Potential of Albiglutide, a Long-Acting GLP-1 Receptor Agonist, in Type 2 Diabetes a Randomized Controlled Trial Exploring Weekly, Biweekly, and Monthly Dosing

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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 glucagon 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 Rosenstock and Associates

RESEARCH DESIGN AND METHODS — This phase II trial was a 3.50† 0.87† 3.8 1.0 Ϯ Ϯ Ϯ prospective randomized double-blind pla- Ϯ cebo-controlled parallel-group study con- 1.22 ducted between April 2007 and May 2008 0.87 Ϫ at 118 sites in the U.S. (n ϭ 106), Mexico Ϫ (n ϭ 9), Chile (n ϭ 2), and the Dominican 2.77 1.01 2.7 9.8 ϭ 0.8 8.1 Republic (n 1) (online appendix 1, avail- 0.05 vs. placebo. Ϯ Ϯ Ϯ Ϯ able at http://care.diabetesjournals.org/cgi/ Ͻ content/full/dc09-0366/DC1). Men and P 0.72 0.55 Ϫ women of non-childbearing potential (age Ϫ 18–75 years) were eligible for inclusion if diagnosed with type 2 diabetes Ն3 months 3.52† 1.04† 3.2 9.3 before screening. Subjects were drug naïve 0.7 7.9 Ϯ Ϯ Ϯ (diet and exercise) or treated with met- Ϯ

Ͼ es were conducted. † 1.32 formin monotherapy and stable for 3 0.79 Ϫ months before prescreening (1 week prior Ϫ to screening visit). Only subjects treated 2.06† 0.98† 3.3 10.0 with metformin monotherapy were eligible 1.0 7.9 Ϯ Ϯ Ϯ for the exenatide arm (consistent with label- Ϯ ing). Additional inclusion criteria included 2 1.58 BMI Ն20 and Յ40 kg/m and A1C at 0.79 Ϫ screening Ն7 and Յ10%. Ϫ

Exclusion criteria included any oral Albiglutide 2.43 0.97 2.7 9.5 antidiabetic monotherapy (except met- 1.0 8.0 Ϯ Ϯ Ϯ formin) Յ3 months prior to screening or Ϯ Ͻ 1.28 insulin 1 month prior to screening and 0.56 Ϫ not used for Ͼ7 days; pancreatitis within Ϫ 5 years; significant cardiovascular, cere- brovascular, renal, or hepatobiliary dis- 2.03† 0.65† 3.1 10.2 eases; fasting serum triglycerides Ն800 0.9 8.2 Ϯ Ϯ Ϯ Ϯ mg/dl (9 mmol/l) at screening; or hema- 1.44 tological profiles considered to be clin- 0.87 Ϫ ically significant. Lipid-lowering Ϫ medications must have been maintained 1.68 0.74 2.9 9.6 at the same dose for 3 months prior to 0.9 8.0 Ϯ Ϯ Ϯ enrollment, and no prescription or over- Ϯ the-counter weight-loss drugs were Weekly Biweekly Monthly 0.72 0.49 Ϫ permitted. Ϫ The study protocol was approved by 3.12 1.16 3.9 9.5 an institutional review board and con- 1.0 8.0 Ϯ Ϯ Ϯ ducted in accordance with the Declara- Ϯ tion of Helsinki. Written informed 4mg 15mg 30mg 15mg 30mg 50mg 50mg 100mg 0.47 consent was obtained from all subjects at 0.11 Ϫ prescreening. A data safety monitoring Ϫ committee of independent experts as- g 2.48 0.91 2.4 10.9 0.9 8.2

