bluuebunny/crossref_metadata_2025_split huggingface dataset:
1006-P: Real-World Effectiveness of Semaglutide in Early Users from a U.S. Commercially Insured (CI) and Medicare Advantage (MA) Population
Authors: VISARIA JAY , DANG-TAN TAM , PETRARO PAUL V. , NEPAL BAL K. , WILLEY VINCENT 
Published: June 2019

Background: With semaglutide’s FDA approval in Dec 2017, this study sought to provide real-world evidence on its effectiveness in a cohort of early users.
Methods: Claims and lab result data from a broad national U.S. CI and MA population were used to identify T2DM patients who initiated semaglutide between 12/1/17 - 6/30/18 (first claim date set as index). Of these, patients who had ≥12-month pre-index health plan eligibility as well as ≥1 HbA1c result within both ≤3 months pre- and ≥3 months post-index were selected. Changes in HbA1c were assessed in all patients, GLP-1 naïve patients and GLP-1 naïve patients with a pre-index HbA1c &gt;9%.
Results:Of 107 individuals with T2DM initiating semaglutide, 48.6% were female with median age of 52 years. HbA1c was significantly reduced in all patients (-1.3%), GLP-1 naïve patients (-2.0%) and HbA1c &gt;9% GLP-1 naïve patients (-2.9%) (all p&lt;0.001, Figure 1). Attainment of HbA1c &lt;7% increased from pre- to post-index: 22.4 - 46.7% (all), 11.8 - 49.0% (GLP-1 naïve) and 0 - 32.0% (pre-index HbA1c &gt;9% GLP-1 naïve) (all p&lt;0.001).
Conclusions: Semaglutide initiation was associated with a significant reduction in HbA1c and increase in HbA1c goal attainment in real-world practice in this preliminary T2DM cohort. Ongoing research will include a broader group of semaglutide users as well as allow for longer post-initiation follow-up to fully assess its effect.

Disclosure
J. Visaria: Employee; Self; HealthCore. T. Dang-Tan: Employee; Self; Novo Nordisk Inc. P.V. Petraro: Employee; Self; Novo Nordisk Inc. B.K. Nepal: None. V. Willey: Employee; Self; HealthCore.

Funding
Novo Nordisk
1009-P: The Dual GIP and GLP-1 Receptor Agonist Tirzepatide Regulates Lipid and Carbohydrate Metabolism through GIPR in Adipose Tissue
Authors: SAMMS RICARDO JUSTIN , CHRISTE MICHAEL E. , RUAN XIAOPING , MOYERS JULIE , REGMI AJIT , ROELL WILLIAM C. 
Published: June 2019

Tirzepatide (TZP), a GIP receptor and GLP-1 receptor (GIPR/GLP-1R) dual agonist, has demonstrated profound effects on glycemic control and bodyweight lowering in T2D subjects. However, the mechanism of action for the dual agonism of TZP is incompletely understood. Adipose expresses GIPR but not GLP-1R and therefore presents a key target tissue to investigate TZP biology. Using differentiated human adipocytes, we explored TZP regulation of lipid and carbohydrate metabolism. TZP demonstrated significant modulation of lipid accumulation, efflux, and oxidation. Similar to insulin, TZP increased expression and secretion of active LPL. While it had no effect on its own, TZP dose dependently suppressed insulin stimulated de novo lipogenesis in [14C]glucose and [14C]acetate incorporation assays. Insulin and TZP counter-regulated lipolysis characterized by insulin suppression and TZP stimulation of glycerol release. Uncoupled oxygen consumption was increased by TZP and subsequently reduced by CPT1 inhibition (etomoxir) demonstrating regulation of fatty acid oxidation. In adipose glycemic control, TZP exhibited both direct and insulin-dependent regulation of glucose transport. TZP at low dose (10pM) provided indirect (insulin sensitizing) effects while higher doses (10 nM) directly stimulated [14C]glucose uptake in adipocytes. While acute GIP infusion in a rat hyperinsulinemic/euglycemic clamp demonstrated no change in total body glucose infusion rate (GIR), chronic treatment (two week) with TZP or GIPR agonist increased GIR and adipose tissue [14C]glucose accumulation. This suggests both tissue-specific and whole-body insulin sensitization through GIPR agonism. Taken together, this data demonstrates GIPR specific activity of TZP in regulating adipose function. These findings and ongoing pathway integration studies will provide clues to the metabolic benefit of TZP GIPR/GLP-1R dual agonism compared with GLP-1R agonism alone.

