E m e r g i n g T r e a t m e n t s a n d T e c h n o l o g i e s
`O R I G I N A L
`A R T I C L E
`
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`
`Potential of Albiglutide, a Long-Acting
`GLP-1 Receptor Agonist, in Type 2
`Diabetes
`A randomized controlled trial exploring weekly, biweekly, and monthly
`dosing
`
`JULIO ROSENSTOCK, MD
`2,3
`JANE REUSCH, MD
`4
`MARK BUSH, PHD
`
`1
`
`5
`FRED YANG, PHD
`5
`MURRAY STEWART, DM, FRCP
`FOR THE ALBIGLUTIDE STUDY GROUP
`
`OBJECTIVE — To evaluate the efficacy, safety, and tolerability of incremental doses of albi-
`glutide, a long-acting glucagon-like peptide-1 receptor agonist, administered with three dosing
`schedules in patients with type 2 diabetes inadequately controlled with diet and exercise or
`metformin monotherapy.
`
`RESEARCH DESIGN AND METHODS — In this randomized multicenter double-
`blind parallel-group study, 356 type 2 diabetic subjects with similar mean baseline characteris-
`tics (age 54 years, diabetes duration 4.9 years, BMI 32.1 kg/m2, A1C 8.0%) received
`subcutaneous placebo or albiglutide (weekly [4, 15, or 30 mg], biweekly [15, 30, or 50 mg], or
`monthly [50 or 100 mg]) or exenatide twice daily as an open-label active reference (per labeling
`in metformin subjects only) over 16 weeks followed by an 11-week washout period. The main
`outcome measure was change from baseline A1C of albiglutide groups versus placebo at week
`16.
`
`RESULTS — Dose-dependent reductions in A1C were observed within all albiglutide sched-
`ules. Mean A1C was similarly reduced from baseline by albiglutide 30 mg weekly, 50 mg
`biweekly (every 2 weeks), and 100 mg monthly (⫺0.87, ⫺0.79, and ⫺0.87%, respectively)
`versus placebo (⫺0.17%, P ⬍ 0.004) and exenatide (⫺0.54%). Weight loss (⫺1.1 to ⫺1.7 kg)
`was observed with these three albiglutide doses with no significant between-group effects. The
`incidence of gastrointestinal adverse events in subjects receiving albiglutide 30 mg weekly was
`less than that observed for the highest biweekly and monthly doses of albiglutide or exenatide.
`
`CONCLUSIONS — Weekly albiglutide administration significantly improved glycemic con-
`trol and elicited weight loss in type 2 diabetic patients, with a favorable safety and tolerability
`profile.
`
`Diabetes Care 32:1880–1886, 2009
`
`E arly intervention to improve glyce-
`
`the American Diabetes Association (ADA)
`target A1C level (⬍7%) (6 – 8). Moreover,
`mic control reduces microvascular
`weight gain and treatment-induced hypo-
`complications in type 2 diabetes
`glycemic episodes (9,10) are major barri-
`(1– 4) and may provide long-term macro-
`ers to achieving glycemic control (10).
`vascular benefits (5). Despite numerous
`Antidiabetic therapies based on glu-
`available therapies, over half of patients
`cagon-like peptide-1 (GLP-1) retain the
`with type 2 diabetes are unable to achieve
`● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●
`
`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
`Veterans Affairs Medical Center, Denver, Colorado; 4GlaxoSmithKline, Research Triangle Park, North
`Carolina; and 5GlaxoSmithKline, King of Prussia, Pennsylvania.
`Corresponding author: Julio Rosenstock, juliorosenstock@dallasdiabetes.com.
`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.
`Clinical trial reg. no. NCT00518115, clinicaltrials.gov.
`© 2009 by the American Diabetes Association. Readers may use this article as long as the work is properly
`cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.
`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
`marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
`
`ability of native GLP-1 to stimulate glu-
`cose-dependent insulin secretion and
`suppress inappropriately elevated gluca-
`gon secretion (11,12). Native GLP-1 also
`slows gastric emptying and reduces food
`intake, which leads to modest weight loss
`(11). However, native GLP-1 is rapidly
`inactivated (half-life 1–2 min) by dipepti-
`dyl peptidase-4 (DPP-4), limiting its ther-
`apeutic potential (13). Exenatide (half-life
`2.4 h) improves glycemic control in com-
`bination with metformin, a sulfonylurea,
`or a thiazolidinedione (14 –18). Despite
`modest weight loss and improved glyce-
`mic control, gastrointestinal (GI) intoler-
`ability and twice-daily administration
`may lead to discontinuation (19).
