bluuebunny/crossref_metadata_2025_split huggingface dataset:
794-P: Effectiveness and Safety of iGlarLixi in People with Type 2 Diabetes (Pw2D), Not at Target on Basal Insulin (BI) and Oral Antidiabetic Therapy (BOT)—Results from the Observational, Prospective Study CHANCE
Authors: WIESNER TOBIAS , PFOHL MARTIN , PEGELOW KATRIN , MÜLLER JULIA , SEUFERT JOCHEN 
Published: June 2023

iGlarLixi, a fixed-ratio combination of insulin glargine 100 U/mL and lixisenatide, is a once-daily treatment advancement option for Pw2D not at target on BOT. CHANCE investigated effectiveness and safety of switching the BI to iGlarLixi in daily clinical practice. Primary objective was to assess absolute change in HbA1c 24 weeks (W24) after switching to iGlarLixi. Secondary objectives included changes in fasting plasma glucose (FPG), bodyweight (BW), use of oral antidiabetic drugs (OADs), dose of previous BI, and hypoglycemia incidence. Overall, data from 70 Pw2D were analyzed. Mean BI dose was 38.9 units per day and individual target HbA1c was 6.9%. iGlarLixi was started with 30 dose steps per day (DS/d); at W24, mean dose was 41.6 DS/d. HbA1c decreased by -0.7% (P &lt; 0.001), while FPG trended down by ~20 mg/dL. This was accompanied by a -3.0 kg decrease in BW (P = 0.442). Numbers of OADs used decreased markedly 24 weeks after switching to iGlarLixi (P &lt; 0.05). Hypoglycemia incidence was low before and did not change significantly after switching to iGlarLixi. In conclusion, advancing BOT by switching the BI to iGlarLixi, improved glycemic control of Pw2D in daily clinical practice without BW gain and with low hypoglycemia incidence; however, titration was not sufficient to reach glycemic targets after 24 weeks.

Disclosure
T.Wiesner: Advisory Panel; Roche Diabetes Care, Sanofi-Aventis Deutschland GmbH, Speaker's Bureau; Sanofi-Aventis Deutschland GmbH, Lilly Diabetes, Boehringer Ingelheim Inc., Abbott Diabetes, Novo Nordisk, Dexcom, Inc., Novartis. M.Pfohl: Advisory Panel; Boehringer Ingelheim and Eli Lilly Alliance, Sanofi-Aventis Deutschland GmbH, Speaker's Bureau; Sanofi-Aventis Deutschland GmbH. K.Pegelow: Employee; Sanofi-Aventis Deutschland GmbH, Stock/Shareholder; Sanofi-Aventis Deutschland GmbH. J.Müller: Employee; Sanofi-Aventis Deutschland GmbH, Stock/Shareholder; Bayer Inc., Inmunebio Inc. J.Seufert: Advisory Panel; Abbott Diabetes, Boehringer Ingelheim Pharma GmbH&Co.KG, Sanofi-Aventis Deutschland GmbH, Speaker's Bureau; Abbott Diabetes, Bayer Inc., Boehringer Ingelheim Pharma GmbH&Co.KG, Merck Sharp & Dohme Corp., Sanofi-Aventis Deutschland GmbH, Novartis, Novo Nordisk.

Funding
Sanofi-Aventis Deutschland GmbH
798-P: Shift to a Lower BMI Category Is Associated with Improved Cardiometabolic Measures in Adults with T2D Treated with Tirzepatide
Authors: WIESE RUSSELL , DIB ANNE , NICOLAY CLAUDIA , ALLEN SHERYL , LEE CLARE 
Published: June 2023

