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Introduction: Efpeglenatide is a long-acting glucagon-like peptide-1 receptor agonist being developed to improve glycemic control in type 2 diabetes (T2D). In the BALANCE 205 study (NCT02075281), efpeglenatide significantly reduced body weight versus placebo in patients with obesity, or overweight with comorbidities, and without T2D. These subanalyses explore the efficacy and safety of efpeglenatide in subgroups of patients with pre-diabetes and stratified by body mass index (BMI) or age from the BALANCE study., Research Design and Methods: The 20-week BALANCE study randomized patients with BMI ≥30 kg/m 2 or ≥27 kg/m 2 with comorbidities, and without diabetes, to efpeglenatide 4 mg or 6 mg once weekly, 6 mg or 8 mg once every 2 weeks, or placebo. For these subanalyses, patients were stratified by pre-diabetes status (glycated hemoglobin (HbA 1c ) 5.7%-6.4% (39-46 mmol/mol) or fasting plasma glucose (FPG) 100-125 mg/dL) and by BMI or age < or ≥ median values (34.9 kg/m 2 and 44 years, respectively) at baseline., Results: In patients with pre-diabetes at baseline, all efpeglenatide doses led to greater proportions of patients reverting to normoglycemia (40.6%-64.3%) versus placebo (10.0%), and greater reductions in HbA 1c (0.30%-0.38%), FPG (7.7-14.1 mg/dL), and weight (5.6-7.3 kg) versus placebo (nominal p<0.05 for all). In patients with BMI or age < or ≥ median, greater reductions in weight were observed with all efpeglenatide doses versus placebo (nominal p<0.01 for all). The most common adverse events in patients receiving efpeglenatide across patient subgroups were gastrointestinal adverse events., Conclusions: These results are consistent with the overall BALANCE population and suggest beneficial effects of efpeglenatide on glycemic control and body weight regardless of pre-diabetes status, age, or BMI at baseline. The effects of efpeglenatide on glycemic control in patients with pre-diabetes suggest it might help reduce the likelihood of at-risk patients developing diabetes., Competing Interests: Competing interests: REP has served as a consultant for AstraZeneca, Glytec, Janssen Pharmaceuticals, Merck, MundiPharma, Novo Nordisk, Pfizer, Sanofi, Sanofi US Services, Scohia Pharma, and Sun Pharmaceutical Industries; has received grants and research support from Hanmi Pharmaceutical, Janssen Pharmaceuticals, Metavention, Novo Nordisk, Poxel SA, and Sanofi; and has received honoraria from Novo Nordisk; honoraria and fees for these activities were directed to a non-profit organization with the exception of those from Sanofi US Services, which were personal fees. SB is an employee of Hanmi Pharmaceutical. MET is a consultant of ProSciento; has received consulting fees from Atrogi, CeQur SA, Hanmi Pharmaceutical, Kinexum, Novo Nordisk, and Servier; and is on the Data Monitoring Board for Profil. MH is an employee and shareholder of ProSciento and has received grants from Hanmi Pharmaceutical. OH is an employee of Hanmi Pharmaceutical. JS is an employee and shareholder of Sanofi. AS was an employee of Sanofi during the development of this publication. CHS was an employee and shareholder of Sanofi during the development of this publication. SJ has received personal fees from AstraZeneca, Boehringer Ingelheim, Lilly, MSD, Novo Nordisk, and Sanofi. K-HY has nothing to declare., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: To evaluate the effects of efpeglenatide, a long-acting glucagon-like peptide-1 receptor agonist (GLP-1 RA), on gastric emptying, glucose metabolism, and islet beta-cell function versus liraglutide and placebo in people with type 2 diabetes., Research Design and Methods: This phase Ib study (ClinicalTrials.gov identifier: NCT02059564) randomized participants (n=47) to three cohorts. Within the first two cohorts, participants were randomized to placebo, efpeglenatide 6 mg weekly (QW; first cohort), or efpeglenatide 16 mg monthly (QM; second cohort). The third cohort received liraglutide 1.8 mg daily (QD). Gastric emptying was assessed through the pharmacokinetic (PK) profile of acetaminophen at baseline and steady state. Glucose metabolism and beta-cell function were assessed based on mixed-meal tolerance testing and a graded glucose infusion procedure., Results: Treatment duration was approximately 3 months for efpeglenatide 16 mg QM and 1 month for efpeglenatide 6 mg QW and liraglutide. At peak drug concentrations, efpeglenatide 6 mg QW was non-inferior to liraglutide 1.8 mg QD in delaying gastric emptying, as assessed by acetaminophen PK (lower bound of 90% CI for the efpeglenatide:liraglutide ratio >0.8 for area under the curve (AUC) 0-120 , AUC 0-180 , AUC 0-360 and maximum concentration (C max )). Efpeglenatide 16 mg QM did not decrease the rate of gastric emptying to as great an extent as liraglutide (ie, non-inferiority was not shown). Compared with liraglutide, both efpeglenatide dosing regimens demonstrated comparable or more favorable glucometabolic effects and improved beta-cell function. All gastrointestinal