`Albiglutide (formerly known as alb-
`ugon) is a GLP-1 receptor agonist devel-
`oped through the fusion of two repeats of
`human GLP-1 (7–36) molecules to re-
`combinant human albumin (20). The
`GLP-1 dimer was used to avoid potential
`reductions of the interaction of the GLP-1
`moiety of the monomer with its receptor
`in the presence of albumin. A single
`amino acid substitution (ala83gly) ren-
`ders the molecule resistant to DPP-4. The
`structure of albiglutide provides an ex-
`tended half-life (⬃5 days), which may al-
`low weekly or less frequent dosing.
`Furthermore, albiglutide is relatively im-
`permeant to the central nervous system
`(21), which may have implications for GI
`tolerability. In nonclinical studies, albig-
`lutide stimulated cAMP production
`through the GLP-1 receptor and induced
`insulin secretion from INS-1 cells in vitro
`and in animal models (21–22). It also de-
`layed gastric emptying and reduced food
`intake in rodents (21–23).
`This study was designed to explore a
`wide range of doses (4 –100 mg) and
`schedules (weekly to monthly) to assess
`glycemic control and adverse event pro-
`files for albiglutide. Exenatide was in-
`cluded as an open-label reference to
`provide clinical perspective for a GLP-1
`receptor agonist.
`
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`
`Rosenstock and Associates
`
`Dataaremeans⫾SDfortheintent-to-treatpopulation,lastobservationcarriedforward.*Exenatidewasusedtoprovideclinicalreference;nostatisticalanalyseswereconducted.†P⬍0.05vs.placebo.
`
`⫺0.10⫾2.90⫺0.80⫾2.48⫺0.47⫾3.12⫺0.72⫾1.68⫺1.44⫾2.03†⫺1.28⫾2.43⫺1.58⫾2.06†⫺1.32⫾3.52†⫺0.72⫾2.77⫺1.22⫾3.50†
`
`9.8⫾3.8
`
`9.3⫾2.7
`
`10.0⫾3.2
`
`9.5⫾3.3
`
`10.2⫾2.7
`
`9.6⫾3.1
`
`9.5⫾2.9
`
`10.9⫾3.9
`
`9.5⫾2.4
`
`9.9⫾3.7
`
`33
`
`34
`
`32
`
`32
`
`28
`
`29
`
`32
`
`32
`
`33
`
`47
`
`⫺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†
`
`8.1⫾1.0
`
`33
`
`100mg
`
`7.9⫾0.8
`
`35
`
`50mg
`
`7.9⫾0.7
`
`34
`
`50mg
`
`Monthly
`
`8.0⫾1.0
`
`32
`
`30mg
`
`Biweekly
`
`8.2⫾1.0
`
`30
`
`15mg
`
`8.0⫾0.9
`
`29
`
`30mg
`
`Albiglutide
`
`8.0⫾0.9
`
`34
`
`15mg
`
`Weekly
`
`8.2⫾1.0
`
`34
`
`4mg
`
`8.0⫾0.9
`
`34
`
`5–10␮g
`twicedaily,
`Exenatide*
`
`7.8⫾0.9
`
`50
`
`Placebo
`
`baseline(%)
`weeksvs.
`⌬FPGat16
`(mmol/l)
`
`BaselineFPG
`n(FPGdata)
`
`baseline
`weeksvs.
`⌬A1Cat16
`BaselineA1C(%)
`n(A1Cdata)
`
`RESEARCH DESIGN AND
`METHODS — This phase II trial was a
`prospective randomized double-blind pla-
`cebo-controlled parallel-group study con-
`ducted between April 2007 and May 2008
`at 118 sites in the U.S. (n ⫽ 106), Mexico
`(n ⫽ 9), Chile (n ⫽ 2), and the Dominican
`Republic (n ⫽ 1) (online appendix 1, avail-
`able at http://care.diabetesjournals.org/cgi/
`content/full/dc09-0366/DC1). Men and
`women of non-childbearing potential (age
`18–75 years) were eligible for inclusion if
`diagnosed with type 2 diabetes ⱖ3 months
`before screening. Subjects were drug naïve
`(diet and exercise) or treated with met-
`formin monotherapy and stable for ⬎3
`months before prescreening (1 week prior
`to screening visit). Only subjects treated
`with metformin monotherapy were eligible
`for the exenatide arm (consistent with label-
`ing). Additional inclusion criteria included
`BMI ⱖ20 and ⱕ40 kg/m2 and A1C at
`screening ⱖ7 and ⱕ10%.