sessed safety data on an ongoing basis. ␮ Ϯ Ϯ Ϯ Ϯ

Randomization 5–10 0.80 0.54 Exenatide* twice daily, Ϫ Subjects were randomized into 1 of 10 Ϫ treatment arms: double-blind placebo (matched to albiglutide arms); albiglutide 2.90 1.01 3.7 9.5 weekly (4, 15, or 30 mg), every 2 weeks 0.9 8.0 Ϯ Ϯ Ϯ Ϯ (biweekly; 15, 30, or 50 mg), or monthly Placebo 0.10 (50 or 100 mg); or open-label exenatide 0.17 Ϫ (5 ␮g twice daily for 4 weeks followed by Ϫ 12 weeks of 10 ␮g twice daily). Albig- SD for the intent-to-treat population, last observation carried forward. *Exenatide was used to provide clinical reference; no statistical analys lutide (formulated in 10 mmol/l sodium Ϯ phosphate, 4.2% trehalose, 2.8% manni- Change from baseline in glycemic parameters at 16 weeks tol, 0.01% polysorbate-80) and placebo (mmol/l) 9.9 weeks vs. baseline (%) (same formulation without active princi- weeks vs. baseline (FPG data) 47 33 32 32 29 28 32 32 34 33 (A1C data) 50 34 34 34 29 30 32 34 35 33 FPG at 16 A1C at 16 n Baseline FPG ⌬ ⌬ n Baseline A1C (%) 7.8 ple) were administered in the physician’s Table 1— Data are means care.diabetesjournals.org DIABETES CARE, VOLUME 32, NUMBER 10, OCTOBER 2009 1881 Albiglutide dose regimen study ofﬁce over the course of 16 weeks. Sub- A Albiglutide Albiglutide Albiglutide jects receiving 4 mg albiglutide were weekly (mg) biweekly (mg) monthly (mg) given 1.0 ml (4 mg/ml solution). Subjects Placebo Exenatide 4 15 3015 30 50 50 100 receiving 15, 30, or 50 mg albiglutide 0 were given 0.32, 0.65, or 1.0 ml (50 mg/ml solution). Subjects receiving 100 -0.2 mg albiglutide were given two 1.0-ml in- jections (50 mg/ml solution, Ͼ1 inch apart). Placebo volumes were matched to -0.4 active treatment. Albiglutide/placebo in- jections were subcutaneous to the abdo- -0.6 men using 30-G needles. Subjects were * observed for Ն30 min to monitor for in-

Change in A1C (%) -0.8 jection site reactions. Subjects receiving exenatide initiated treatment in the phy- -1 sician’s ofﬁce and subsequently self- ††† administered according to the package 50 34 34 34 29 3032 34 35 33 n -1.2 insert. After 16 weeks, subjects entered an 7.8 8.0 8.2 8.0 8.08.2 8.0 7.9 7.9 8.1 Baseline A1C (%) 11-week washout phase to assess safety 7.7 7.4 8.0 7.5 7.17.6 7.2 7.1 7.4 7.2 Week 16 A1C (%) and immunogenicity. B Assessments 60 52% 53% On therapy. A1C and fasting plasma glu- 50% 48% cose (FPG) measurements were per- 50 formed at screening, baseline, and weeks 2 (FPG only), 4, 5, 7, 8, 9, 12, 15, and 16. 40 35% 35% Fasting fructosamine, C-peptide, glucagon, insulin, and lipids were measured at 30 27% baseline and weeks 5, 8, 12, and 16. 23% ␤ 20% -Cell function was calculated using ho- 20 18% meostasis model assessment (24). Adverse event assessments and safety

Percent attaining A1C goal attaining (<7%) Percent 10 analyses were conducted throughout the study. Nausea and vomiting were moni- 0 tored for occurrence and duration. Im- Placebo Exenatide 4 15 3015 30 50 50 100 munogenicity samples were taken at Albiglutide Albiglutide Albiglutide baseline and weeks 1, 4, 8, 12, and 16 and weekly (mg) biweekly (mg) monthly (mg) were screened for anti-albiglutide antibodies via ELISA (20). Plasma samples C 0.5 were collected to characterize the pharmacokinetics of albiglutide, quantified by 0 ELISA (20) at baseline and at weeks 4, 5, 7, 8, 9, 12, 15, and 16. Population phar- -0.5 macokinetics analysis was performed us- * ing a nonlinear mixed-effect modeling -1 approach with NONMEM software † † (ICON Development Solutions, Ellicott -1.5 † City, MD). Eleven-week washout. A1C, FPG, -2 Placebo and albiglutide concentrations were ob- Exenatide tained at weeks 17, 18, 20, 23, and 27; Change in FPG from baseline (mmol/l) baseline from in FPG Change -2.5 Albiglutide 30 mg weekly fasting fructosamine, C-peptide, gluca- Albiglutide 50 mg biweekly Albiglutide 100 mg monthly gon, insulin, and lipid profiles were ob- -3 tained at weeks 20 and 27; and 0681012141624 immunogenicity assessments were exam- Week ined at weeks 20, 23, and 27. Figure 1—Effects of albiglutide on glycemic parameters. A: The reduction in A1C from baseline Statistical analysis at 16 weeks. Data are presented as mean change from baseline (–SE). B: The proportion of subjects achieving ADA A1C target of Ͻ7%. Data are presented as % at goal. C: Change in fasting plasma The primary objective was to evaluate the Ϯ dose response of albiglutide for safety and glucose over time. Data are presented as mean change from baseline ( SE). *No formal statistical comparisons versus exenatide (open label) were conducted. †P Ͻ 0.05 vs. placebo. efficacy. With 30 subjects planned in each arm, a two-sided 95% CI for each group