Disclosure
R.J. Samms: Employee; Self; Eli Lilly and Company. M.E. Christe: Employee; Self; Eli Lilly and Company. X. Ruan: Employee; Self; Eli Lilly and Company. J. Moyers: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. A. Regmi: Employee; Self; Eli Lilly and Company. W.C. Roell: Employee; Self; Eli Lilly and Company.
1019-P: Glucagon-Like Peptide-1 Receptor Agonists Predominantly Reduce Body Fat Mass in Patients with Type 2 Diabetes
Authors: FUJITA YUKI , KUBOTA SODAI , KUWATA HITOSHI , YABE DAISUKE , HAMAMOTO YOSHIYUKI , SEINO YUTAKA 
Published: June 2019

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) helps obese patients with type 2 diabetes (T2DM) lose weight. Because few studies have researched their effectiveness on body composition, this study aimed to investigate the effect of GLP-1 RA on body fat mass (BFM) and skeletal muscle mass (SMM) in patients with T2DM.
In this retrospective study, we reviewed the database of our clinic and identified patients who had been prescribed GLP-1 RAs between 2010-2017. Patients who were either switched from insulin, had used any drugs that affect blood glucose levels (except metformin and sulfonylurea), or who had clinically significant disease were excluded. Both baseline and 12-month body compositions were assessed via the BIA device (Inbody S10 or S20). Body weight (BW), body mass index (BMI), and HbA1c were also measured. Data were analyzed using the paired t-test, with values shown as mean±SD.
A total of 205 patients were identified and 45 were included in the final analysis; 25 were non-insulin users and 20 were insulin users. After 12-month treatment, HbA1c, BW, and BMI were significantly reduced in both groups (Table 1). Interestingly, while BFM was significantly decreased, no differences in fat free mass or SMM were noted.
In conclusion, GLP-1 RA treatment leads to weight loss by predominantly reducing body fat mass in patients with T2DM regardless of being treated or not treated with insulin.

Disclosure
Y. Fujita: None. S. Kubota: None. H. Kuwata: Research Support; Self; Eli Lilly and Company. D. Yabe: Advisory Panel; Self; Abbott. Research Support; Self; Astellas Pharma Inc. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Y. Hamamoto: Speaker's Bureau; Self; Novo Nordisk A/S. Y. Seino: Research Support; Self; Arkray, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Terumo Medical Corporation.
103-OR: Central α-Klotho Suppresses Food Intake and Improves Glucose Regulation in Mouse Models of Metabolic Disease
Authors: LANDRY TAYLOR , LI PEIXIN , BUNNER WYATT P. , RAO ZHIJIAN , HUANG HU 
Published: June 2019