In the Phase 3 SURPASS studies of adults with T2D, the GIP/GLP-1 receptor agonist tirzepatide (TZP) provided clinically meaningful reductions in HbA1c levels and body weight. In this post-hoc analysis of TZP-treated participants in SURPASS 1-5 studies, we assessed whether those shifting to a lower BMI category would improve in cardiometabolic measures such as HbA1c, waist circumference (WC), systolic blood pressure (SBP), and lipid profiles. Changes in BMI category (&lt;25 kg/m², 25- &lt;30 kg/m², 30- &lt;35 kg/m², 35- &lt;40 kg/m², ≥40 kg/m²) from baseline to endpoint were assessed by study (N=3559), regardless of dose. BMI category shifts were grouped into “Improved” (shift to a lower BMI category, by at least one category), or “Stable/Worse” (no change/shift to a higher BMI category). At baseline, participants averaged 58 years, 93.36 kg, 53.6% were male, and 79.5% were white. While improvements in cardiometabolic measures were observed in both subsets of participants, numerically greater improvements in HbA1c, WC, SBP and lipid profile were observed for the 59% who improved their BMI category (Table 1). In the SURPASS studies, shifting to a lower and improved BMI category compared to a stable or worse BMI category was associated with greater improvement in cardiometabolic measures including HbA1c, WC, SBP, and lipid profile.

Disclosure
R.Wiese: Employee; Eli Lilly and Company. A.Dib: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. C.Nicolay: Employee; Eli Lilly and Company. S.Allen: None. C.Lee: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company.

Funding
Eli Lilly and Company
815-P: Enhanced Disulphide Bond Stability Contributes to the Once Weekly PD Profile of Insulin Icodec
Authors: HUBALEK FRANTISEK , CRAMER CHRISTIAN , HELLEBERG HANS , JOHANSSON EVA , SCHLUCKEBIER GERD , STEENSGAARD DORTE B. , STURIS JEPPE , KJELDSEN THOMAS 
Published: June 2023

Insulin icodec is a novel basal insulin analogue with a long half-life (196 hours) that is in clinical development for the treatment of diabetes with once weekly dosing. Insulin icodec was developed based on the hypothesis that lowering the insulin receptor affinity in the presence of a strong HSA-binding moiety would result in a long half-life, provided that non-receptor mediated clearance is diminished. The observation that insulin icodec retains its full potency over weeks has been attributed to low non-insulin receptor mediated clearance as well as to limited degradation in circulation, due to the amino acid modifications in insulin icodec that confer proteolytically-stabilization. Here, we report a previously undescribed insulin clearance mechanism, resulting in splitting insulin molecules into A- and B-chains by a thiol-disulfide exchange reaction. We found that the amino acid substitution of Tyr in A14 to Glu provided a major stabilization of insulin against such degradation while only minor improvements were introduced by the Tyr in B16 to His and Phe in B25 to His substitutions. These results correlate with improvements in the folding stability and likely reflect reduced exposure of insulin icodec's disulfide bonds to the thiol-disulfide exchange reaction. Even though insulin icodec's amino acid substitutions significantly limit its susceptibility to this new clearance mechanism, some free B-chain has been observed in plasma samples from minipigs and people with type 2 diabetes. In summary, we have identified thiol-disulfide exchange reactions as an additional insulin clearance mechanism and minimizing insulin icodec's susceptibility to this process has significantly contributed to its long PD, making it suitable for once weekly dosing.

Disclosure
F.Hubalek: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. C.Cramer: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. H.Helleberg: Employee; Novo Nordisk A/S. E.Johansson: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. G.Schluckebier: Employee; Novo Nordisk. D.B.Steensgaard: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk. J.Sturis: Employee; Novo Nordisk A/S, Other Relationship; Novozymes, Stock/Shareholder; Novo Nordisk A/S. T.Kjeldsen: Employee; Novo Nordisk, Stock/Shareholder; Novo Nordisk.
826-P: Treatment of MODY3 Disease by AAV-Hnf1a-Mediated Gene Therapy
Authors: CASANA LORENTE ESTEFANIA , JIMENEZ VERONICA , GARCIA MIQUEL , CASELLAS ALBA , MORRÓ MERITXELL , PUJOL ANNA , FERRÉ TURA , SACRISTÁN VÍCTOR , JAMBRINA CLAUDIA , LEON XAVIER , FRANCKHAUSER SYLVIE , BOSCH FATIMA 
Published: June 2023