1882 DIABETES CARE, VOLUME 32, NUMBER 10, OCTOBER 2009 care.diabetesjournals.org Rosenstock and Associates mean response had a half-width of 0.36% cluded loss to follow-up, protocol viola- the 16-week end point for each of the on the A1C scale, assuming a standard tions, and voluntary withdrawal. highest doses (Fig. 1C). Statistically sig- deviation of 1.00%. Baseline demographics and charac- nificant reductions were seen for FPG The primary efficacy end point was teristics were comparable across groups compared with placebo at week 16 change from baseline A1C at week 16 ver- (online appendix 3). Mean duration of di- (Ϫ1.38 mmol/l [P Ͻ 0.02], Ϫ1.16 sus placebo across different doses within abetes was 4.9 years. Baseline A1C levels mmol/l [P Ͻ 0.03], and Ϫ1.17 mmol/l each schedule (weekly, biweekly, and (mean 8.0%) were evenly distributed [P Ͻ 0.03] for 30 mg weekly, 50 mg bi- monthly). The primary analysis was an AN- across arms. A similar proportion of sub- weekly, and 100 mg monthly albiglutide COVA model with main effects for group jects receiving placebo or albiglutide were doses, respectively). The 4- and 15-mg and prior metformin therapy, adjusting for drug naïve (25.7–34.4%) or receiving weekly dose regimens of albiglutide re- baseline A1C. Dose response was evaluated metformin monotherapy. All subjects reduced FPG but were less effective. The using contrasts within the ANCOVA model ceiving exenatide were on metformin greatest fluctuations in FPG over time framework. Pairwise comparisons were monotherapy. The groups were similar in were observed in subjects receiving albi- performed in the same ANCOVA model. terms of race/ethnicity (43.8–71.0% Cau- glutide 100 mg monthly (Fig. 1C). Ex- Secondary end points were similarly ana- casian; 87.1 and 12.9% of subjects were enatide was associated with a relatively lyzed. Responder analysis and incidence of from U.S. and Latin American clinics, re- consistent FPG profile over time that was hypoglycemia were summarized by group spectively), and the rates of dyslipidemia, numerically less than FPG reductions statistics. No formal statistical comparisons hypertension, and coronary artery disease seen with the highest doses of albiglutide versus exenatide were conducted. Safety were 50.0–80.0, 47.1–67.6, and (Fig. 1C). and tolerability data were categorically 0–15.2%, respectively. Neither fasting insulin nor glucagon collected. levels were consistently or significantly al- Comparisons were made on the intent- Efficacy tered. Small improvements in ␤-cell func- to-treat population, defined as all randomly After 16 weeks, albiglutide significantly tion (assessed by homeostasis model assigned subjects with at least one postbase- reduced A1C in a generally dose- assessment of ␤-cell function) were noted line assessment of the primary end point, dependent manner within each dose in subjects receiving albiglutide (online using last observation carried forward. The schedule (Table 1) (Fig. 1A). Mean A1C appendix 4). safety population included all randomized reductions from baseline in subjects re- There was no significant difference in subjects who received at least one dose of ceiving the highest dose in each treatment weight reduction among groups. A con- any medication. An interim analysis was schedule were Ϫ0.87, Ϫ0.79, and sistent trend in weight reduction was conducted at 8 weeks for administrative Ϫ0.87% for 30 mg weekly, 50 mg bi- noted with average weight loss ranging purposes by an independent statistical anal- weekly, and 100 mg