Background/Aims: α-Klotho is a circulating factor with well-documented anti-aging properties; however, the central role of α-Klotho in metabolism remains largely unexplored. We aimed to investigate the potential role of central α-klotho as a novel regulator of energy balance and glucose homeostasis.
Methods: Central administration of α-klotho was performed by using intracerebroventricular (ICV) injection for seven days in diet-induced obesity (DIO) and streptozotocin-injected (STZ) mice. hrNPY-GFP reporter mice were utilized for electrophysiology and immunofluorescent staining experiments to investigate the effects of α-klotho on NPY/AgRP neurons. To determine the mechanism/s of hypothalamic α-klotho, we used GT1-7 immortal hypothalamic cells in vitro along with ICV administration of fibroblast growth factor receptor 1 (FGFR1) antagonist in vivo.
Results: Central α-klotho administration decreased food intake and improved glucose profiles in DIO and STZ mice. Liver lipid content and gluconeogenic gene expression were also reduced. Electrophysiology and immunofluorescent staining revealed AgRP/NPY neurons exhibit hyperpolarization and reduced firing rate in response to α-klotho treatment. These effects are, at least partially, due to increased magnitude of mIPSC’s. In vitro, α-klotho blunted serum-starvation-induced AgRP gene expression and increased phosphorylation of ERK44/42, AKTser473, and Foxo1ser256. These downstream effects were abolished by pretreatment with inhibitors of either FGFR1 or PI3kinase. Furthermore, α-klotho-mediated suppression of food intake, but not glucose levels, was blunted in response to inhibition of FGFR1 signaling.
Conclusion: These results indicate a prominent role of hypothalamic α-klotho-FGFR1-PI3K signaling in regulation of NPY/AgRP neuron activity, energy balance, and glucose homeostasis, thus providing new insight into the pathophysiology of metabolic disease.

Disclosure
T. Landry: None. P. Li: None. W.P. Bunner: None. Z. Rao: None. H. Huang: None.

Funding
East Carolina University
1034-P: Liraglutide and Dapagliflozin Induce an Increase in Plasma GLP-1 and GLP-2 Concentrations
Authors: GHANIM HUSAM , GREEN KELLY , DANDONA PARESH 
Published: June 2019

Since liraglutide suppresses plasma glucagon concentrations and dapagliflozin increases glucagon concentrations, although both improve glycemia in patients with type 1 diabetes, we have now investigated whether they alter the concentrations of the two other products of the proglucagon gene, GLP-1 and GLP-2. Thirty patients with type 1 diabetes, treated with liraglutide for 26 weeks were randomized into receiving dapagliflozin 10 mg daily (n=20) or placebo (n=10) for 12 weeks. Fasting blood samples were obtained prior to liraglutide treatment, at the onset of dapagliflozin treatment and at the end of dapagliflozin treatment. At the end of 26 weeks liraglutide treatment and then 12 weeks of dapagliflozin therapy, mean HbA1c fell by 0.31±0.19% (NS) and 0.66±0.22% (p=0.0004), respectively. There was a significant increase in the plasma concentrations of GLP-1 (by 89±24%, from 30.4±5.1pM to 48.6±8.2pM, P=0.001) but not GLP-2 after 26 weeks of liraglutide treatment with a fall in glucagon levels. Dapagliflozin treatment induced a further significant increase in plasma GLP-1 (by 72±24%, from 48.6±8.2pM to 70.8±9.2pM, P=0.001) and caused an increase in GLP-2 concentrations (by 48±18%, from 2.01±0.42ng/ml to 2.97±0.51pM, P=0.01) along with an increase in glucagon concentrations. We conclude that while liraglutide suppresses glucagon, it induces an increase in GLP-1 concentrations. In addition, dapagliflozin increases both GLP-1 and GLP-2 concentrations while also increasing glucagon.

Disclosure
H. Ghanim: None. K. Green: None. P. Dandona: Advisory Panel; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Intarcia Therapeutics, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Research Support; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi.
1043-P: Glycemic Profiles and Treatment Patterns: Real-World Data from 8,020 Adults with Type 1 Diabetes Using the Omnipod® Insulin Management System with Cloud-Based Data Management
Authors: LAYNE JENNIFER E. , HE JIALUN , JANTZ JAY , ZHENG YIBIN , BENJAMIN ERIC , LY TRANG T. 
Published: June 2019

