Emerging Treatments and Technologies ORIGINAL ARTICLE Potential of Albiglutide, a Long-Acting GLP-1 Receptor Agonist, in Type 2 Diabetes A randomized controlled trial exploring weekly, biweekly, and monthly dosing 1 5 JULIO ROSENSTOCK, MD FRED YANG, PHD ability of native GLP-1 to stimulate glu- 2,3 5 JANE REUSCH, MD MURRAY STEWART, DM, FRCP cose-dependent insulin secretion and 4 MARK BUSH, PHD FOR THE ALBIGLUTIDE STUDY GROUP suppress inappropriately elevated gluca- gon secretion (11,12). Native GLP-1 also slows gastric emptying and reduces food OBJECTIVE — To evaluate the efficacy, safety, and tolerability of incremental doses of albi- intake, which leads to modest weight loss glutide, a long-acting glucagon-like peptide-1 receptor agonist, administered with three dosing (11). However, native GLP-1 is rapidly schedules in patients with type 2 diabetes inadequately controlled with diet and exercise or inactivated (half-life 1–2 min) by dipepti- metformin monotherapy. dyl peptidase-4 (DPP-4), limiting its ther- RESEARCH DESIGN AND METHODS — In this randomized multicenter double- apeutic potential (13). Exenatide (half-life blind parallel-group study, 356 type 2 diabetic subjects with similar mean baseline characteris- 2.4 h) improves glycemic control in com- tics (age 54 years, diabetes duration 4.9 years, BMI 32.1 kg/m2, A1C 8.0%) received bination with metformin, a sulfonylurea, subcutaneous placebo or albiglutide (weekly [4, 15, or 30 mg], biweekly [15, 30, or 50 mg], or or a thiazolidinedione (14–18). Despite monthly [50 or 100 mg]) or exenatide twice daily as an open-label active reference (per labeling modest weight loss and improved glyce- in metformin subjects only) over 16 weeks followed by an 11-week washout period. The main mic control, gastrointestinal (GI) intoler- outcome measure was change from baseline A1C of albiglutide groups versus placebo at week ability and twice-daily administration 16. may lead to discontinuation (19). RESULTS — Dose-dependent reductions in A1C were observed within all albiglutide sched- Albiglutide (formerly known as alb- ules. Mean A1C was similarly reduced from baseline by albiglutide 30 mg weekly, 50 mg ugon) is a GLP-1 receptor agonist devel- biweekly (every 2 weeks), and 100 mg monthly (Ϫ0.87, Ϫ0.79, and Ϫ0.87%, respectively) oped through the fusion of two repeats of versus placebo (Ϫ0.17%, P Ͻ 0.004) and exenatide (Ϫ0.54%). Weight loss (Ϫ1.1 to Ϫ1.7 kg) human GLP-1 (7–36) molecules to re- was observed with these three albiglutide doses with no significant between-group effects. The combinant human albumin (20). The incidence of gastrointestinal adverse events in subjects receiving albiglutide 30 mg weekly was GLP-1 dimer was used to avoid potential less than that observed for the highest biweekly and monthly doses of albiglutide or exenatide. reductions of the interaction of the GLP-1 moiety of the monomer with its receptor CONCLUSIONS — Weekly albiglutide administration significantly improved glycemic con- in the presence of albumin. A single trol and elicited weight loss in type 2 diabetic patients, with a favorable safety and tolerability 3 profile. amino acid substitution (ala8 gly) ren- ders the molecule resistant to DPP-4. The Diabetes Care 32:1880–1886, 2009 structure of albiglutide provides an ex- tended half-life (ϳ5 days), which may al- arly intervention to improve glyce- the American Diabetes Association (ADA) low weekly or less frequent dosing. mic control reduces microvascular target A1C level (Ͻ7%) (6–8). Moreover, Furthermore, albiglutide is relatively im- E complications in type 2 diabetes weight gain and treatment-induced hypo- permeant to the central nervous system (1–4) and may provide long-term macro- glycemic episodes (9,10) are major barri- (21), which may have implications for GI vascular benefits (5). Despite numerous ers to achieving glycemic control (10). tolerability. In nonclinical studies, albig- available therapies, over half of patients Antidiabetic therapies based on glu- lutide stimulated cAMP production with type 2 diabetes are unable to achieve cagon-like peptide-1 (GLP-1) retain the through the GLP-1 receptor and induced ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● insulin secretion from INS-1 cells in vitro and in animal models (21–22). It also de- From the 1Dallas Diabetes and Endocrine Center at Medical City, Dallas, Texas; the 2Division of Endocri- nology, Metabolism and Diabetes, University of Colorado–Denver AMC, Denver, Colorado; the 