Maturity-onset diabetes of the young (MODY) are a group of monogenic diabetes characterized by onset of hyperglycemia at an early adult age, normally before 25 years. MODY3, the most common type of MODY, is caused by mutations in the gene encoding for the transcription factor hepatocyte nuclear factor 1A (HNF1A). MODY3 patients are usually treated with sulfonylureas, but they tend to become unresponsive to these drugs and adverse effects associated to chronic administration of sulfonylureas have been reported. Presently, there are no current treatments addressing the root cause of MODY3. Here, we have developed a new gene therapy approach to treat this disease. To this end, using the CRISPR/Cas9 technology, we first generated a novel MODY3 mouse model that showed pancreatic down-regulation of HNF1A protein production. These mice developed β-cell dysfunction and hyperglycemia, recapitulating the main alterations observed in human patients. Treatment of MODY3 mice by intra-pancreatic duct administration of adeno-associated viral vectors (AAVs) encoding Hnf1α, under control of β-cell-specific promoter, resulted in HNF1A expression in β-cells, which upregulated the expression of HNF1A main target genes, such as GLUT2 and L-PK. AAV-Hnf1α-mediated gene therapy counteracted hyperglycemia, increased insulinemia, improved glucose tolerance and enhanced insulin secretion by pancreatic β-cells, thus reverting the MODY3 disease. This study represents the first demonstration for the genetic counteraction of a monogenic diabetes and paves the way for the clinical translation of AAV-Hnf1α-based gene therapy to treat MODY 3 patients in the future. Moreover, these results may also contribute to the development of new gene therapy strategies for other monogenic forms of diabetes.

Disclosure
E.Casana lorente: None. X.Leon: None. S.Franckhauser: None. F.Bosch: None. V.Jimenez: None. M.Garcia: None. A.Casellas: None. M.Morró: None. A.Pujol: None. T.Ferré: None. V.Sacristán: None. C.Jambrina: None.

Funding
Fundació La Marató de TV3 (201603-31-32-33); Ministerio de Economía, Industria y Competitividad (SAF2017-86266R); Agencia Estatal de Investigación; Fondo Europeo de Desarrollo Regional; Programa Estatal de I+D+i Orientada a los Retos de la Sociedad; MCIN/AEI/10.13039/501100011033 (PID2020-113864RB-I00); Generalitat de Catalunya, Spain 2017 SGR 1508 (to F.B.)
830-P: Preclinical Development of ALN-KHK, an Investigational RNAi Therapeutic for Type 2 Diabetes Mellitus
Authors: NOETZLI LEILA , BORODOVSKY ANNA , YU CHUA XIEN , TYMON ROXANNE , DARCY JUSTIN , BELOZEROVA SABRINA , KEIBLER MARK , TU HO-CHOU , MARATOS-FLIER ELEFTHERIA 
Published: June 2023