While clinical trials have demonstrated significant benefits of insulin pump therapy for type 1 diabetes, there is increasing recognition of the importance of real-world population data to better understand the impact of diabetes technology on treatment outcomes. This study retrospectively analyzed data from a large cohort of adults with type 1 diabetes using the Omnipod® Insulin Management System (Insulet Corp., Acton, MA) with an integrated BG meter (Abbott Diabetes Care Inc., Alameda, CA) and data management system (Glooko, Mountain View, CA) to characterize glycemic profiles, insulin use and treatment patterns. From January 2015 through September 2018, pump system data were uploaded to the data management system and matched via device serial number to a second database of self-reported demographic data and de-identified. BG and insulin data from ≥3 mo of system use per patient were analyzed. Adults ≥18 y with type 1 diabetes (n=8,020) were age (mean±SD) 40.8±15.3y, 60% female, 61% used a tubeless insulin pump for ≥1 y and 13% used CGM for &gt;50% of overall time of system use. Glycemic profiles included mean glucose 177±39 mg/dL, estimated A1C 7.8%, percent time in target range 70-180 mg/dL, hypoglycemia &lt;70 mg/dL and hyperglycemia &gt;180 mg/dL: 50.2±17.3, 5.9±5.0, and 43.9±18.3, respectively. The total daily insulin was 43.4±18.7 U/d which was delivered as 54% basal and 46% bolus. There were an average of 4.7±2.2 bolus deliveries per day and the average bolus amount was 4.5±2.8 U. These real-world glycemic profiles in adults with type 1 diabetes using the Omnipod® System support the use of diabetes technology in the management of type 1 diabetes. These data indicate that use of a tubeless insulin pump is associated with outcomes that compare favorably to large national registries including the T1D Exchange.

Disclosure
J.E. Layne: Employee; Self; Insulet Corporation. J. He: Employee; Self; Insulet Corporation. J. Jantz: Employee; Self; Insulet Corporation. Employee; Spouse/Partner; Insulet Corporation. Y. Zheng: Employee; Self; Insulet Corporation. Stock/Shareholder; Self; Insulet Corporation. E. Benjamin: Employee; Self; Insulet Corporation. T.T. Ly: Employee; Self; Insulet Corporation.

Funding
Insulet Corporation
1045-P: Efficacy and Safety of a 24-Hour Wearable Insulin Delivery Device for Basal-Bolus Therapy in Older Adults
Authors: ZEIDAN TRISHA , NIKKEL CARLA C. , DZIENGELEWSKI ELIZABETH A. 
Published: June 2019

Basal-bolus insulin therapy in older patients is challenging due to the complexities of multiple daily injections and the higher risk of adverse consequences associated with hypoglycemia in this population. The purpose of this analysis was to evaluate the clinical outcomes and prevalence of hypoglycemia in patients 65 years of age or older when delivering basal-bolus therapy with a wearable insulin delivery device (V-Go). A retrospective analysis of electronic medical records in 54 patients with T2DM evaluated change in A1C, weight, insulin total daily dose (TDD) and prevalence of hypoglycemia. Baseline mean ± SD characteristics were age 71 ± 4 years (range 65 to 83), A1C 9.5 ± 1.6%, weight 99 ± 20 kg and TDD 64 ± 41 u/day (range 10 to 224) with 81% of patients prescribed insulin and 83% prescribed concomitant anti-hyperglycemic agents. Baseline hypoglycemia documented in 36% of patients. After a mean duration of 5 months of V-Go use, mean ± SD decreases in A1C (-1.5 ± 1.8%; p&lt;0.0001) and TDD (-9 ± 35 u/day; p=0.107) were observed. Change in weight +0.65 kg; p&lt;0.208. Prevalence of overall and severe hypoglycemia was markedly decreased with V-Go. As people with T2DM age, it may become necessary to simplify complex insulin regimens due to a decline in self-management ability while being mindful of risk factors. In this analysis, use of V-Go in an older population proved safe and efficacious.

