Exenatide: pharmacokinetics, clinical use, and future directions

Figures & data

Figure 1. a) Mechanism of exenatide once weekly release from poly-(D,L-lactide-co-glycolide) microspheres [24]. Reproduced with permission from DeYoung MB, et al. Diabetes Technol Ther. 2011;13:1145–1154, Published by Mary Ann Liebert, Inc., New Rochelle, NY; b) A theoretical model of the plasma concentrations of exenatide after multiple subcutaneous doses of exenatide once weekly. The concentration profile was produced by adding single-dose concentration profiles together at weekly intervals. Reprinted from Clin Ther, Vol. 38, Brunton S, Davidson JA, Exenatide once weekly: a review of pharmacology and treatment considerations in type 2 diabetes, 582–594, Copyright (2016), with permission from Elsevier [33]; c) Schematic of the exenatide once-weekly dual-chamber pen [29]. Republished with permission of J Diabetes Sci Technol, from Evaluation of the dual-chamber pen design for the injection of exenatide once weekly for the treatment of type 2 diabetes, LaRue S, Malloy J, vol. 9, 2015; permission conveyed through Copyright Clearance Center, Inc.

Table 1. Phase 3 DURATION trials and extension studies.

Study (acronym)	Study design (duration)	Treatment (n)	Background therapy	Change from baseline
				HbA1c, %	FG, mmol/L	Body weight, kg
Drucker et al. 2008 (DURATION-1) [17]	Multicenter, open-label, parallel, randomized in pts with T2D (30 wks)	ExQW 2 mg (148)	Monotherapy	ExQW: –1.9	ExQW: –2.3	ExQW: –3.7
		ExBID 5–10 μg BID (147)	or adjunct to OADs	ExBID: –1.5**	ExBID: –1.4***	ExBID: –3.6
Buse et al. 2010 (DURATION-1 extension) [14]	Extension of DURATION-1 (52 wks)	After initial 30 wks, switch from ExBID to ExQW (130) or continued ExQW (128)	Monotherapy or adjunct to OADs	ExQW: –2.0	ExQW: –2.6^a	ExQW: –4.1
				ExBID→ExQW: –2.0	ExBID→ExQW: –2.4^a	ExBID→ExQW: –4.5
MacConell et al. 2013 (DURATION-1 extension) [36]	Extension of DURATION-1 (3 yrs)	All patients received ExQW after initial 30 wks (194)	Monotherapy or adjunct to OADs	ExQW: –1.6	ExQW: −1.8	ExQW: –2.3
Wysham et al. 2015 (DURATION-1 extension) [37]	Extension of DURATION-1 (5 yrs)	All patients received ExQW after initial 30 wks (153)	Monotherapy or adjunct to OADs	ExQW: –1.6	ExQW: –1.6^a	ExQW: –3.0
Bergenstal et al. 2010 (DURATION-2) [12]	Double-blind, multicenter, parallel, randomized in pts with T2D (26 wks)	ExQW 2 mg (160)	MET	ExQW: –1.5	ExQW: –1.8	ExQW: –2.3
		SITA 100 mg OD (166)		SITA: –0.9***	SITA: –0.9**	SITA: –0.8***
		PIO 45 mg OD (165)		PIO: –1.2*	PIO: –1.5	PIO: +2.8***
Diamant et al. 2010 (DURATION-3) [16]	Multicenter, open-label, parallel, randomized in pts with T2D (26 wks)	ExQW 2 mg (233)	OADs	ExQW: –1.5	ExQW: –2.1	ExQW: –2.6
		INS glargine^b (223)		INS: –1.3*	INS: –2.8***	INS: +1.4***
Diamant et al. 2012 (DURATION-3 extension) [38]	Extension of DURATION-3 (84 wks)	ExQW 2 mg (233)	OADs	ExQW: –1.2	ExQW: –2.4	ExQW: –2.1
		INS glargine^b (223)		INS: –1.0*	INS: –3.0**	INS: +2.4***
Diamant et al. 2014 (DURATION-3 extension) [20]	Extension of DURATION-3 (156 wks)	ExQW 2 mg (233)	OADs	ExQW: –1.01	ExQW: –1.73	ExQW: –2.49
		INS glargine^b (223)		INS: –0.81*	INS: –2.65***	INS: +2.01***
Russell-Jones et al. 2012 (DURATION-4) [18]	Double-blind, multicenter, parallel, randomized in treatment-naïve pts with T2D (26 wks)	ExQW 2 mg (248)	None	ExQW: –1.53	ExQW: –2.3	ExQW: –2.0
		MET 2000 mg/day (246)		MET: –1.48	MET: –2.0	MET: –2.0
		PIO 45 mg OD (163)		PIO: –1.63	PIO: –2.6	PIO: +1.5***
		SITA 100 mg OD (163)		SITA: –1.15***	SITA: –1.1***	SITA: –0.8***
Blevins et al. 2011 (DURATION-5) [13]	Multicenter, open-label, randomized in pts with T2D (24 wks)	ExQW 2 mg (129)	Monotherapy or adjunct to OADs	ExQW: –1.6	ExQW: –1.9	ExQW: –2.3
		ExBID 5–10 μg (123)		ExBID: –0.9***	ExBID: –0.7***	ExBID: –1.4
Buse et al. 2013 (DURATION-6) [15]	Multicenter, open-label, parallel, randomized in pts with T2D (26 wks)	ExQW 2 mg (461)	OADs	ExQW: –1.28	ExQW: –1.76	ExQW: –2.68
		LIRA 1.8 mg OD (450)		LIRA: –1.48**	LIRA: –2.12*	LIRA: –3.57***
Frìas et al. 2016 (DURATION-8) [39]	Multicenter, double-blind, randomized in pts with T2D (28 wks)	ExQW 2 mg + DAPA 10 mg OD (231)	MET	ExQW + DAPA: –2.0**,^‡	ExQW + DAPA: –2.30**,^‡	ExQW + DAPA: –3.41**,^†
		ExQW 2 mg (231)		ExQW: –1.6	ExQW: –1.19	ExQW: –1.54
		DAPA 10 mg OD (233)		DAPA: –1.4	DAPA: –1.46	DAPA: –2.19