Fructose consumption is implicated in increased rates of metabolic syndrome and type 2 diabetes worldwide. In the liver, ketohexokinase (KHK) is required for fructose metabolism, phosphorylating fructose to fructose-1-phosphate (F1P), a substrate for synthesis of fatty acids, contributing to nonalcoholic fatty liver. Excess liver fat is associated with insulin resistance and loss of glycemic control. Lowering KHK expression should reduce fatty acid synthesis and thus reduce insulin resistance and improve glycemic control in obese individuals with T2DM. We developed a robust RNAi therapeutics platform for delivery of siRNAs to liver using GalNAc conjugates to specifically silence hepatocyte-expressed genes. Liver-directed silencing of KHK improved insulin sensitivity in pre-clinical models of T2DM. ALN-KHK was selected based on in vitro assessment of a large set of GalNAc-siRNAs targeting human and primate KHK. ALN-KHK demonstrated suppression of liver KHK mRNA and protein in cynomolgus macaques after a single subcutaneous (SC) injection with potent and durable reduction in KHK protein (94.1% lowering through day 85 at the 10 mg/kg dose) supporting evaluation of infrequent dosing in the clinic. To evaluate impact of KHK silencing on fructose metabolism and establish circulating biomarkers of pharmacology, cynomolgus macaques were administered an oral fructose bolus on Day 30 following SC injection of ALN-KHK of 0.3, 3 or 10 mg/kg. ALN-KHK treatment resulted in a dose-dependent increase in circulating fructose with a 4.6-fold increase and a 10.7-fold decrease in FGF21 (which is regulated by liver F1P), at 2 hr post fructose bolus, associated with 90.7% KHK liver protein reduction. These data suggest monitoring of circulating fructose and FGF21 to assess KHK silencing in the clinic. In IND-enabling rat and non-human primate toxicology studies ALN-KHK was safe and well tolerated, supporting the planned initiation of first-in-human studies in obese healthy volunteers.

Disclosure
L. Noetzli: Employee; Alnylam Pharmaceuticals, Inc. Stock/Shareholder; Alnylam Pharmaceuticals, Inc. A. Borodovsky: Employee; Alnylam Pharmaceuticals, Inc. Stock/Shareholder; Alnylam Pharmaceuticals, Inc. X. Chua: Employee; Alnylam Pharmaceuticals, Inc. Stock/Shareholder; Alnylam Pharmaceuticals, Inc. R. Tymon: Employee; Alnylam Pharmaceuticals, Inc. Stock/Shareholder; Alnylam Pharmaceuticals, Inc. J. Darcy: None. S. Belozerova: Employee; Alnylam Pharmaceuticals, Inc. Stock/Shareholder; Alnylam Pharmaceuticals, Inc. M. Keibler: Employee; Alnylam Pharmaceuticals, Inc. Stock/Shareholder; Alnylam Pharmaceuticals, Inc. H. Tu: Employee; Alnylam Pharmaceuticals, Inc. Stock/Shareholder; Alnylam Pharmaceuticals, Inc. E. Maratos-Flier: Employee; Novartis, Alnylam Pharmaceuticals, Inc.
838-P: Reversion of Nonalcoholic Steatohepatitis by Skeletal-Muscle Directed FGF21 Gene Therapy
Authors: JIMENEZ VERONICA , SACRISTÁN VÍCTOR , JAMBRINA CLAUDIA , LUISA JAÉN MARIA , MUNOZ SERGIO A. , CASANA ESTEFANIA , GARCIA MIQUEL , GRASS IGNASI , LEON XAVIER , ELIAS IVET , RIBERA ALBERT , ELIAS GEMMA , SANCHEZ VICTOR , CASELLAS ALBA , FERRÉ TURA , MOLAS MARIA , BOSCH FATIMA 
Published: June 2023

Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease, which is driven by the global obesity and type 2 diabetes epidemic. NASH is characterized by liver inflammation and fibrosis that can progress to cirrhosis, liver failure, cancer and death. Currently, NASH is an unmet medical need. Recent studies revealed the therapeutic potential of fibroblast growth factor 21 (FGF21) analogues/mimetics against NASH in pre-clinical models and in human patients, although periodic administrations are required and immunological responses may raise due to the use of engineered, non-native, proteins. Here, we demonstrated that adeno-associated viral (AAV) vector-mediated-FGF21 genetic engineering of skeletal muscle of high-fat diet-fed obese and insulin-resistant mice resulted in increased circulating levels of native FGF21. AAV-FGF21-treatment normalized liver fat content, liver inflammatory and fibrotic markers and counteracted hepatocyte damage, consistent with NASH resolution. It also precluded progression from NASH to cirrhosis and hepato-cellular carcinoma. Moreover, circulating FGF21 reversed adipose tissue hypertrophy and inflammation, increased energy expenditure, normalized glycemia and insulinemia, and increased insulin sensitivity. Scale-up of muscular FGF21 gene transfer to large animals also successfully resulted in long-term secretion of biologically active FGF21 and therapeutic effects in key target tissues, in the absence of adverse events. All these results point out the potential of the AAV-FGF21-mediated gene therapy to treat NASH and support the clinical translation of the approach.