adverse events reported with efpeglenatide were mild or moderate in severity and transient over treatment and follow-up., Conclusions: The glucometabolic effects of efpeglenatide 6 mg QW and 16 mg QM were comparable to liraglutide. Additional studies are necessary to further examine these benefits of efpeglenatide., Trial Registration Number: NCT02059564., Competing Interests: Competing interests: MH is an employee and shareholder of ProSciento. JK was an employee of Hanmi Pharmaceutical at the time the study was conducted. OH is an employee of Hanmi Pharmaceutical. MET is a consultant of ProSciento; has received consulting fees from Atrogi, CeQur SA, Hanmi Pharmaceutical, Kinexum, Novo Nordisk, and Servier; and is on the Data Monitoring Board for Profil. CHS was an employee and shareholder of Sanofi during the development of this publication. JS is an employee and shareholder of Sanofi. IO was an employee of Sanofi during the development of this publication and is a shareholder of Lexicon Pharmaceuticals. LM is a consultant to ProSciento and to TVM Capital Life Science., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: To assess the efficacy, safety and pharmacokinetic/pharmacodynamic properties of efpeglenatide, a long-acting glucagon-like peptide-1 receptor agonist, in patients with type 2 diabetes (T2D)., Research Design and Methods: Two randomized, double-blind, placebo-controlled phase 2 trials were conducted. The single-dose study (n = 48) was a first-in-patient, sequential dose-escalation study. Patients received a single subcutaneous injection of efpeglenatide (2-100 μg/kg) or placebo. The repeated-dose study (n = 71) was a multiple-ascending-dose trial. Patients received weekly (1, 2 or 4 mg once weekly; 8-week period) or monthly (8, 12 or 16 mg once monthly; 9-week period) subcutaneous injections of efpeglenatide or placebo (without titration)., Results: Both studies demonstrated dose-proportional increases in efpeglenatide serum concentrations. The median time to attain maximum serum concentration (t max ) for efpeglenatide ranged from 72 to 144 hours in the single-dose study and from 48 to 120 hours in the repeated-dose study (following final dose). Geometric mean t 1/2 ranged from 135 to 180 hours across studies. Peak-to-trough ratios in the repeated-dose study ranged from 1.3 to 1.4 with once-weekly dosing and from 5.9 to 12.9 with once-monthly dosing. Following a single dose of efpeglenatide 14-100 μg/kg, fasting plasma glucose and postprandial plasma glucose levels were decreased at week 1 and remained below baseline levels for ≥3 weeks post-dosing. Repeated doses of efpeglenatide led to significant reductions in glycated haemoglobin vs placebo. In both studies, efpeglenatide was generally well tolerated. Gastrointestinal disorders were the most frequently reported treatment-emergent adverse events in efpeglenatide-treated patients., Conclusions: The delayed t max, long half-life, and low peak-to-trough ratios observed demonstrate potential for improved efficacy and dosing flexibility, with good tolerability of efpeglenatide in patients with T2D., (© 2020 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: To determine the optimal dose(s) of once-monthly administration of efpeglenatide, a long-acting glucagon-like peptide-1 receptor agonist (GLP-1RA), in patients with type 2 diabetes (T2D) inadequately controlled on metformin., Materials and Methods: In this phase 2, randomized, placebo-controlled, double-blind trial (NCT02081118), patients were randomized 1:1:1:1 to subcutaneous efpeglenatide (8, 12 or 16 mg once monthly; n = 158) or placebo (n = 51). The 16-week treatment period included a 4-week titration phase with once-weekly efpeglenatide 4 mg, followed by one dose of efpeglenatide 8 mg once monthly and two doses of the assigned once-monthly dose. The primary endpoint was change in glycated haemoglobin (HbA1c) from baseline to week 17., Results: All efpeglenatide doses significantly reduced HbA1c versus placebo (P < 0.0001 for all). Overall, the least squares mean difference in HbA1c reductions between efpeglenatide and placebo was -7.7 mmol/mol (-0.71%; baseline to week 17). At week 17, a significantly greater proportion of efpeglenatide patients had an HbA1c level <53 mmol/mol (<7%) versus placebo (48.7% vs. 30.6%; P = 0.0320). Significant body weight loss occurred across all efpeglenatide doses (placebo-corrected reduction -2.0 kg [efpeglenatide overall]; P = 0.0003). The safety profile was consistent with GLP-1RAs, with gastrointestinal (GI) disorders being the most common treatment-emergent adverse events. Fluctuations in effects on glucose levels and rates of GI events occurred between peak and trough efpeglenatide concentrations., Conclusions: Efpeglenatide once monthly (following once-weekly titration) has significant benefits with regard to HbA1c and weight reduction versus placebo in patients with T2D. Further studies are needed to evaluate the long-term efficacy and safety of efpeglenatide once monthly., (© 2020 John Wiley & Sons Ltd.)