^aConverted from mg/dL to mmol/L using the conversion factor 0.055499.

^bInsulin glargine was titrated to achieve an FG of 4.0–5.5 mmol/L.

*p < .05 vs. ExQW; **p < .01 vs. ExQW; ***p ≤ .001 vs. ExQW; ^†p < .01 vs. DAPA; ^‡p ≤ .001 vs. DAPA.

DAPA: dapagliflozin; ExBID: exenatide twice daily; ExQW: exenatide once weekly; FG: fasting glucose; HbA1c: glycated hemoglobin; INS: insulin; LIRA: liraglutide; MET: metformin; OADs: oral antidiabetes drugs; OD: once daily; PIO: pioglitazone; pts: patients; SITA: sitagliptin; T2D: type 2 diabetes; wks: weeks; yrs: years.

Figure 2. Effect of exenatide once weekly on glycemic end points and body weight after 3 years of treatment. a) HbA1c; b) fasting serum glucose; c) self-monitored blood glucose; d) body weight [20]. HbA1c: glycated hemoglobin. Republished with permission of Lancet Diabetes Endocrinol, from Exenatide once weekly versus insulin glargine for type 2 diabetes (DURATION-3): 3-year results of an open-label randomised trial, Diamant M, et al. vol. 2, 2014.

Figure 3. Effect of exenatide once weekly on glycemic end points and body weight after 5 years of treatment. a) HbA1c; b) FPG; c) body weight [37]. *p < .05 for change from baseline. Conversion factor for FPG: 1 mg/dL = 0.0555 mmol/L. FPG: fasting plasma glucose; HbA1c: glycated hemoglobin; LS: least-squares; SE: standard error. Reprinted from Mayo Clin Proc, Vol. 90, Wysham CH, et al. Five-year efficacy and safety data of exenatide once weekly: long-term results from the DURATION-1 randomized clinical trial, 356–365, Copyright (2015), with permission from Elsevier.