`Exclusion criteria included any oral
`antidiabetic monotherapy (except met-
`formin) ⱕ3 months prior to screening or
`insulin ⬍1 month prior to screening and
`not used for ⬎7 days; pancreatitis within
`5 years; significant cardiovascular, cere-
`brovascular, renal, or hepatobiliary dis-
`eases; fasting serum triglycerides ⱖ800
`mg/dl (9 mmol/l) at screening; or hema-
`tological profiles considered to be clin-
`ically significant. Lipid-lowering
`medications must have been maintained
`at the same dose for 3 months prior to
`enrollment, and no prescription or over-
`the-counter weight-loss drugs were
`permitted.
`The study protocol was approved by
`an institutional review board and con-
`ducted in accordance with the Declara-
`tion of Helsinki. Written informed
`consent was obtained from all subjects at
`prescreening. A data safety monitoring
`committee of independent experts as-
`sessed safety data on an ongoing basis.
`
`Randomization
`Subjects were randomized into 1 of 10
`treatment arms: double-blind placebo
`(matched to albiglutide arms); albiglutide
`weekly (4, 15, or 30 mg), every 2 weeks
`(biweekly; 15, 30, or 50 mg), or monthly
`(50 or 100 mg); or open-label exenatide
`(5 ␮g twice daily for 4 weeks followed by
`12 weeks of 10 ␮g twice daily). Albig-
`lutide (formulated in 10 mmol/l sodium
`phosphate, 4.2% trehalose, 2.8% manni-
`tol, 0.01% polysorbate-80) and placebo
`(same formulation without active princi-
`ple) were administered in the physician’s T
`
`able1—Changefrombaselineinglycemicparametersat16weeks
`
`care.diabetesjournals.org
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`

`0
`
`-0.2
`
`-0.4
`
`-0.6
`
`-0.8
`
`-1
`
`-1.2
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`A
`
`Change in A1C (%)
`
`B
`
`Percent attaining A1C goal (<7%)
`
`0.5
`
`0
`
`-0.5
`
`-1
`
`-1.5
`
`-2
`
`-2.5
`
`C
`
`Change in FPG from baseline (mmol/l)
`
`Albiglutide dose regimen study
`
`office over the course of 16 weeks. Sub-
`jects receiving 4 mg albiglutide were
`given 1.0 ml (4 mg/ml solution). Subjects
`receiving 15, 30, or 50 mg albiglutide
`were given 0.32, 0.65, or 1.0 ml (50
`mg/ml solution). Subjects receiving 100
`mg albiglutide were given two 1.0-ml in-
`jections (50 mg/ml solution, ⬎1 inch
`apart). Placebo volumes were matched to
`active treatment. Albiglutide/placebo in-
`jections were subcutaneous to the abdo-
`men using 30-G needles. Subjects were
`observed for ⱖ30 min to monitor for in-
`jection site reactions. Subjects receiving
`exenatide initiated treatment in the phy-
`sician’s office and subsequently self-
`administered according to the package
`insert. After 16 weeks, subjects entered an
`11-week washout phase to assess safety
`and immunogenicity.
`
`Assessments
`On therapy. A1C and fasting plasma glu-
`cose (FPG) measurements were per-
`formed at screening, baseline, and weeks
`2 (FPG only), 4, 5, 7, 8, 9, 12, 15, and 16.
`Fasting fructosamine, C-peptide, gluca-
`gon, insulin, and lipids were measured at
`baseline and weeks 5, 8, 12, and 16.
`␤-Cell function was calculated using ho-
`meostasis model assessment (24).
`Adverse event assessments and safety
`analyses were conducted throughout the
`study. Nausea and vomiting were moni-
`tored for occurrence and duration. Im-
`munogenicity samples were taken at
`baseline and weeks 1, 4, 8, 12, and 16 and
`were screened for anti-albiglutide anti-
`bodies via ELISA (20). Plasma samples
`were collected to characterize the phar-
`macokinetics of albiglutide, quantified by
`ELISA (20) at baseline and at weeks 4, 5,
`7, 8, 9, 12, 15, and 16. Population phar-
`macokinetics analysis was performed us-
`ing a nonlinear mixed-effect modeling
`approach with NONMEM software
`(ICON Development Solutions, Ellicott
`City, MD).
`Eleven-week washout. A1C, FPG,
`and albiglutide concentrations were ob-
`tained at weeks 17, 18, 20, 23, and 27;
`fasting fructosamine, C-peptide, gluca-
`gon, insulin, and lipid profiles were ob-
`tained at weeks 20 and 27; and
`immunogenicity assessments were exam-
`ined at weeks 20, 23, and 27.
