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
`
`Effects of Once-Weekly Dosing of a Long-
`Acting Release Formulation of Exenatide
`on Glucose Control and Body Weight in
`Subjects With Type 2 Diabetes
`
`1
`DENNIS KIM, MD
`1
`LEIGH MACCONELL, PHD
`1
`DONGLIANG ZHUANG, PHD
`PRAJAKTI A. KOTHARE, PHD
`
`2
`
`MICHAEL TRAUTMANN, MD
`1
`MARK FINEMAN, MS
`KRISTIN TAYLOR, PHD
`
`1
`
`3
`
`OBJECTIVE — In patients with type 2 diabetes, exenatide reduces A1C, postprandial and
`fasting glucose, and weight. In this study we investigated the effects of continuous exenatide
`administration from a long-acting release (LAR) formulation.
`
`RESEARCH DESIGN AND METHODS — In this randomized, placebo-controlled
`phase 2 study, exenatide LAR (0.8 or 2.0 mg) was administered subcutaneously once weekly for
`15 weeks to subjects with type 2 diabetes (n ⫽ 45) suboptimally controlled with metformin
`(60%) and/or diet and exercise (40%): 40% female, A1C (mean ⫾ SD) 8.5 ⫾ 1.2%, fasting
`plasma glucose 9.9 ⫾ 2.3 mmol/l, weight 106 ⫾ 20 kg, and diabetes duration 5 ⫾ 4 years.
`
`RESULTS — From baseline to week 15, exenatide LAR reduced mean ⫾ SE A1C by ⫺1.4 ⫾
`0.3% (0.8 mg) and ⫺1.7 ⫾ 0.3% (2.0 mg), compared with ⫹0.4 ⫾ 0.3% with placebo LAR (P ⬍
`0.0001 for both). A1C of ⱕ7% was achieved by 36 and 86% of subjects receiving 0.8 and 2.0 mg
`exenatide LAR, respectively, compared with 0% of subjects receiving placebo LAR. Fasting
`plasma glucose was reduced by ⫺2.4 ⫾ 0.9 mmol/l (0.8 mg) and ⫺2.2 ⫾ 0.5 mmol/l (2.0 mg)
`compared with ⫹1.0 ⫾ 0.7 mmol/l with placebo LAR (P ⬍ 0.001 for both). Exenatide LAR
`reduced self-monitored postprandial hyperglycemia. Subjects receiving 2.0 mg exenatide LAR
`had body weight reductions (⫺3.8 ⫾ 1.4 kg) (P ⬍ 0.05), whereas body weight was unchanged
`with both placebo LAR and the 0.8-mg dose. Mild nausea was the most frequent adverse event.
`No subjects treated with exenatide LAR withdrew from the study.
`
`CONCLUSIONS — Exenatide LAR offers the potential of 24-h glycemic control and weight
`reduction with a novel once-weekly treatment for type 2 diabetes.
`
`I n the U.S., diabetes affects ⬎21 million
`
`people, with combined direct and in-
`direct costs of $132 billion annually
`(1). Treatment of this chronic, progres-
`sive disease often requires daily blood
`glucose monitoring and multiagent treat-
`ment regimens. However, despite the
`
`Diabetes Care 30:1487–1493, 2007
`
`many medications available, the majority
`of people with type 2 diabetes are unable
`to maintain long-term glycemic control
`(2). The high prevalence of obesity in this
`population compounds this problem, as
`obesity is a risk factor for developing type
`2 diabetes and worsens hyperglycemia
`
`● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●
`
`From the 1Amylin Pharmaceuticals, Inc., San Diego, California; 2Eli Lilly and Company, Indianapolis,
`Indiana; and 3Eli Lilly and Company, Hamburg, Germany.
`Address correspondence and reprint requests to Dennis Kim, MD, Amylin Pharmaceuticals, Inc., 9360
`Towne Centre Dr., Suite 110, San Diego, CA 92121. E-mail: dkim@amylin.com.
`Received for publication 20 November 2006 and accepted in revised form 28 February 2007.
`Published ahead of print at http://care.diabetesjournals.org on 12 March 2007. DOI: 10.2337/dc06-2375.
`Clinical trial reg. no. NCT00103935, clinicaltrials.gov.
`D.K., L.M., D.Z., M.F., and K.T. are employees and stockholders of Amylin Pharmaceuticals. P.K. and
`M.T. are employees and shareholders of Eli Lilly.
`Abbreviations: BID, twice daily; GLP-1, glucagon-like peptide-1; ITT, intention to treat; LAR, long-acting
`release.
`A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion
`factors for many substances.
`© 2007 by the American Diabetes Association.
`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.
`
`and insulin resistance (3,4). Furthermore,
`use of many antihyperglycemic medica-
`tions is associated with weight gain (5).