Table 2. Trials of alternative formulations of exenatide.^a

ClinicalTrials.gov identifier (acronym)	Study design (duration)	Patient population (background glucose-lowering therapy)	Treatment(s)	Expected enrollment	Primary end point	Study status	Available data
Exenatide once-weekly suspension for autoinjection
NCT01652716 (DURATION-NEO-1)	Multicenter, open-label, parallel, randomized (28 wks)	T2D; ≥18 yrs (lifestyle modification; MET, SU, or PIO)	ExQW autoinjector ExBID	377	HbA1c	Completed	Wysham et al. 2014 [52]
NCT01652729 (DURATION-NEO-2)	Multicenter, open-label, parallel, randomized (28 wks)	T2D; ≥18 yrs (MET)	ExQW 2 mg autoinjector SITA 100 mg OD PBO	365	HbA1c	Completed	ClinicalTrials.gov record [53]
Exenatide once-monthly suspension
NCT01104701 (BCB111)	Multicenter, open-label, randomized (20 wks)	T2D; ≥18 yrs (lifestyle modification; MET, PIO, or MET/PIO)	ExQW ExQM	121	HbA1c	Completed	Wysham et al. 2016 [54]
Exenatide continuous sub-dermal delivery (ITCA 650)
NCT00943917	Multicenter, open-label, randomized (24 wks + 24-wk extension)	T2D; ≥18 yrs (MET)	ITCA 650 20 μg/day ITCA 650 40 μg/day ExBID 5–10 μg BID	155	HbA1c	Completed	Henry et al. 2013 [55,56]
NCT01798264	Multicenter, open-label, randomized (4 wks)	T2D; ≥30 yrs (MET, TZD, or MET/TZD)	ITCA 650 40 or 80 μg/day	44	Tolerability	Completed	Henry et al. 2013 [57]
NCT01455870	Multicenter, randomized, double-blind (52 wks)	T2D; ≥18 yrs (MET)	ITCA 650 60 μg/day SITA 100 mg/day	535	HbA1c	Completed	ClinicalTrials.gov record [58]
NCT01455857	Multicenter, randomized, double-blind, placebo-controlled (39 wks)	T2D; ≥18 yrs (lifestyle modification, MET, SU, TZD, or MET/SU, MET/TZD, or SU/TZD)	ITCA 650 40 μg/day ITCA 650 60 μg/day ITCA PBO	460	HbA1c	Completed	ClinicalTrials.gov record [59]
NCT01785771	Multicenter, open-label (39 wks + 26-wk extension)	T2D; ≥18 yrs; HbA1c >10% and ≤12% (lifestyle modification ± MET, SU, TZD, or a combination)	ITCA 650 20–60 μg/day	100	HbA1c	Ongoing, not recruiting	ClinicalTrials.gov record [60]
NCT01455896	Multicenter, randomized, double-blind (104 wks)	T2D; ≥40 yrs (NA)	ITCA 650 60 μg/day ITCA PBO	4000	Time to first occurrence of any MACE component	Ongoing, not recruiting	ClinicalTrials.gov record [61]
NCT02638805	Multicenter, open-label, parallel, randomized (26 wks)	T2D; 18–80 yrs; switching from liraglutide	ITCA 650 20/60 µg/day ITCA 60 µg/day	126	Safety: nausea/vomiting events	Recruiting	ClinicalTrials.gov record [62]

^aStatus of all trials from ClinicalTrials.gov correct as of 28 September 2016.

ExBID: exenatide twice daily; ExQW: exenatide once weekly; ExQM: exenatide once monthly; HbA1c: glycated hemoglobin; MACE: major adverse cardiovascular event; MET: metformin; NA: not available; OD: once daily; PBO: placebo; PIO: pioglitazone; SITA: sitagliptin; SU: sulfonylurea; T2D: type 2 diabetes; TZD: thiazolidinedione; wks: weeks; yrs: years.

Table 3. Ongoing and recently completed trials with exenatide once weekly and twice daily.^a