Disclosure
T. Zeidan: Advisory Panel; Self; Corcept Therapeutics. Research Support; Self; Valeritas, Inc. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Valeritas, Inc. C.C. Nikkel: Employee; Self; Valeritas, Inc. Stock/Shareholder; Self; Valeritas, Inc. E.A. Dziengelewski: Employee; Self; Valeritas, Inc. Stock/Shareholder; Self; Valeritas, Inc.
1052-P: Time-in-Target Glucose Range and the Glucose Management Indicator during Real-World MiniMed™ 670G System Use
Authors: GOPALAKRISHNAN SHWETA , CORDERO TONI L. , SADEGHZADEH MAHTA , STONE MICHAEL , AGRAWAL PRATIK 
Published: June 2019

Continuous glucose monitoring data can be reviewed, analyzed, and ultimately leveraged for diabetes treatment decision making. The Glucose Management Indicator (GMI) which determines an average A1C level based on mean continuous glucose monitoring data (Bergenstal RM, et al. 2018;41:2275-2280) was evaluated alongside time in target glucose range (TIR) during MiniMed™ 670G system use by over 3,000 real-world individuals living with diabetes. MiniMed™ 670G system data from individuals with T1D aged 14-22 years (n=291) and &gt;22 years (n= 3174) were voluntarily uploaded from 3/17/2017 to 12/17/2018, de-identified, and analyzed if captured over the course of ≥365 days. The percentage of time in Auto Mode, TIR (70-180 mg/dL [3.9-10.0 mmol/L]) and time spent in hypoglycemia (&lt;54 mg/dL [3.0 mmol/L]) were assessed alongside the GMI (3.31 + 0.02392 x [mean glucose in mg/dL]), 7-10 days after starting SmartGuard™ Auto Mode use. Over the analysis period, the median (min-max) of Auto Mode use was 77% (70.0-85.5%) in the &gt;22 years cohort, and 62% (50.4-75.0%) in the younger cohort. In both cohorts, the mean TIR was above 70.0% and the time spent at &lt;54 mg/dL stayed below 1.0% (&lt;14min). The GMI for the older and younger cohorts was on an average 6.9% and 7.3% respectively, which is under 7.0% and 7.5%, meeting ADA recommended A1C targets for adult and pediatric age groups with diabetes, respectively. These findings indicate maintained glycemic control with concomitant Auto Mode usage and TIR, without increasing hypoglycemia, in real-world settings for individuals living with T1D and using the MiniMed™ 670G system.

Disclosure
S. Gopalakrishnan: Employee; Self; Medtronic. T.L. Cordero: Employee; Self; Medtronic. M. Sadeghzadeh: Employee; Self; Medtronic. M. Stone: None. P. Agrawal: Employee; Self; Medtronic MiniMed, Inc. Stock/Shareholder; Self; Medtronic.
1061-P: Effect of the Omnipod® Insulin Management System on Glycemic Control in Adults with Type 1 Diabetes Previously Treated with MDI or CSII
Authors: MEHTA SANJEEV N. , KRUGER DAVIDA F. , BODE BRUCE W. , LAYNE JENNIFER E. , DUMAIS BONNIE , GALLAGHER JACK R. , LY TRANG T. 
Published: June 2019

This multi-site, retrospective study evaluated the effect of treatment with a tubeless insulin pump (Omnipod Insulin Management System, Insulet Corp., Acton, MA) on glycemic control in adults with type 1 diabetes (n=166) compared to prior treatment with multiple daily injections (MDI) (63%) or continuous subcutaneous insulin infusion (CSII) (37%). The primary outcome was change in A1C from baseline to 12 months post-Omnipodinitiation. Secondary outcomes included change in A1C at 3- and 6-months, and change in A1C stratified by baseline A1C and prior treatment with MDI or other CSII. Baseline characteristics were mean±SD: age 44±14 y, diabetes duration 24±14 y, 57% female, A1C 8.1±1.5%. The decrease in A1C at 12 months post-Omnipod therapy was -0.2±1.2% (8.1±1.5% vs. 7.9±1.3%; p=0.01) compared to prior treatment. A decrease in A1C was observed at 3- and 6-mo: -0.3±1.2% (n=95; p=0.005) and -0.3±1.1% (n=87; p=0.04), respectively. The within group reduction in A1C at 12 months for prior MDI use was -0.35% (8.1±1.5% vs. 7.8±1.2%; p=0.008) vs. -0.03% (8.0±1.4% vs. 8.0±1.5%; p=0.761) for CSII. The proportion of patients grouped by A1C category is shown in the Figure.
In conclusion, long-term use of the Omnipod System was associated with significant improvement in A1C in adults with type 1 diabetes, most notably in those with A1C ≥9.0% and those previously treated with MDI.