`
`Statistical analysis
`The primary objective was to evaluate the
`dose response of albiglutide for safety and
`efficacy. With 30 subjects planned in each
`arm, a two-sided 95% CI for each group
`
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`
`Placebo Exenatide
`
`Albiglutide
`weekly (mg)
`4
`15 30
`
`Albiglutide
`biweekly (mg)
`30
`15
`50
`
`Albiglutide
`monthly (mg)
`50 100
`
`*
`
`34
`8.0
`7.4
`
`50
`7.8
`7.7
`
`†
`29
`34
`34
`8.2 8.0 8.0
`8.0 7.5 7.1
`
`30
`8.2
`7.6
`
`32
`8.0
`7.2
`
`†
`34
`7.9
`7.1
`
`†
`33
`35
`7.9 8.1
`7.4 7.2
`
`n
`Baseline A1C (%)
`Week 16 A1C (%)
`
`52%
`
`53%
`
`50%
`
`48%
`
`35%
`
`35%
`
`20%
`
`18%
`
`27%
`
`23%
`
`Placebo
`
`Exenatide
`
`15 30
`4
`Albiglutide
`weekly (mg)
`
`50
`15
`30
`Albiglutide
`biweekly (mg)
`
`50 100
`Albiglutide
`monthly (mg)
`
`* †††
`
`Placebo
`Exenatide
`Albiglutide 30 mg weekly
`Albiglutide 50 mg biweekly
`Albiglutide 100 mg monthly
`
`-3
`
`0
`
`2
`
`4
`
`6
`
`8
`Week
`
`10
`
`12
`
`14
`
`16
`
`Figure 1—Effects of albiglutide on glycemic parameters. A: The reduction in A1C from baseline
`at 16 weeks. Data are presented as mean change from baseline (–SE). B: The proportion of subjects
`achieving ADA A1C target of ⬍7%. Data are presented as % at goal. C: Change in fasting plasma
`glucose over time. Data are presented as mean change from baseline (⫾SE). *No formal statistical
`comparisons versus exenatide (open label) were conducted. †P ⬍ 0.05 vs. placebo.
`
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`
`Rosenstock and Associates
`
`the 16-week end point for each of the
`highest doses (Fig. 1C). Statistically sig-
`nificant reductions were seen for FPG
`compared with placebo at week 16
`(⫺1.38 mmol/l [P ⬍ 0.02], ⫺1.16
`mmol/l [P ⬍ 0.03], and ⫺1.17 mmol/l
`[P ⬍ 0.03] for 30 mg weekly, 50 mg bi-
`weekly, and 100 mg monthly albiglutide
`doses, respectively). The 4- and 15-mg
`weekly dose regimens of albiglutide re-
`duced FPG but were less effective. The
`greatest fluctuations in FPG over time
`were observed in subjects receiving albi-
`glutide 100 mg monthly (Fig. 1C). Ex-
`enatide was associated with a relatively
`consistent FPG profile over time that was
`numerically less than FPG reductions
`seen with the highest doses of albiglutide
`(Fig. 1C).
`Neither fasting insulin nor glucagon
`levels were consistently or significantly al-
`tered. Small improvements in ␤-cell func-
`tion (assessed by homeostasis model
`assessment of ␤-cell function) were noted
`in subjects receiving albiglutide (online
`appendix 4).
`There was no significant difference in
`weight reduction among groups. A con-
`sistent trend in weight reduction was
`noted with average weight loss ranging
`from ⫺1.1 to ⫺1.7 kg in subjects receiv-
`ing the highest albiglutide dose in each
`schedule. These reductions were numer-
`ically greater than those for subjects re-
`ceiving placebo (⫺0.7 kg) but less than
`those for subjects receiving exenatide
`(⫺2.4 kg). Albiglutide and exenatide
`tended to reduce mean systolic and dia-
`stolic blood pressure but did not signifi-
`cantly change the plasma lipoprotein
`profile (online appendix 4).
`
`Safety and tolerability
`The percentage of subjects reporting at
`least one adverse event was similar across
`groups (67– 85%). The most frequently
`reported adverse events included nausea
`(11.8 –54.3%), vomiting (0 – 41.2%),
`headache (5.9 –23.5%), dizziness (5.7–
`14.3%), nasopharyngitis (5.7–11.4%),
`back pain (0 –14.3%), influenza (0 –
`9.7%), upper respiratory tract infections
`(0 –15.2%), and local skin reactions (2.9 –
`28.6%) (online appendix 5).