monthly, respec- from Ϫ1.1 to Ϫ1.7 kg in subjects receiv- ysis group; blinding was retained for study tively, versus placebo (Ϫ0.17%) or ing the highest albiglutide dose in each investigators and study personnel with exenatide (Ϫ0.54%). A1C reductions schedule. These reductions were numer- daily operational responsibility. No formal (based on ANCOVA model) for the high- ically greater than those for subjects re- interim inferential hypothesis testing was est doses compared with placebo were ceiving placebo (Ϫ0.7 kg) but less than conducted; the study conduct was unal- statistically significant: 30 mg weekly, those for subjects receiving exenatide tered based on the results of the interim Ϫ0.62% (95% CI Ϫ1.03 to Ϫ0.22), P Ͻ (Ϫ2.4 kg). Albiglutide and exenatide analysis. 0.003; 50 mg biweekly, Ϫ0.57% (Ϫ0.96 tended to reduce mean systolic and dia- to Ϫ0.19), P Ͻ 0.003; and 100 mg stolic blood pressure but did not signifi- RESULTS monthly, Ϫ0.60% (Ϫ0.99 to Ϫ0.22), cantly change the plasma lipoprotein P Ͻ 0.002. Numerically greater reduc- profile (online appendix 4). Subject disposition and baseline tions in A1C were observed in subjects characteristics with baseline A1C Ն8.5%. Safety and tolerability A total of 774 subjects were screened. Of The proportion of subjects achieving The percentage of subjects reporting at 361 subjects randomized, 356 received the ADA target A1C (Ͻ7.0%) at week 16 least one adverse event was similar across treatment and were included in the safety increased with increasing doses of albig- groups (67–85%). The most frequently analysis, 345 were included in the efficacy lutide within each schedule; similar pro- reported adverse events included nausea analysis, and 255 completed the 16-week portions of subjects achieved target A1C (11.8–54.3%), vomiting (0–41.2%), trial. Withdrawal rates were similar across at the highest albiglutide dose among the headache (5.9–23.5%), dizziness (5.7– groups (online appendix 2); the most fre- three schedules. More subjects receiving 14.3%), nasopharyngitis (5.7–11.4%), quent reason for withdrawal was adverse albiglutide 30 mg weekly (52%), 50 mg back pain (0–14.3%), influenza (0– events. Adverse events occurring in at least biweekly (53%), and 100 mg monthly 9.7%), upper respiratory tract infections one subject leading to withdrawal included (48%) achieved A1C Ͻ7.0% compared (0–15.2%), and local skin reactions (2.9– hyperglycemia (0–11.8%, n ϭ 24, mostly with subjects receiving placebo (20%) 28.6%) (online appendix 5). in placebo and lower-dose groups), GI and exenatide (35%) (Fig. 1B). The proportion of subjects who expe- events (0–11.4%, n ϭ 10, across groups), The time course of albiglutide- rienced nausea and/or vomiting was injection site events (0–9.7%, n ϭ 11, induced changes in FPG demonstrated lower with administration of Յ30 mg al- mostly in higher-dose groups), and hyper- that each schedule elicited a dose- biglutide compared with the proportion triglyceridemia (0–5.7%, n ϭ 2of35re- dependent FPG reduction over 16 weeks, of subjects receiving higher doses. In the ceiving 50 mg albiglutide biweekly, deemed with no changes in FPG observed with 30-mg weekly arm, 29.0% of subjects ex- unrelated to study drug; 0% in other placebo. Rapid reductions in FPG were perienced nausea and/or vomiting, com- groups). Other reasons for withdrawal in- observed, with similar FPG reductions at pared with 54.3% in the 50-mg biweekly care.diabetesjournals.org DIABETES CARE, VOLUME 32, NUMBER 10, OCTOBER 2009 1883 Albiglutide dose regimen study