Disclosure
S.N. Mehta: None. D.F. Kruger: Advisory Panel; Self; Abbott, Boehringer Ingelheim Pharmaceuticals, Inc., Insulet Corporation. Consultant; Self; CeQur Corporation, Hygieia. Speaker's Bureau; Self; AstraZeneca, Dexcom, Inc., Eli Lilly and Company. Stock/Shareholder; Self; Dexcom, Inc. Other Relationship; Self; Novo Nordisk Inc. B.W. Bode: Consultant; Self; ADOCIA, Lexicon Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; Becton, Dickinson and Company, Dexcom, Inc., Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Eyenuk Inc., Insulet Corporation, National Institutes of Health, Novo Nordisk Inc., Sanofi Research & Development, Senseonics, Xeris Pharmaceuticals, Inc. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi US, Senseonics. Stock/Shareholder; Self; AgaMatrix, Glytec, LLC. J.E. Layne: Employee; Self; Insulet Corporation. B. Dumais: None. J.R. Gallagher: None. T.T. Ly: Employee; Self; Insulet Corporation.

Funding
Insulet Corporation
1068-P: A Prospective, Multicenter, Randomized, Open-Label, Parallel-Group Clinical Trial Comparing the Safety Profile of a Needle-Free Insulin Injector with Conventional Insulin Pen Injections in Chinese Patients with Type 2 Diabetes Mellitus
Authors: CHEN LIMING , JI LINONG , WANG YANGANG , MA ZHONGSHU , RAN XINGWU , SUN ZILIN , XU XIANGJIN , WANG GUIXIA , GUO LIXIN , SHAN ZHONGYAN 
Published: June 2019

Background: Needle-free insulin delivery has been shown to accelerate the absorption and the action of insulin, and to be well tolerated.
Objective: To determine the safety profile of a needle-free injector with that of conventional insulin pen injections in patients with T2DM.
Methods: A total of 427 patients with T2DM were enrolled in a multicenter, prospective, randomized, open-label clinical trial, and were randomized 1:1 to receive basal or premixed insulin via a needle-free injector or via conventional insulin pen injections. Adverse events occurring during the study were recorded in the 2 groups, and the incidences of hypoglycemia and injection site reactions were compared.
Result: The adverse events rates in the needle-free injector and insulin pen groups were 5.31% and 3.35%, respectively, but no statistically significant difference between the 2 groups (P = 0.3468). Rates of hypoglycemia (25.60% vs. 18.18%, respectively; P = 0.0671), and local injection-site reactions (bleeding/ecchymosis and redness) were also similar in the 2 groups. However, the incidence of skin scratches was decreased significantly in the needle-free injector group (15.53% vs. 23.92%; P = 0.0319). There was no new indurations observed in needle-free injector group compared 4.00% in the conventional insulin pen group (P = 0.006). Patients in the needle-free injector group also showed lower overall VAS pain scores than those in the conventional insulin pen group (mean scores, 1.11 ± 1.21 vs. 1.98 ± 1.99; P &lt; 0.0001).
Conclusion: Administration of insulin by a needle-free injector could provide a better safety profile than insulin pen injections, by reducing skin scratches, indurations, and pain.

Disclosure
L. Chen: Research Support; Self; Becton, Dickinson and Company. L. Ji: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck KGaA, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi, Takeda Pharmaceutical Company Limited. Research Support; Self; AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Roche Pharma, Sanofi. Y. Wang: None. Z. Ma: None. X. Ran: None. Z. Sun: None. X. Xu: None. G. Wang: None. L. Guo: None. Z. Shan: None.