Disclosure
V. Jimenez: None. V. Sacristán: None. C. Jambrina: None. M. Jaén: None. S.A. Munoz: None. E. Casana: None. M. Garcia: None. I. Grass: None. X. Leon: None. I. Elias: None. A. Ribera: None. G. Elias: None. V. Sanchez: None. A. Casellas: None. T. Ferré: None. M. Molas: None. F. Bosch: None.
854-P: ENT-03, a Centrally Acting Endogenous Spermine Bile Acid with PTP1B Inhibitory Activity, Has Potent Effects on Metabolism and Weight in a Mouse Model of Diet-Induced Obesity (DIO)
Authors: BARBUT DENISE , BAUR JOSEPH A. , TITCHENELL PAUL M. , DAVIS JAMES G. , ZEMEL MICHAEL B. , ALEXANDER FLEMING G. , MOSES ALAN C. , ZASLOFF MICHAEL 
Published: June 2023

Background: We have discovered ENT-03, a spermine-bile acid of unprecedented structure in the brain of neonatal mice. ENT-03 appears postnatally at a time when the maternal supply of milk is inadequate to support maximal growth and development. ENT-03 has PTP1B inhibitory activity and acts centrally to normalize glycemia and reverse obesity.
Methods: ENT-03 (25mg/kg), semaglutide (0.04mg/kg) or vehicle were administered subcutaneously twice weekly for 10 weeks to DIO mice (n=5/group).
Results: In ENT-03 treated mice on a high fat diet, non-fasting glucose rapidly fell to within normal range prior to any significant weight loss (p=2×10-5), remaining normal thereafter. In contrast, in semaglutide treated mice, glucose fell in proportion to weight loss, remaining elevated throughout (p=0.2). ENT-03 treated mice were restored to lean body weight. Body weight and glucose improved partially in semaglutide treated mice. Body fat decreased by 49% in ENT-03 (p=10-5) and by 19% in semaglutide treated mice (p=0.1). Basal glucose uptake in muscle was increased 3-fold in ENT-03 treated mice compared to controls.
Conclusion: ENT-03 is a novel endogenous, centrally acting mammalian steroid which rapidly normalizes glucose, independent of body weight and causes gradual but marked weight loss in DIO mice. Phase 1 studies will begin in Q2 2023.

Disclosure
D.Barbut: None. J.A.Baur: Consultant; Cytokinetics Inc., Pfizer Inc., Other Relationship; Elysium Health, Research Support; Pfizer Inc., Metro Biotech. P.M.Titchenell: Consultant; Alnylam, Guidepoint, AstraZeneca. J.G.Davis: None. M.B.Zemel: None. G.Fleming: Board Member; NuSirt, Consultant; Amolyt, Oramed Pharmaceuticals, Adocia, Aerami, TixiMed, Biocon, Hagar, CMC Magnetics, AdioPharm. A.C.Moses: Advisory Panel; Enterin, ViaCyte, Inc., GentiBio, TixiMed, Consultant; Virta Health Corp., ARMI (Advanced Regenerative Manufacturing Institute), Stock/Shareholder; Minutia. M.Zasloff: None.
860-P: Evaluation of Efficacy and Safety of Glucokinase Activators—A Systematic Review and Meta-analysis
Authors: YANG WENJIA 
Published: June 2023