A 45 D 45 40 40 35 35 30 30 25 25 20 20 15 15 10 10 5 5 Nausea and/or vomiting and/or Nausea (%) 0 vomiting and/or Nausea (%) 0 121 345678910111213141516 121 345678910111213141516 Week Week

B 45 E 45 40 40 35 35 30 30 25 25 20 20 15 15 10 10 5 5 Nausea and/or vomiting and/or Nausea (%) 0 Nausea and/or vomiting (%) 0 121 345678910111213141516 121 345678910111213141516 Week Week

C 45 40 35 30 25 20 15 10 5 Figure 2—Time course of nausea and vomiting as adverse events. The percentage of subjects experiencing vomiting with or without nausea (o) Nausea and/or vomiting (%) 0 121 345678910111213141516 or nausea ( ) adverse events during each week of the 16-week trial for albiglutide 30 mg weekly (A), albiglutide 50 mg biweekly (B), albig- Week lutide 100 mg monthly (C), placebo (D), and exenatide (E). group and 55.9% in the 100-mg monthly ceiving the 100-mg monthly dose also ex- (0–3.1%) relative to placebo (3.9%) and group. The percentage of exenatide sub- perienced higher rates of nausea and/or exenatide (2.9%). Cardiac-related ad- jects who experienced nausea and/or vomiting, with peak incidence occurring verse events (eight subjects; six assessed vomiting also was higher (45.7%) than in following each monthly dose administra- as severe) were distributed across groups, the 30-mg weekly albiglutide group. tion. The overall rate was higher for with no dose-dependent trends (online Examination of the time course (Fig. 100-mg monthly than for the other albi- appendix 5). No episodes of pancreatitis 2) of nausea and/or vomiting revealed that glutide groups (Fig. 2C). The incidence of were reported. the proportion of subjects experiencing nausea and/or vomiting with exenatide Eight subjects (2.5%) had conﬁrmed these adverse events each week was low in reached 20% by week 2, increased at positive anti-albiglutide antibodies at the 30-mg weekly arm (Ͻ10%) and de- week 5 to a peak incidence of 29% (due to least once in the placebo and albiglutide clined over the course of the study, with label-based titration), and also declined arms after baseline measurement. How- no reports of nausea or vomiting after 8 over the study period (Fig. 2E). ever, two subjects tested positive prior to weeks (Fig. 2A). Although the proportion Other adverse events were less com- albiglutide treatment, and one subject of nausea and/or vomiting for the 50-mg mon than GI-related events and were who tested positive received placebo. The biweekly dose was greater than for the similar across groups with no dose- remaining ﬁve albiglutide-positive sub- 30-mg weekly dose, it also declined over dependent trends. Documented hypogly- jects were detected in the weekly and bi- the study period (Fig. 2B). Subjects re- cemia was not increased with albiglutide weekly arms. The appearance of anti-