ClinicalTrials.gov identifier (acronym)	Sponsor	Study design (duration)	Patient population (background glucose-lowering therapy)	Treatment(s)	Expected enrollment	Primary end point	Study status	Expected completion date
ExQW
T1D
NCT01928329	Yale University	Phase 2, multicenter, randomized, double-blind, parallel (6 mos)	T1D; 18–60 yrs (INS)	ExQW 2 mg PBO	120	HbA1c	Recruiting	April 2018
New combinations, new outcomes, new patient subpopulations, and long-term safety
New combinations
NCT02229383	AstraZeneca	Phase 3, multicenter, randomized, double-blind, parallel (28 wks)	T2D; ≥18 yrs (INS glargine; INS glargine/MET, INS glargine/MET/SU)	ExQW 2 mg	808	HbA1c	Completed	N/A
NCT02229396	AstraZeneca	Phase 3, multicenter, randomized, double-blind, parallel (28 wks then 24-wk extension)	T2D; ≥18 yrs (MET)	ExQW 2 mg + DAPA 10 mg/day ExQW 2 mg DAPA 10 mg/day	695	HbA1c	Active, no longer recruiting	December 2017
NCT02811484	Weill Medical College, Cornell University	Phase 4, randomized, double-blind (24 wks)	Overweight/obese with T2D on insulin; 18–75 yrs (INS)	ExQW 2 mg + DAPA 10 mg/day ExQW 2 mg INS	75	HbA1c	Recruiting	December 2018
New outcomes
NCT02288273	AstraZeneca	Phase 4, multicenter, randomized, double-blind, parallel (10 wks)	T2D; 12–75 yrs (MET)	ExQW 2 mg PBO	239	24-h mean weighted glucose	Completed	N/A
NCT01144338 (EXSCEL)	AstraZeneca	Phase 4, multicenter, randomized, double-blind, parallel (NR)	T2D; ≥18 yrs (OAD(s) ± INS or INS alone)	ExQW 2 mg PBO	14,000	Composite end point of CV death, nonfatal MI, or nonfatal stroke	Active, no longer recruiting	April 2018
NCT02162550	Phoenix VA Health Care System	Phase 4, randomized, double-blind, parallel (18 mos)	T2D; 21–75 yrs (OAD(s) ± INS)	ExQW 2 mg PBO	148	Carotid plaque volume	Recruiting	June 2018
NCT02380521	University of Palermo	Phase 4, open-label (8 mos)	T2D; 18–80 yrs (MET)	ExQW 2 mg	60	Subclinical atherosclerosis	Recruiting	November 2016
New patient populations
NCT02251431	Baylor Research Institute	Phase 3, double-blind, parallel, randomized (38 wks)	T2D; type 4 cardiorenal syndrome; ≥18 yrs (OADs NR; ± INS)	ExQW 2 mg PBO	104	Myocardial injury, kidney injury, cardiac fibrosis, left ventricular strain	Recruiting	June 2018
NCT02496611	University of Minnesota – Clinical and Translational Science Institute	Phase 2, double-blind, parallel, randomized (52 wks)	Severely obese; 12–17 yrs (N/A)	ExQW (dose NR) PBO	100	Weight loss maintenance	Recruiting	July 2020
NCT02635386	Woman’s Hospital Baton Rouge, LA	Phase 3, single-blind, randomized, parallel (24 wks)	Obese, polycystic ovary syndrome; 18–45 yrs (N/A)	ExQW 2 mg DAPA 10 mg ExQW 2 mg + DAPA 10 mg DAPA 10 mg + MET ER 2000 mg	135	Insulin sensitivity/insulin action	Recruiting	September 2018
NCT01794429	Bjørn H. Ebdrup	Phase 3, double-blind, randomized, parallel (3 mos)	Drug-induced obesity: obese pts with a schizophrenic spectrum diagnosis on antipsychotic medication (N/A)	ExQW (dose NR) PBO	45	Weight loss	Completed	N/A
NCT02417142	University of Massachusetts, Worcester	Phase 4, double-blind, randomized (24 wks)	Schizophrenia, schizoaffective disorder (N/A)	ExQW 2 mg PBO	70	Negative symptoms	Recruiting	September 2017
NCT02664441	Seattle Children’s Hospital	Phase 3, double-blind, randomized, parallel, multicenter (36 wks)	Hypothalamic obesity with history of craniopharyngioma; 10–25 yrs (NR)	ExQW (dose NR) PBO	48	BMI	Recruiting	July 2019
NCT02847403	Azienda Ospedaliero–Universitaria di Roma	Phase 3, open-label, randomized, parallel (32 wks)	Dysglycemia or prediabetes with mild cognitive impairment (NR)	ExQW 2 mg PBO	40	Cognitive function (ADAS-cog)	Recruiting	July 2018
Safety
NCT01940770	AstraZeneca	Observational, multicenter (≥3 yrs)	T2D; Japanese (lifestyle modification; SU, MET, TZDs alone or in combination)	ExQW 2 mg	1100	Tolerability	Ongoing, no longer recruiting	April 2020
NCT02533453	AstraZeneca	Phase 4, open-label, multicenter (12–24 wks)	T2D; Korean (MET, SU, TZD, MET/SU, MET/TZD)	ExQW 2 mg	115	Proportion of pts with AEs and SAEs; nature, incidence, and severity of AEs	Ongoing, no longer recruiting	January 2017
ExBID
T1D
NCT01269034	Albert Einstein College of Medicine of Yeshiva University	Phase 4, open-label, randomized, crossover (NR)	New-onset T1D	ExBID 1.25 μg INS ExBID 1.25 μg + INS	20	Postprandial hyperglycemia	Recruiting	December 2017
T2D
NCT02455076	Emory University	Phase 4, open-label, randomized, parallel (10 days)	T2D inpatients (lifestyle modification; OADs; low-dose INS)	ExBID 5 μg INS glargine OADs Rapid-acting INS	150	HbA1c, blood glucose	Recruiting	December 2016