`The proportion of subjects who expe-
`rienced nausea and/or vomiting was
`lower with administration of ⱕ30 mg al-
`biglutide compared with the proportion
`of subjects receiving higher doses. In the
`30-mg weekly arm, 29.0% of subjects ex-
`perienced nausea and/or vomiting, com-
`pared with 54.3% in the 50-mg biweekly
`
`mean response had a half-width of 0.36%
`on the A1C scale, assuming a standard
`deviation of 1.00%.
`The primary efficacy end point was
`change from baseline A1C at week 16 ver-
`sus placebo across different doses within
`each schedule (weekly, biweekly, and
`monthly). The primary analysis was an AN-
`COVA model with main effects for group
`and prior metformin therapy, adjusting for
`baseline A1C. Dose response was evaluated
`using contrasts within the ANCOVA model
`framework. Pairwise comparisons were
`performed in the same ANCOVA model.
`Secondary end points were similarly ana-
`lyzed. Responder analysis and incidence of
`hypoglycemia were summarized by group
`statistics. No formal statistical comparisons
`versus exenatide were conducted. Safety
`and tolerability data were categorically
`collected.
`Comparisons were made on the intent-
`to-treat population, defined as all randomly
`assigned subjects with at least one postbase-
`line assessment of the primary end point,
`using last observation carried forward. The
`safety population included all randomized
`subjects who received at least one dose of
`any medication. An interim analysis was
`conducted at 8 weeks for administrative
`purposes by an independent statistical anal-
`ysis group; blinding was retained for study
`investigators and study personnel with
`daily operational responsibility. No formal
`interim inferential hypothesis testing was
`conducted; the study conduct was unal-
`tered based on the results of the interim
`analysis.
`
`RESULTS
`
`Subject disposition and baseline
`characteristics
`A total of 774 subjects were screened. Of
`361 subjects randomized, 356 received
`treatment and were included in the safety
`analysis, 345 were included in the efficacy
`analysis, and 255 completed the 16-week
`trial. Withdrawal rates were similar across
`groups (online appendix 2); the most fre-
`quent reason for withdrawal was adverse
`events. Adverse events occurring in at least
`one subject leading to withdrawal included
`hyperglycemia (0–11.8%, n ⫽ 24, mostly
`in placebo and lower-dose groups), GI
`events (0–11.4%, n ⫽ 10, across groups),
`injection site events (0 –9.7%, n ⫽ 11,
`mostly in higher-dose groups), and hyper-
`triglyceridemia (0–5.7%, n ⫽ 2 of 35 re-
`ceiving 50 mg albiglutide biweekly, deemed
`unrelated to study drug; 0% in other
`groups). Other reasons for withdrawal in-
`
`cluded loss to follow-up, protocol viola-
`tions, and voluntary withdrawal.
`Baseline demographics and charac-
`teristics were comparable across groups
`(online appendix 3). Mean duration of di-
`abetes was 4.9 years. Baseline A1C levels
`(mean 8.0%) were evenly distributed
`across arms. A similar proportion of sub-
`jects receiving placebo or albiglutide were
`drug naïve (25.7–34.4%) or receiving
`metformin monotherapy. All subjects re-
`ceiving exenatide were on metformin
`monotherapy. The groups were similar in
`terms of race/ethnicity (43.8 –71.0% Cau-
`casian; 87.1 and 12.9% of subjects were
`from U.S. and Latin American clinics, re-
`spectively), and the rates of dyslipidemia,
`hypertension, and coronary artery disease
`were 50.0 – 80.0, 47.1– 67.6, and
`0 –15.2%, respectively.
`
`Efficacy
`After 16 weeks, albiglutide significantly
`reduced A1C in a generally dose-
`dependent manner within each dose
`schedule (Table 1) (Fig. 1A). Mean A1C
`reductions from baseline in subjects re-
`ceiving the highest dose in each treatment
`schedule were ⫺0.87, ⫺0.79, and
`⫺0.87% for 30 mg weekly, 50 mg bi-
`weekly, and 100 mg monthly, respec-
`tively, versus placebo (⫺0.17%) or
`exenatide (⫺0.54%). A1C reductions
`(based on ANCOVA model) for the high-
`est doses compared with placebo were
`statistically significant: 30 mg weekly,
`⫺0.62% (95% CI ⫺1.03 to ⫺0.22), P ⬍
`0.003; 50 mg biweekly, ⫺0.57% (⫺0.96
`to ⫺0.19), P ⬍ 0.003; and 100 mg
`monthly, ⫺0.60% (⫺0.99 to ⫺0.22),
`P ⬍ 0.002. Numerically greater reduc-
`tions in A1C were observed in subjects
`with baseline A1C ⱖ8.5%.