Aim: To evaluate the safety of efpeglenatide, a long-acting glucagon-like peptide-1 receptor agonist (GLP-1RA), and its effects on body weight management in adults without diabetes., Materials and Methods: In this phase II, randomized, placebo-controlled, double-blind trial, participants with a body mass index (BMI) ≥30 kg/m 2 or ≥27 kg/m 2 with comorbidity were randomized 1:1:1:1:1 to efpeglenatide (4 mg once weekly, 6 mg once weekly, 6 mg once every 2 wk, or 8 mg once every 2 wk; n = 237) or placebo (n = 60) in combination with a hypocaloric diet. The primary endpoint was body weight change from baseline after 20 wk of treatment, assessed using a mixed-effect model with repeated measures with an unstructured covariance matrix over all post-screening visits; treatment comparisons were based on least squares mean estimates., Results: Over 20 wk, all doses of efpeglenatide significantly reduced body weight from baseline versus placebo (P < 0.0001), with placebo-adjusted reductions ranging between -6.3 kg (6 mg once every 2 wk) and -7.2 kg (6 mg once weekly). Greater proportions of efpeglenatide-treated participants had body weight loss of ≥5% or ≥10% versus placebo (P < 0.01, all comparisons). Efpeglenatide led to significant improvements in glycaemic variables (fasting plasma glucose and glycated haemoglobin) and lipid profiles (cholesterol, triglycerides) versus placebo. Rates of study discontinuations as a result of adverse events ranged from 5% to 19% with efpeglenatide. Gastrointestinal effects were the most common treatment-emergent adverse events., Conclusions: Efpeglenatide once weekly and once every 2 wk led to significant body weight reduction and improved glycaemic and lipid variables versus placebo. It was also well tolerated for weight management in adults without diabetes., (© 2019 John Wiley & Sons Ltd.)

Objective: To explore the efficacy, safety, and tolerability of once-weekly efpeglenatide, a long-acting glucagon-like peptide 1 receptor agonist (GLP-1 RA), in early type 2 diabetes (T2D) (drug naive or on metformin monotherapy)., Research Design and Methods: EXCEED 203 was a 12-week, randomized, placebo-controlled, double-blind, parallel-group, dose-ranging study of efpeglenatide once weekly referenced to open-label liraglutide 1.8 mg (exploratory analysis). Participants, ∼90% on metformin monotherapy, were randomized to one of five efpeglenatide doses (0.3, 1, 2, 3, or 4 mg q.w.; n = 181), placebo ( n = 37), or liraglutide (≤1.8 mg daily; n = 36). The primary efficacy end point was change in HbA 1c from baseline to week 13., Results: From a baseline HbA 1c of 7.7-8.0% (61.0-63.9 mmol/mol), all efpeglenatide doses ≥1 mg significantly reduced HbA 1c versus placebo (placebo-adjusted least squares [LS] mean changes 0.6-1.2%, P < 0.05 for all) to a final HbA 1c of 6.3-6.8% (45.4-50.6 mmol/mol); masked efpeglenatide 4 mg was noninferior to open-label liraglutide. Greater proportions treated with efpeglenatide ≥1 mg than placebo achieved HbA 1c <7% (61-72% vs. 24%, P < 0.05 for all), and greater reductions in body weight were observed with efpeglenatide 3 and 4 mg versus placebo (placebo-adjusted LS mean differences -1.4 and -2.0 kg, respectively, P < 0.05 for both). Rates of nausea and vomiting were consistent with other GLP-1 RAs and rapidly subsided after the initial 2 weeks. No neutralizing antibodies were detected with efpeglenatide., Conclusions: Efpeglenatide once weekly led to significant reductions in HbA 1c and weight, with a safety profile consistent with the GLP-1 RA class in patients with early T2D mostly on metformin monotherapy., (© 2019 by the American Diabetes Association.)