NCT02449603	Xijing Hospital	Phase 4, multicenter, open-label, randomized, parallel (16 wks)	T2D; ≥18 yrs; Chinese (MET)	ExBID 5–10 μg INS aspart 30	150	Glycemic excursions	Recruiting	September 2017
NCT02042664	Assistance Publique Hopitaux De Marseille	Phase 3, open-label, parallel (3 yrs)	T2D; obese (BMI ≥30 kg/m^2); ≥18 yrs (NR)	ExBID (dose NR) MET (dose NR)	44	Intracardiac triglycerides	Completed	N/A
NCT02118376	Shanghai 10th People’s Hospital	Open-label (3 mos)	T2D; obese; 18–65 yrs (NR)	ExBID 5 μg	20	Fat distribution	Unknown	December 2014
NCT02303730	Fudan University	Phase 4, multicenter, open-label, randomized, parallel (24 wks)	T2D; NAFLD; 18–70 yrs (NR)	ExBID 5 μg (4 wks) then 10 μg (20 wks) INS glargine	76	Liver fat content	Recruiting	May 2017
NCT02690883	Nanfang Hospital, Southern Medical University	Phase 4, multicenter, open-label, randomized, parallel (24 wks)	T2D, diabetic nephropathy; 18–70 yrs (NR)	ExBID 5 μg then 10 μg INS lispro	90	UAER	Not yet recruiting	October 2017
Combination therapy
NCT02467920	Huazhong University of Science and Technology	Phase 4, open-label, randomized, parallel (24 wks)	T2D (INS + MET)	INS glargine + ExBID (dose NR) Aspart 30	350	HbA1c	Recruiting	December 2017
NCT01107717	The University of Texas Health Science Center at San Antonio	Open-label, randomized, parallel (3 yrs)	T2D (none or MET <3 mos)	MET + PIO + ExBID MET, GLYB, INS glargine	600	HbA1c	Recruiting	December 2017
Prediabetes
NCT02104739	The University of Texas Health Science Center, Houston	Phase 4, double-blind, randomized, crossover single-dose study (+ 6-wk nonrandomized extension)	Obese (BMI 30–35 kg/m^2); prediabetes; 30–70 yrs (N/A)	ExBID 10 μg SAXA 5 mg PIO 45 mg PBO Extension: ExQW 2 mg	50	Free fatty acids	Recruiting	March 2018
Obesity
NCT01590433	Eleftheria Maratos-Flier	Single-blind, randomized, parallel (52 wks)	Overweight/obese (BMI 28–48 kg/m^2); female; 18–70 yrs (N/A)	ExBID 5 μg then 10 μg PBO	300	Weight	Recruiting	September 2016
NCT01484873	Vanderbilt University	Phase 2, open-label (52 wks)	Hypothalamic obesity (BMI >30 kg/m^2); 18–40 yrs (N/A)	ExBID 5 μg (4 wks) then 10 μg (46 wks)	10	Weight	Completed	N/A
NCT02860923(CRANIOEXE)	University Hospital, Bordeaux	Phase 3, multicenter, double-blind, randomized, parallel (6 mos)	Hypothalamic obesity after cranio-pharyngioma therapy; 18–75 yrs (N/A)	ExBID 5 μg then 10 μg PBO	50	Weight	Not yet recruiting	April 2017
NCT00856609	National Institute of Diabetes and Digestive and Kidney Diseases	Phase 2, double-blind, randomized, parallel (24 wks)	Obese (BMI >30 kg/m^2); 18–55 yrs (N/A)	ExBID 10 µg PBO	180	Weight, energy expenditure, and food intake	Completed	N/A
NCT00845507	University of Cincinnati	Phase 4, double-blind, randomized, parallel (28 days)	Drug-induced obesity (BMI >30 kg/m^2); 18–55 yrs (N/A)	ExBID 5 μg then 10 μg PBO	60	Weight	Completed	N/A
NCT01783717	Huashan Hospital	Open-label (12 wks)	Overweight/obese (BMI ≥28 kg/m^2) or T2D due to hypothalamic damage (NR)	ExBID 5 μg (4 wks) then 10 μg (8 wks)	10	Weight, BMI, HbA1c, glucose, β-cell function, insulin sensitivity	Unknown	July 2015
Cardiac patients
NCT01969149 (ExSTRESS)	Centre Hospitalier Universitaire de Besancon	Phase 2/3, multicenter, open-label, randomized, parallel (NR)	Prevention of stress hyperglycemia in cardiac surgery; ≥18 yrs (NR)^b	EXE IV 0.05 μg/min bolus then 0.025 μg/min INS	544	Proportion of pts with >50% of time in glycemic target range (100–140 mg/dL)	Recruiting	December 2017
NCT00766857	VU University Medical Center	Phase 4, open-label, randomized, parallel (26 wks)	T2D; congestive heart failure (MET)	ExBID 5 μg then 10 μg INS	27	Global cardiac function (LVEF)	Completed	N/A
NCT02432976 (ExeQOL)	Centre Hospitalier Universitaire de Besancon	Phase 2/3, open-label, randomized, parallel (3 mos)	Management of postoperative stress hyperglycemia after CABG (NR)^b	EXE IV 0.05 μg/min bolus then 0.025 μg/min INS	544	Variation in SF-36 score	Recruiting	December 2017
NCT02344641	Chinese Academy of Medical Sciences & Fuwai Hospital	Open-label, randomized, parallel (4 wks)	T2D; heart failure (NR)	EXE 5 μg Control	234	Plasma NT-proBNP	Not yet recruiting	December 2016
NCT01938235 (EMPRES)	University Heath Network, Toronto	Phase 2, double-blind, randomized, parallel (NR)	STEMI with emergent PCI	EXE IV 1.5 µg, then 1.2 µg/h, then 1.9 µg/h PBO	198	Infarct size	Recruiting	January 2018
NCT02404376 (COMBAT-MI)	Hospital Universitari Vall d’Hebron Research Institute	Phase 3, double-blind, randomized (2–7 days)	STEMI (NR)	EXE IV (dose NR) + RIC EXE RIC	360	Myocardial infarct size; MI	Recruiting	September 2018