`The proportion of subjects achieving
`the ADA target A1C (⬍7.0%) at week 16
`increased with increasing doses of albig-
`lutide within each schedule; similar pro-
`portions of subjects achieved target A1C
`at the highest albiglutide dose among the
`three schedules. More subjects receiving
`albiglutide 30 mg weekly (52%), 50 mg
`biweekly (53%), and 100 mg monthly
`(48%) achieved A1C ⬍7.0% compared
`with subjects receiving placebo (20%)
`and exenatide (35%) (Fig. 1B).
`The time course of albiglutide-
`induced changes in FPG demonstrated
`that each schedule elicited a dose-
`dependent FPG reduction over 16 weeks,
`with no changes in FPG observed with
`placebo. Rapid reductions in FPG were
`observed, with similar FPG reductions at
`
`care.diabetesjournals.org
`
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`
`Albiglutide dose regimen study
`
`
`
`1 21
`
`3 4 5 6
`
`7 8 9 10 11 12 13 14 15 16
`Week
`
`
`4545
`
`4040
`
`3535
`
`3030
`
`2525
`
`2020
`
`1515
`
`1010
`
`05
`05
`
`D
`
`Nausea and/or vomiting (%)
`
`45A
`45
`
`4040
`
`3535
`
`3030
`
`2525
`
`2020
`
`1515
`
`1010
`
`Nausea and/or vomiting (%)
`
`
`
`1 21
`
`3 4 5 6
`
`7 8 9 10 11 12 13 14 15 16
`Week
`
`05
`05
`
`45E
`40
`35
`30
`25
`20
`15
`
`1010
`
`Nausea and/or vomiting (%)
`
`
`
`1 21
`
`3 4 5 6
`
`7 8 9 10 11 12 13 14 15 16
`Week
`
`05
`05
`
`Figure 2—Time course of nausea and vomiting as adverse events. The
`percentage of subjects experiencing vomiting with or without nausea (o)
`or nausea (䡺) adverse events during each week of the 16-week trial for
`albiglutide 30 mg weekly (A), albiglutide 50 mg biweekly (B), albig-
`lutide 100 mg monthly (C), placebo (D), and exenatide (E).
`
`45B
`45
`
`4040
`
`3535
`
`3030
`
`2525
`
`2020
`
`1515
`
`1010
`
`Nausea and/or vomiting (%)
`
`
`
`1 21
`
`3 4 5 6
`
`7 8 9 10 11 12 13 14 15 16
`Week
`
`05
`05
`
`45C
`45
`
`4040
`
`3535
`
`3030
`
`2525
`
`2020
`
`1515
`
`1010
`
`Nausea and/or vomiting (%)
`
`
`
`1 21
`
`3 4 5 6
`
`7 8 9 10 11 12 13 14 15 16
`Week
`
`05
`05
`
`group and 55.9% in the 100-mg monthly
`group. The percentage of exenatide sub-
`jects who experienced nausea and/or
`vomiting also was higher (45.7%) than in
`the 30-mg weekly albiglutide group.
`Examination of the time course (Fig.
`2) of nausea and/or vomiting revealed that
`the proportion of subjects experiencing
`these adverse events each week was low in
`the 30-mg weekly arm (⬍10%) and de-
`clined over the course of the study, with
`no reports of nausea or vomiting after 8
`weeks (Fig. 2A). Although the proportion
`of nausea and/or vomiting for the 50-mg
`biweekly dose was greater than for the
`30-mg weekly dose, it also declined over
`the study period (Fig. 2B). Subjects re-
`
`ceiving the 100-mg monthly dose also ex-
`perienced higher rates of nausea and/or
`vomiting, with peak incidence occurring
`following each monthly dose administra-
`tion. The overall rate was higher for
`100-mg monthly than for the other albi-
`glutide groups (Fig. 2C). The incidence of
`nausea and/or vomiting with exenatide
`reached 20% by week 2, increased at
`week 5 to a peak incidence of 29% (due to
`label-based titration), and also declined
`over the study period (Fig. 2E).
`Other adverse events were less com-
`mon than GI-related events and were
`similar across groups with no dose-
`dependent trends. Documented hypogly-
`cemia was not increased with albiglutide
`
`(0 –3.1%) relative to placebo (3.9%) and
`exenatide (2.9%). Cardiac-related ad-
`verse events (eight subjects; six assessed
`as severe) were distributed across groups,
`with no dose-dependent trends (online
`appendix 5). No episodes of pancreatitis
`were reported.