Aims: Glucokinase activators (GKAs) promote the activity of glucokinase (GK) and is under development for the treatment of diabetes. The efficacy and safety of GKAs require evaluation.
Methods: This meta-analysis included randomized controlled trials (RCTs) with a duration of at least 12 weeks conducted in patients with diabetes. The primary objective of this meta-analysis was the difference of hemoglobin A1c (HbA1c) change from baseline to study end between GKA groups and placebo groups. Risk of hypoglycemia and laboratory indicators were also evaluated. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated for the continuous outcomes, odd ratios (ORs) and 95% CI were calculated for the risk of hypoglycemia.
Results: Data from 13 RCTs with 2,748 participants treated with GKAs and 2,681 control participants were analyzed. Overall, the level of HbA1c decreased significantly in patients with GKA treatment compared with placebo (WMD=-0.316%, 95% CI -0.426 to -0.206%, P&lt;0.001). The OR comparing GKA versus placebo was 1.88 for risk of hypoglycemia (95% CI 1.51 to 2.33, P&lt;0.001). The WMD comparing GKA versus placebo was 0.308mmol/L for triglyceride (TG) levels (95% CI 0.153 to 0.464mmol/L, P&lt;0.001). The sensitivity analysis demonstrated difference when stratified by drug type, selectivity, and study duration.
Conclusion: In patients with diabetes, GKA treatment was associated with a better glycemic control, but a significant increased risk of hypoglycemia and elevation in TG concentration in general. The efficacy and safety varied with drug type and selectivity.

Disclosure
W.Yang: None.

Funding
National Natural Science Foundation of China (81903711, 81970698, 81970708); Beijing Natural Science Foundation (7202216)
861-P: The Effect of Dual Amylin and Calcitonin Receptor Agonist Treatment on Spatial Memory in Rat Models of Metabolic Syndrome
Authors: ELHADY MOHAMED KHALED , LARSEN ANNA T. , MELANDER SIMONE A. , KARSDAL MORTEN A. , HENRIKSEN KIM 
Published: June 2023

Obesity and metabolic-related complications, especially insulin resistance, have been linked to cognitive dysfunction. Dual amylin and calcitonin receptor agonists (DACRAs) elicit beneficial effects on body weight, glucose control, and insulin action, making them novel candidates for treating obesity and related comorbidities. Whether DACRAs affect cognition has yet to be addressed. With these studies, we evaluated the effect of DACRA treatment on spatial learning and memory in rat models of metabolic syndrome. Spatial learning and spatial memory retention were evaluated by Morris Water Maze in ZDSD rats treated with KBP-336 (4.5 nmol/kg Q3D) for 7 months and ZSF1 rats treated with KBP-336 (4.5 nmol/kg Q3D) for 2 months. In the ZDSD study, rats performed 8 training trials with a hidden platform in a constant position and a 60 s probe without the platform. At the study end, rats performed a 60 s probe followed by 4 re-training trials and another probe. At study end of the ZSF1 study, rats performed 6 training trials with a hidden platform in a constant position followed by a 60 s probe without the platform. In both studies, KBP-336 treatment improved the overall metabolic status, including glucose control and insulin action. In ZDSD rats, KBP-336-treated rats spent more time and traveled longer distances in Whishaw's corridor than vehicle-treated rats during the probes at the study end. Together indicating a possible treatment improvement in spatial memory on KBP-336. In ZSF1 rats, KBP-336 treatment resulted in increased time spent in the platform quadrant and Whishaw's corridor, as well as increased distance, traveled in Whishaw's corridor during the probe. In both studies, the treatment did not affect the spatial learning evaluated as latency to reach the hidden platform during the training trials. Altogether, we found that the improved metabolic status obtained with KBP-336 treatment might have a beneficial effect on spatial memory in diabetic and obese rat models.

Disclosure
K.Mohamed: Employee; Nordic Bioscience. A.T.Larsen: Employee; Nordic Bioscience A/S. S.A.Melander: None. M.A.Karsdal: Speaker's Bureau; Pfizer Inc. K.Henriksen: Employee; Nordic Bioscience A/S, Stock/Shareholder; Nordic Bioscience A/S.

Funding
Danish Research Foundation; Innovation Fund Denmark; European Union’s Horizon 2020 Research and Innovation Program (814244)