A protocol consisting of a single donor-specific transfusion (DST) plus a brief course of anti-CD154 monoclonal antibody (anti-CD40 ligand mAb) induces permanent islet allograft survival in chemically diabetic mice, but its efficacy in mice with autoimmune diabetes is unknown. Confirming a previous report, we first observed that treatment of young female NOD mice with anti-CD154 mAb reduced the frequency of diabetes through 1 year of age to 43%, compared with 73% in untreated controls. We also confirmed that spontaneously diabetic NOD mice transplanted with syngeneic (NOD-Prkdc(scid)/Prkdc(scid)) or allogeneic (BALB/c) islets rapidly reject their grafts. Graft survival was not prolonged, however, by pretreatment with either anti-CD154 mAb alone or anti-CD154 mAb plus DST. In addition, allograft rejection in NOD mice was not restricted to islet grafts. Anti-CD154 mAb plus DST treatment failed to prolong skin allograft survival in nondiabetic male NOD mice. The inability to induce transplantation tolerance in NOD (H2g7) mice was associated with non-major histocompatibility complex (MHC) genes. Treatment with DST and anti-CD154 mAb prolonged skin allograft survival in both C57BL/6 (H2b) and C57BL/6.NOD-H2g7 mice, but it was ineffective in NOD, NOD.SWR-H2q, and NOR (H2g7) mice. Mitogen-stimulated interleukin-1beta production by antigen-presenting cells was greater in strains susceptible to tolerance induction than in the strains resistant to tolerance induction. The results suggest the existence of a general defect in tolerance mechanisms in NOD mice. This genetic defect involves defective antigen-presenting cell maturation, leads to spontaneous autoimmune diabetes in the presence of the H2g7 MHC, and precludes the induction of transplantation tolerance irrespective of MHC haplotype. Promising islet transplantation methods based on overcoming the alloimmune response by interference with costimulation may require modification or amplification for use in the setting of autoimmune diabetes.

The enzyme cyclooxygenase (COX)-1 is constitutive whereas COX-2 is regulated in virtually all tissues. To assess whether this dogma holds true in the pancreatic islet, we examined basal and interleukin (IL)-1-regulated expression of COX-2 in HIT-T15 cells, Syrian hamster and human islets, and other Syrian hamster tissues. We found that COX-2, and not COX-1, gene expression is dominant in pancreatic islet tissue under both basal and IL-1-stimulated conditions. Control tissues (liver, spleen, and kidney) showed the expected predominance of COX-1 gene expression. Basal and IL-1-stimulated prostaglandin E2 synthesis were blocked by a specific COX-2 inhibitor. IL-1 stimulation had a biphasic effect on COX-2 mRNA levels with an initial mild increase at 2-4 hr followed by a more dramatic decrease below basal level by 24 hr. The IL-1-induced increase in COX-2 mRNA levels was accompanied by a parallel increase in NF-kappaB binding to COX-2 promoter elements. The subsequent decrease in COX-2 mRNA levels was accompanied by a parallel decrease in NF-IL-6 binding activity and COX-2 promoter activity. Specific mutation of the NF-IL-6 binding motif within the COX-2 promoter reduced basal promoter activity by 50% whereas mutation of the NF-kappaB motif had no effect. These studies provide documentation of NF-IL-6 in the pancreatic islet and that COX-2, rather than COX-1, is dominantly expressed. They suggest coordinate regulation by IL-1 of COX-2 mRNA, NF-kappaB, and NF-IL-6 and raise the issue of whether intrinsically high levels of COX-2 gene expression predisposes the normal islet for microenvironmentally induced overproduction of islet prostaglandin E2.