3Denver layed gastric emptying and reduced food Veterans Affairs Medical Center, Denver, Colorado; 4GlaxoSmithKline, Research Triangle Park, North intake in rodents (21–23). Carolina; and 5GlaxoSmithKline, King of Prussia, Pennsylvania. This study was designed to explore a Corresponding author: Julio Rosenstock, [email protected]. wide range of doses (4–100 mg) and Received 24 February 2009 and accepted 6 July 2009. Published ahead of print at http://care.diabetesjournals.org on 10 July 2009. DOI: 10.2337/dc09-0366. schedules (weekly to monthly) to assess Clinical trial reg. no. NCT00518115, clinicaltrials.gov. glycemic control and adverse event pro- © 2009 by the American Diabetes Association. Readers may use this article as long as the work is properly files for albiglutide. Exenatide was in- cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons. cluded as an open-label reference to org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby provide clinical perspective for a GLP-1 marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. receptor agonist. 1880 DIABETES CARE, VOLUME 32, NUMBER 10, OCTOBER 2009 care.diabetesjournals.org (5 (50 or 100 mg);(biweekly; or 15, open-label 30, or exenatide 50weekly mg), (4, or monthly 15, or(matched 30 to mg), albiglutide arms); every albiglutide 2treatment weeks arms: double-blindSubjects placebo were randomizedRandomization into 1 of 10 sessed safety data on ancommittee ongoing of basis. independentprescreening. experts A as- dataconsent safety was obtained monitoring from alltion subjects at of Helsinki.ducted Written in accordance informed an with institutional the review Declara- board and con- permitted. the-counter weight-loss drugsenrollment, and were no prescriptionat or over- the samemedications dose must for have 3 beenically months maintained prior significant. to Lipid-lowering tological profiles considered tomg/dl be (9 clin- mmol/l) ateases; screening; or fasting hema- serumbrovascular, triglycerides renal, or5 hepatobiliary years; dis- significant cardiovascular, cere- 12 weeks of 10 not used for insulin formin) antidiabetic monotherapy (except met- ( at 118 sites inducted the between U.S. April ( 2007 andcebo-controlled May parallel-group 2008 studyprospective con- randomized double-blind pla- METHODS RESEARCH DESIGN AND care.diabetesjournals.org D ple) were administered in the(same physician’s formulation without activetol, princi- 0.01% polysorbate-80)phosphate, and 4.2% placebo trehalose, 2.8% manni- lutide (formulated in 10 mmol/l sodium screening BMI ing). Additional inclusion criteria included for the exenatide arm (consistent with label- with metformin monotherapy were eligible to screening visit).months Only before prescreening subjects (1formin week treated prior monotherapy and(diet stable and exercise) for before screening. or Subjects were treated drugdiagnosed with naïve with type 2 met- diabetes 18–75 years) were eligiblewomen for of inclusion non-childbearing if potentialcontent/full/dc09-0366/DC1). (age Menable at and http://care.diabetesjournals.org/cgi/ Republic ( n ϭ ␮ The study protocol was approved by Exclusion criteria included any oral g twice daily for 4 weeks followed by 9), Chile ( Ն 20 and Ͻ Յ 1 month prior to screening and Ն n 3 months prior to screening or ϭ 7 and Ͼ 1) (online appendix 1, avail- — This phase II trial was a 7 days; pancreatitis within n Յ ϭ ␮ Յ 40 kg/m g twice daily). Albig- 2), and the Dominican 10%. n ϭ 2 106), Mexico and A1C at Ն 3 months Ն 800 Ͼ 3 Table 1—Change from baseline in glycemic parameters at 16 weeks Albiglutide Exenatide* Weekly Biweekly Monthly twice daily, Placebo 5–10 ␮g 4mg 15mg 30mg 15mg 30mg 50mg 50mg 100mg n (A1C data) 50 34 34 34 29 30 32 34 35 33 Baseline A1C (%) 7.8 Ϯ 0.9 8.0 Ϯ 0.9 8.2 Ϯ 1.0 8.0 Ϯ 0.9 8.0 Ϯ 0.9 8.2 Ϯ 1.0 8.0 Ϯ 1.0 7.9 Ϯ 0.7 7.9 Ϯ 0.8 8.1 Ϯ 1.0 ⌬A1C at 16 weeks vs. Ϫ Ϯ Ϫ Ϯ Ϫ Ϯ Ϫ Ϯ Ϫ Ϯ Ϫ Ϯ Ϫ Ϯ Ϫ Ϯ Ϫ Ϯ Ϫ Ϯ IABETES baseline 0.17 1.01 0.54 0.91 0.11 1.16 0.49 0.74 0.87 0.65† 0.56 0.97 0.79 0.98† 0.79 1.04† 0.55 1.01 0.87 0.87† n (FPG data) 47 33 32 32 29 28 32 32 34 33 Baseline FPG C Ϯ Ϯ Ϯ Ϯ Ϯ Ϯ Ϯ Ϯ Ϯ Ϯ ARE (mmol/l) 9.9 3.7 9.5 2.4 10.9 3.9 9.5 2.9 9.6 3.1 10.2 2.7 9.5 3.3 10.0 3.2 9.3 2.7 9.8 3.8 ⌬ , FPG at 16 VOLUME weeks vs. baseline (%) Ϫ0.10 Ϯ 2.90 Ϫ0.80 Ϯ 2.48 Ϫ0.47 Ϯ 3.12 Ϫ0.72 Ϯ 1.68 Ϫ1.44 Ϯ 2.03† Ϫ1.28 Ϯ 2.43 Ϫ1.58 Ϯ 2.06† Ϫ1.32 Ϯ 3.52† Ϫ0.72 Ϯ 2.77 Ϫ1.22 Ϯ 3.50† 32, Data are means Ϯ SD for the intent-to-treat population, last observation carried forward.