`Eight subjects (2.5%) had confirmed
`positive anti-albiglutide antibodies at
`least once in the placebo and albiglutide
`arms after baseline measurement. How-
`ever, two subjects tested positive prior to
`albiglutide treatment, and one subject
`who tested positive received placebo. The
`remaining five albiglutide-positive sub-
`jects were detected in the weekly and bi-
`weekly arms. The appearance of anti-
`
`1884
`
`DIABETES CARE, VOLUME 32, NUMBER 10, OCTOBER 2009
`
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`
`Rosenstock and Associates
`
`ment of immediate hypersensitivity reac-
`tions. In this study, anti-albiglutide
`antibodies were detected in 2.5% (n ⫽ 8)
`of subjects. However, the observation that
`positive titers of anti-albiglutide antibod-
`ies were detected in three subjects at base-
`line suggests that the immunogenicity
`rate may be overestimated. Exenatide,
`which has 53% homology to human
`GLP-1 (14), is associated with antibody
`development following administration
`with twice-daily (15–18) and weekly (25)
`formulations (⬎40%). Antibody forma-
`tion may attenuate efficacy, especially
`among patients developing high levels of
`anti-exenatide antibodies (25).
`There are limitations to this phase II
`study. First, the number of subjects in
`each arm is relatively small compared
`with phase III studies. Second, relative to
`the number of subjects, the dropout rate
`was high owing to adverse events, loss to
`follow-up, and voluntary withdrawals.
`Third, the duration of active treatment
`was 16 weeks, so the magnitude or dura-
`bility of response cannot be fully appreci-
`ated. Fourth, no escalating doses were
`tested for biweekly and monthly dosing,
`which may have attenuated GI adverse
`events and FPG fluctuations. Finally, be-
`cause exenatide was administered open
`label, formal statistical comparisons were
`not conducted between exenatide and
`albiglutide.
`In conclusion, albiglutide improved
`glucose control in a dose-dependent man-
`ner when given weekly and biweekly.
`Higher monthly doses of albiglutide were
`efficacious, but their use was constrained
`by the higher frequency of GI-related ad-
`verse events. Weekly albiglutide signifi-
`cantly improved glycemic control with an
`acceptable safety and tolerability profile
`and modest weight loss without increas-
`ing the risk of hypoglycemia or immuno-
`logical response in subjects with type 2
`diabetes. Future studies may elucidate
`whether titration dosing or biweekly
`scheduling could be options for patients
`who respond to and tolerate the initial
`weekly regimen.
`
`Acknowledgments — This study was spon-
`sored by GlaxoSmithKline, Middlesex, U.K.
`J.Ro. has received research grants and con-
`sulting honoraria for serving on scientific ad-
`visory boards from GlaxoSmithKline. J.Re. has
`received research grants from and acted as a
`consultant for GlaxoSmithKline. M.B., F.Y., and
`M.S. are employees/stockholders of Glaxo-
`SmithKline. No other potential conflicts of in-
`terest relevant to this article were reported.
`
`albiglutide antibodies was largely
`transient: one subject remained positive
`at week 27. Antibodies were non-
`neutralizing and low titer and showed
`cross-reactivity with GLP-1 in four of five
`subjects. There was no obvious associa-
`tion between the presence of anti-
`albiglutide antibodies and either efficacy
`or safety.
`Injection site local skin reactions,
`most of which were small, were observed
`in the study and were more common in
`the albiglutide groups (2.9 –28.6%) com-
`pared with placebo (5.9%) and exenatide
`(2.9%). Injection site reactions tended to
`occur once per person in subjects receiv-
`ing 30 mg albiglutide and approximately
`twice per person in subjects receiving
`higher albiglutide doses. Skin reactions
`were not associated with positive IgE an-
`tibodies or neutralizing antibodies and
`did not worsen upon repeated dosing or
`exhibit dose dependency. No systemic al-
`lergic reactions attributable to albiglutide
`were observed.
`
`Pharmacokinetics
`Albiglutide exhibited a plasma half-life of
`⬃5 days. Steady-state albiglutide levels
`were reached within ⬃4 to 5 weeks of the
`first dose (online appendix 6). Greater
`peak/trough fluctuations in circulating al-
`biglutide concentrations were observed
`with less frequent administration of
`higher doses.
`
`CONCLUSIONS — In this study, the
`dose- and time-dependent effects of albi-
`glutide, a long-acting GLP-1 receptor ag-
`onist, was evaluated to identify potential
`dose regimens for future studies. Within
`each dose schedule, albiglutide was asso-
`ciated with generally dose-dependent
`A1C reductions that were significantly
`different from placebo. Maximum doses
`in each schedule (albiglutide 30 mg
`weekly, 50 mg biweekly, and 100 mg
`monthly) elicited similar responses in
`A1C, providing meaningful reductions
`within the range of ⬃0.8 – 0.9% from a
`mean baseline A1C of 8.0%.