A role for the Epstein-Barr virus in initiating Type 1 (insulin-dependent) diabetes mellitus has been proposed since Epstein-Barr virus BOLF1 (497-513) AVTPL RIFIVPPAAEY has an 11 amino acid identity with HLA-DQw8 beta (49-60) AVTPL GPPAAEY. Rabbit antisera to the BOLF1 (496-515) peptide crossreacted with the homologous DQw8 beta (44-63) peptide but not with the related DQw7 beta (44-63) peptide, which differed from the DQw8 peptide only in an ALA to ASP substitution in position 57. Antisera to DQw8 beta (49-60) reacted with the DQw8 beta (44-63) peptide and BOLF1 (496-515), but not with DQw7 beta (44-63). The antiserum to the BOLF1 peptide bound to denatured class II major histocompatibility complex beta chains from Epstein-Barr virus-transformed DQw8-positive lymphocytes in an immunoblotting analysis. Epstein-Barr virus antibodies were detected at equal frequencies and similar titres in sera of 30 patients with Type 1 diabetes (16 of 30; 63%) and in sera of 20 non-diabetic control subjects (13 of 20; 65%). Sera from diabetic patients did not bind to DQw8 beta (44-63) or BOLF1 (496-515) peptides. From these data we conclude that there is no simple relationship between serological evidence of Epstein-Barr virus infection and crossreactions between homologous Epstein-Barr virus and class II major histocompatibility complex peptides.

Two proteins, p70 and p80, were found in chemically crosslinked complexes with class II MHC molecules and Ii after 3-12 hr labelings with [35S]methionine. Two-dimensional, nonreduced/reduced SDS gel electrophoresis of immunoprecipitated complexes revealed 1) endogenous disulfide linkages between Ii-Ii and Ii-p70 and 2) chemically crosslinked, nearest neighbors of alpha-beta, alpha-Ii, Ii-p70, and alpha-p80. Although such nearest neighbors within multimeric complexes were identified as dimers in nonreduced/reduced 2D gels, stoichiometries could not be determined in the high molecular weight complex(es), which included alpha, beta, Ii, p70, and p80, and were not separated in the first dimension. p80 was not the chondroitin-sulfate form of Ii (Ii-CS) because it was not electrophoretically heterogeneous and was not sensitive to chondroitinase ABC. p70 was not hsp72/74 detected with C92 or N27 mAbs, and p80 was not BiP detected with its respective mAb. While only these two proteins associated prominently with class II MHC antigens and Ii late after synthesis, their functions are unknown.

The p35 protein which is hyperexpressed on hairy leukemic cells was determined to be Ii, the electrophoretically invariant glycoprotein that is associated with class II major histocompatibility complex (Ia) antigens from the time of their synthesis. The principal function of class II MHC antigens is to present to T cell receptors those digested foreign antigenic peptides that probably fold as amphipathic alpha-helices and adsorb to a hydrophobic surface (desetope) on Ia. By a novel strip-of-helix hydrophobicity algorithm we found that the sequence Leu-142 to His-170 in Ii formed a five-cycle, amphipathic, alpha-helix, the highest scoring one among a series of proteins commonly used as experimental antigens. This finding led to the hypothesis that this sequence in Ii bound to the antigen-binding site (desetope) of Ia until release and self-aggregation in the endosome in order that digested foreign peptides could then bind to Ia. Abundant expression of Ii in leukemic cells might be associated with an altered capacity of those cells to present foreign or leukemic antigens to the host's immune system.

Antibodies to either Ii or class II major histocompatibility complex (MHC) antigens did not recognize cell surface forms of Ii in immunoprecipitates of cells that had been radioiodinated by the lactoperoxidase method, whereas they bound [35S]methionine metabolically labeled molecules. N-hydroxysuccinimidobiotin (NHS-B) and biotin hydrazide (B-H) were used to react more generally with cell surface proteins via amino groups and nitrene coupling, respectively. Each of these latter compounds labeled alpha and beta chains of class II MHC antigens as seen in Western-blotted, electrophoresed immunoprecipitates probed with 125I-labeled streptavidin but not Ii or its associated forms. Although tyrosine residues might have been inaccessible to radioiodination in carbohydrate-derivatized forms of Ii, the lack of Ii biotinylation in these controlled, sensitive studies was consistent with the view that Ii forms were not surface expressed, with the possible exception of the chondroitin sulfate-derivatized forms of Ii (Ii-CS).