1884 DIABETES CARE, VOLUME 32, NUMBER 10, OCTOBER 2009 care.diabetesjournals.org Rosenstock and Associates albiglutide antibodies was largely achieve consistent therapeutic response ment of immediate hypersensitivity reac- transient: one subject remained positive (i.e., 30 mg), weekly dosing provided tions. In this study, anti-albiglutide at week 27. Antibodies were non- consistent FPG reduction. Greater FPG antibodies were detected in 2.5% (n ϭ 8) neutralizing and low titer and showed fluctuations were observed following bi- of subjects. However, the observation that cross-reactivity with GLP-1 in four of five weekly or monthly dosing, despite similar positive titers of anti-albiglutide antibod- subjects. There was no obvious associa- A1C reductions. ies were detected in three subjects at base- tion between the presence of anti- Albiglutide 30-mg weekly dosing line suggests that the immunogenicity albiglutide antibodies and either efficacy elicited steady and consistent improve- rate may be overestimated. Exenatide, or safety. ments in FPG reductions, with a more fa- which has 53% homology to human Injection site local skin reactions, vorable nausea/vomiting profile than GLP-1 (14), is associated with antibody most of which were small, were observed exenatide. When dosed biweekly, 50 mg development following administration in the study and were more common in albiglutide also improved glycemic in- with twice-daily (15–18) and weekly (25) the albiglutide groups (2.9–28.6%) com- dexes but with higher GI adverse event formulations (Ͼ40%). Antibody forma- pared with placebo (5.9%) and exenatide rates, possibly related to the higher initial tion may attenuate efficacy, especially (2.9%). Injection site reactions tended to dose. In all dosing schedules, rates of nau- among patients developing high levels of occur once per person in subjects receiv- sea and vomiting declined over time. anti-exenatide antibodies (25). ing 30 mg albiglutide and approximately However, when dosed monthly, albig- There are limitations to this phase II twice per person in subjects receiving lutide did not produce stable FPG reduc- study. First, the number of subjects in higher albiglutide doses. Skin reactions tions between dosing and was associated each arm is relatively small compared were not associated with positive IgE an- with higher GI event rates. The increase in with phase III studies. Second, relative to tibodies or neutralizing antibodies and FPG fluctuation and GI events in the bi- the number of subjects, the dropout rate did not worsen upon repeated dosing or weekly and monthly regimens is likely was high owing to adverse events, loss to exhibit dose dependency. No systemic al- due to fluctuations in plasma albiglutide follow-up, and voluntary withdrawals. lergic reactions attributable to albiglutide concentrations resulting from less fre- Third, the duration of active treatment were observed. quent dosing. An escalating-dose titration was 16 weeks, so the magnitude or dura- for the biweekly regimen might have re- bility of response cannot be fully appreci- Pharmacokinetics sulted in a lower frequency of GI events. ated. Fourth, no escalating doses were Albiglutide exhibited a plasma half-life of This approach may be tested in future tested for biweekly and monthly dosing, ϳ5 days. Steady-state albiglutide levels studies to explore the possibility of using which may have attenuated GI adverse were reached within ϳ4 to 5 weeks of the biweekly dosing as a maintenance option events and FPG fluctuations. Finally, be- first dose (online appendix 6). Greater in patients who respond well and tolerate cause exenatide was administered open peak/trough fluctuations in circulating al- the initial weekly regimen. label, formal statistical comparisons were biglutide concentrations were observed Mechanistically, the reasons for dif- not conducted between exenatide and with less frequent administration of ferences in the tolerability of albiglutide albiglutide. higher doses. and exenatide are unknown but may be In conclusion, albiglutide improved due to differences in pharmacokinetics, glucose control in a dose-dependent man- ϳ CONCLUSIONS — In this study, the including gradual absorption (Tmax is 3 ner when given weekly and biweekly. dose- and time-dependent effects of albi- days vs. 2.1 h for albiglutide and ex- Higher monthly doses of albiglutide were glutide, a long-acting GLP-1 receptor ag- enatide, respectively) and a long plasma efficacious, but their use was constrained onist, was evaluated to identify potential half-life of ϳ5 days resulting in a steady by the higher frequency of GI-related ad- dose regimens for future studies. Within state achieved after 4–5 doses for 30 mg verse events. Weekly albiglutide signifi- each dose schedule, albiglutide was asso- albiglutide weekly. The slow accumula- cantly improved glycemic control with an ciated with generally dose-dependent tion of albiglutide may ameliorate GI acceptable safety and tolerability profile A1C reductions that were significantly intolerability often observed with ex- and modest weight loss without increas- different from placebo. Maximum doses enatide, and albiglutide’s relative imper- ing the risk of hypoglycemia or immuno- in each schedule (albiglutide 30 mg meance to the central nervous system may logical response in subjects with type 2 weekly, 50 mg biweekly, and 100 mg result in a more benign profile with re- diabetes. Future studies may elucidate monthly) elicited similar responses in spect to nausea and vomiting than ex- whether titration dosing or biweekly A1C, providing meaningful reductions enatide (21). scheduling could be options for patients within the range of ϳ0.8–0.9% from a Weight loss was similar across albig- who respond to and tolerate the initial mean baseline A1C of 8.0%. lutide arms and numerically less than weekly regimen. Albiglutide also significantly reduced with exenatide, which had a higher base- FPG at week 16 compared with placebo, line BMI. Exploratory post hoc analyses with reductions observed at the time of indicated that there was no obvious cor- Acknowledgments— This study was spon- the first assessment (2 weeks postdose). relation between reduction in A1C and sored by GlaxoSmithKline, Middlesex, U.K. In a previous study, FPG reductions were weight loss for all albiglutide doses (data J.Ro. has received research grants and con- observed as early as 2 days following a not shown). However, larger and longer- sulting honoraria for serving on scientific ad- visory boards from GlaxoSmithKline. J.Re. has single dose (20). term studies will determine the true effect received research grants from and acted as a Variability in glycemic response ap- on weight and cardiometabolic parameters. consultant for GlaxoSmithKline. M.B., F.Y., and peared to be related to circulating concen- Immunogenicity was closely moni- M.S. are employees/stockholders of Glaxo- trations of albiglutide. With a plasma half- tored owing to the possible appearance of SmithKline. No other potential conflicts of in- life of ϳ5 days and at doses sufficient to neutralizing antibodies or the develop- terest relevant to this article were reported. care.diabetesjournals.org DIABETES CARE, VOLUME 32, NUMBER 10, OCTOBER 2009 1885 Albiglutide dose regimen study

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