`Albiglutide also significantly reduced
`FPG at week 16 compared with placebo,
`with reductions observed at the time of
`the first assessment (2 weeks postdose).
`In a previous study, FPG reductions were
`observed as early as 2 days following a
`single dose (20).
`Variability in glycemic response ap-
`peared to be related to circulating concen-
`trations of albiglutide. With a plasma half-
`life of ⬃5 days and at doses sufficient to
`
`achieve consistent therapeutic response
`(i.e., 30 mg), weekly dosing provided
`consistent FPG reduction. Greater FPG
`fluctuations were observed following bi-
`weekly or monthly dosing, despite similar
`A1C reductions.
`Albiglutide 30-mg weekly dosing
`elicited steady and consistent improve-
`ments in FPG reductions, with a more fa-
`vorable nausea/vomiting profile than
`exenatide. When dosed biweekly, 50 mg
`albiglutide also improved glycemic in-
`dexes but with higher GI adverse event
`rates, possibly related to the higher initial
`dose. In all dosing schedules, rates of nau-
`sea and vomiting declined over time.
`However, when dosed monthly, albig-
`lutide did not produce stable FPG reduc-
`tions between dosing and was associated
`with higher GI event rates. The increase in
`FPG fluctuation and GI events in the bi-
`weekly and monthly regimens is likely
`due to fluctuations in plasma albiglutide
`concentrations resulting from less fre-
`quent dosing. An escalating-dose titration
`for the biweekly regimen might have re-
`sulted in a lower frequency of GI events.
`This approach may be tested in future
`studies to explore the possibility of using
`biweekly dosing as a maintenance option
`in patients who respond well and tolerate
`the initial weekly regimen.
`Mechanistically, the reasons for dif-
`ferences in the tolerability of albiglutide
`and exenatide are unknown but may be
`due to differences in pharmacokinetics,
`including gradual absorption (Tmax is ⬃3
`days vs. 2.1 h for albiglutide and ex-
`enatide, respectively) and a long plasma
`half-life of ⬃5 days resulting in a steady
`state achieved after 4 –5 doses for 30 mg
`albiglutide weekly. The slow accumula-
`tion of albiglutide may ameliorate GI
`intolerability often observed with ex-
`enatide, and albiglutide’s relative imper-
`meance to the central nervous system may
`result in a more benign profile with re-
`spect to nausea and vomiting than ex-
`enatide (21).
`Weight loss was similar across albig-
`lutide arms and numerically less than
`with exenatide, which had a higher base-
`line BMI. Exploratory post hoc analyses
`indicated that there was no obvious cor-
`relation between reduction in A1C and
`weight loss for all albiglutide doses (data
`not shown). However, larger and longer-
`term studies will determine the true effect
`on weight and cardiometabolic parameters.
`Immunogenicity was closely moni-
`tored owing to the possible appearance of
`neutralizing antibodies or the develop-
`
`care.diabetesjournals.org
`
`DIABETES CARE, VOLUME 32, NUMBER 10, OCTOBER 2009
`
`1885
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`Narayan KM. Improvements in diabetes
`processes of care and intermediate out-
`comes: United States, 1988 –2002. Ann
`Intern Med 2006;144:465– 474
`8. Ong KL, Cheung BM, Wong LY, Wat NM,
`Tan KC, Lam KS. Prevalence, treatment,
`and control of diagnosed diabetes in the
`U.S. National Health and Nutrition Exam-
`ination Survey 1999 –2004. Ann Epide-
`miol 2008;18:222–229
`9. Carver C. Insulin treatment and the prob-
`lem of weight gain in type 2 diabetes. Di-
`abetes Educ 2006;32:910 –917
`10. Kahn SE, Haffner SM, Heise MA, Herman
`WH, Holman RR, Jones NP, Kravitz BG,
`Lachin JM, O’Neill MC, Zinman B, Viberti
`G; ADOPT Study Group. Glycemic dura-
`bility of rosiglitazone, metformin, or gly-
`buride monotherapy. N Engl J Med 2006;
`355:2427–2443
`11. Deacon CF, Pridal L, Klarskov L, Olesen
`M, Holst JJ. Glucagon-like peptide 1 un-
`dergoes differential tissue-specific metab-
`olism in the anesthetized pig. Am J
`Physiol 1996;271:E458 –E464
`12.