^aStatus of all trials correct as of 28 September 2016.

^bPatients with and without T2D enrolled; only patients with T2D who did not require insulin were included.

ADAS-cog: Alzheimer’s Disease Assessment Scale-cognitive; AEs: adverse events; BMI: body mass index; CABG: coronary artery bypass graft; CV: cardiovascular; DAPA: dapagliflozin; ExBID: exenatide twice daily; ER: extended release; EXE: exenatide; ExQW: exenatide once weekly; GLYB: glyburide; HbA1c: glycated hemoglobin; INS: insulin; IV: intravenous; LVEF: left ventricular ejection fraction; MET: metformin; MI: myocardial infarction; mos: months; N/A: not applicable; NAFLD: nonalcoholic fatty liver disease; NR: not reported; NT-proBNP: N-terminal of the prohormone brain natriuretic peptide; OAD(s): oral antidiabetes drug(s); PBO: placebo; PCI: percutaneous coronary intervention; PIO: pioglitazone; pts: patients; RIC: remote ischemic conditioning; SAEs: serious adverse events; SAXA: saxagliptin; SF-36: 36-item short-form health survey; STEMI: ST-elevation myocardial infarction; SU: sulfonylurea; T1D: type 1 diabetes; T2D: type 2 diabetes; TZD: thiazolidinedione; wks: weeks; UAER: urinary albumin excretion rate; yrs: years.

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