Pharmaceuticals, Inc., Medscape. J.R.Ryder: None. A.S.Shah: None. J.L.Lynch: Research Support; Novo Nordisk. Funding National Institute of Diabetes and Digestive and Kidney Diseases

1725-P: The Role of miR-146a-5p on Cytokine-Induced ß-Cell Mitochondrial Dysfunction and Death

MicroRNAs are small non-coding RNAs with ~22 nucleotides in size involved in the modulation of gene expression. Previously, we observed that miR-146a-5p is upregulated during inflammatory stress in pancreatic islets and pancreatic tissue sections from T1D donors. Although others have linked overexpression of miR-146a-5p to β cell death and impaired insulin secretion, the molecular mechanisms mediating these effects remain unclear. To further understand miR-146a-5p role in β cell health and disease, we have generated stable cell lines that are either overexpressed (OE) or inhibited (ZIP) for miR-146a-5p and assessed for β cell function under inflammatory (IL-1β, IFN-γ, and TNF-α) conditions to model T1D in vitro. Treatment of OE cells with or without pro-inflammatory cytokines increased expression of cleaved caspase-3 and Annexin-V-positive cell death and reduced insulin secretion in both untreated and cytokine treatment. However, ZIP cells are protected from inflammatory stress showing decreased apoptosis and improved insulin secretion. Furthermore, ZIP cells were found to have increased mitochondrial DNA copy numbers, mitochondrial membrane potential, and basal and maximal respiration rate. Notably, cytokines-treated OE cells showed reduced basal respiration rate and ATP production compared to cytokines-treated ZIP cells. In addition, mitochondria isolated from MIN6 cells showed enriched miR-146a-5p under cytokine treatment, suggesting inflammation-mediated enrichment of miR-146a-5p. Finally, RNA sequencing analysis of OE and ZIP cells identified the RNA transcripts regulated by miR-146a-5p, including MAPT, MYRIP, NRG1, and GPX1; pathway enrichment analysis showed pathways related to insulin secretion, apoptosis, and mitochondrial function. Taken together, findings from our study show for the first time that miR-146a-5p upregulation promotes β cell dysfunction and death by suppressing mitochondrial function during T1D pathogenesis. Disclosure P.Krishnan: None. R.C.S.Branco: None. S.A.Weaver: Employee; Eli Lilly and Company. C.Lee: None. F.Syed: None. C.Evans-molina: Advisory Panel; Provention Bio, Inc., DiogenX, Avotres Inc., Neurodon, MaiCell Therapeutics, Other Relationship; Isla Technology, Bristol-Myers Squibb Company, Nimbus Therapeutics, Research Support; Lilly, Astellas Pharma Inc. Funding JDRF (2-SRA-2019-834-S-B, 2-SRA-2018-493-A-B); National Institutes of Health (DK127308, U01DK127786, UC4DK104166)

765-P: A Single Ascending Dose Study of the Novel GLP-1 Receptor Agonist GL0034 (Utreglutide) in Obese Individuals without Diabetes

The novel incretin analogue, GL0034 (GL), has potent agonist activity at glucagon-like peptide 1 (GLP-1RA) receptor. The primary objective of this phase 1 study in people with obesity was to assess the safety and tolerability of single-ascending doses of GL. Healthy individuals (N=24) with BMI ≥30 kg/m2 were randomized (6:2) to increasing doses of subcutaneous GL (1,520, 2,000 and 2,520 μg) or placebo once-weekly during four weeks. GL pharmacokinetics and key exploratory pharmacodynamic parameters (triglyceride, leptin levels and body weight) were assessed (Table). Most common GL-related adverse events were gastrointestinal with dose-dependent nausea, decreased appetite and vomiting. No injection site reactions or any other adverse events were noted. GL maximum concentrations ranged from 227 to 367 ng/mL, and mean half-life ranged from 99 to 118 h. Triglyceride levels were reduced from baseline following treatment with GL 2,000 and 2,520 μg dose at day 8. Decreases in leptin levels were dose-dependent. Reduction in body weight versus baseline reached a maximum of 3.3 kg with the 2,520 μg dose at day 8 and this effect was sustained through day 22 at every GL dose (Table). In conclusion, once-weekly GL demonstrated clinically relevant reductions in body weight in obese individuals and was well tolerated. Disclosure R.Thennati: None. A.Garcia-ocana: Consultant; Sun Pharmaceutical Industries Ltd. G.A.Rutter: Consultant; Sun Pharmaceutical Industries Ltd. R.E.Pratley: Other Relationship; Bayer Inc., Corcept Therapeutics, Dexcom, Inc., Gasherbrum Bio, Inc., Hanmi Pharm. Co., Ltd., Hengrui (USA) Ltd., Merck Sharp & Dohme Corp., Novo Nordisk, Pfizer Inc., Rivus Pharmaceuticals Inc., Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. B.Thorens: Advisory Panel; Sun Pharmaceutical Industries Ltd. T.Vilsbøll: Consultant; AstraZeneca, Boehringer Ingelheim Inc., Gilead Sciences, Inc., Eli Lilly and Company, Mundipharma, Merck & Co., Inc., Novo Nordisk A/S, Sanofi, Sun Pharmaceutical Industries Ltd., Bristol-Myers Squibb Company. V.S.Burade: None. M.Natarajan: None. P.Shahi: None. R.Nagaraja: None. S.T.Panchal: None. S.K.Agrawal: None. B.Jandrain: None. T.Duvauchelle: None.