`Incretin hormones, intestinally de-
`rived hormones that stimulate glucose-
`dependent insulin secretion in response
`to food intake, play an important role in
`glucose homeostasis (6). Glucagon-like
`peptide-1 (GLP-1) is an incretin hormone
`with multiple glucoregulatory actions, in-
`cluding enhancement of glucose-
`dependent insulin secretion, suppression
`of inappropriately elevated glucagon se-
`cretion, slowing of gastric emptying, and
`reduction of food intake and body weight
`(6 –9). Postprandial secretion of GLP-1 is
`reduced in patients with type 2 diabetes
`(10), suggesting that the GLP-1 signaling
`pathway is an attractive therapeutic tar-
`get. However, GLP-1 is rapidly degraded
`by the enzyme dipeptidyl peptidase-IV
`and has a relatively short half-life (⬃2
`min) (6). The therapeutic potential of the
`GLP-1 pathway has led to the develop-
`ment of a class of compounds called in-
`cretin mimetics that share several
`glucoregulatory actions with GLP-1 but
`are resistant to dipeptidyl peptidase-IV
`degradation.
`Exenatide, with a half-life of 2.4 h and
`clinical effects lasting up to 8 h, is the first
`clinically available incretin mimetic (10 –
`16). Compared with GLP-1 in preclinical
`studies, exenatide has a 20- to 30-fold
`longer half-life and 5,500-fold greater po-
`tency in lowering plasma glucose (7,17).
`In placebo-controlled clinical trials in pa-
`tients not achieving adequate glycemic
`control with metformin, a sulfonylurea,
`or a combination of both, 30 weeks of 10
`␮g subcutaneous exenatide twice daily
`(BID) resulted in statistically significant
`reductions in mean A1C, body weight,
`fasting plasma glucose, and postprandial
`plasma glucose excursions (18 –20). Pa-
`tients who continued in open-label exten-
`sion studies for a total of 1.5 years (82
`weeks) of BID exenatide treatment had
`sustained A1C reductions and progres-
`sive body weight reductions (21). In
`open-label comparator trials with insulin
`
`DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007
`
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`Exenatide LAR in subjects with type 2 diabetes
`
`glargine or 70/30 insulin aspart, ex-
`enatide treatment resulted in A1C reduc-
`tions that were similar to those with
`insulin but with better postprandial glu-
`cose control and body weight reduction
`instead of weight gain (22,23). Mild-to-
`moderate nausea, which decreased over
`time, was the most common adverse
`event associated with exenatide in all of
`these trials.
`A long-acting release (LAR) ex-
`enatide formulation for subcutaneous
`injection in patients with type 2 diabe-
`tes is under development to determine
`whether superior glycemic control can
`be achieved when exenatide is continu-
`ously present, compared with BID ex-
`enatide, which may not provide
`complete coverage after midday meals
`and overnight. In this report, we de-
`scribe the effects of once-weekly subcu-
`taneous administration of exenatide
`LAR for 15 weeks on glycemic parame-
`ters, weight, pharmacokinetics, safety,
`and tolerability in patients with type 2
`diabetes.
`
`RESEARCH DESIGN AND
`METHODS — Subjects enrolled in
`this study were 18 –75 years of age, had
`type 2 diabetes treated for at least 3
`months before screening with diet modi-
`fication with exercise (i.e., taking no an-
`tidiabetes agent) and/or metformin, A1C
`of 7.1–11.0%, fasting plasma glucose
`⬍14.4 mmol/l, and BMI 25– 45 kg/m2.
`All of the subjects treated with metformin
`(total daily dose ranging from 500 to
`2,550 mg) continued to receive the same
`dose throughout the study, with the ex-
`ception of a subject in the 2.0 mg ex-
`enatide LAR arm who discontinued
`metformin and added insulin lispro and
`insulin glargine to her regimen 6 weeks
`after the last dose of study medication.
`Another change in antidiabetes treatment
`occurred when, after 9 weeks of placebo
`LAR, a subject initiated treatment with
`glimepiride (this subject subsequently
`withdrew from the study because of loss
`of glucose control). Subjects who had pre-
`viously received exenatide treatment in a
`clinical trial were excluded from the
`study. Additionally, no subjects were
`treated with exenatide during the trial. A
`common clinical protocol was approved
`for each site by an institutional review
`board. All subjects provided written in-
`formed consent before participation, and
`the study was conducted in accordance
`with the principles described in the Dec-
`laration of Helsinki, including all amend-
`
`1488
`
`ments through the 1996 South Africa
`revision (24).
`In this multicenter subject- and in-
`vestigator-blinded phase 2 study, sub-
`jects (n ⫽ 45) were equally randomized
`to placebo LAR or 0.8 or 2.0 mg ex-
`enatide LAR. Blinded, randomized
`study medication kits with unique
`package numbers were prepared sepa-
`rately and shipped to each clinical site.
`The study-site pharmacist contacted an
`interactive voice response system to
`randomly assign subjects to a treatment
`group and find out which medication
`kit to dispense to each subject. Doses
`were targeted to result in concentra-
`tions previously found to be therapeutic
`with exenatide BID. Subjects under-
`went a 3-day lead-in of 5 ␮g exenatide
`or placebo subcutaneous BID to deter-
`mine whether any subjects randomly
`assigned to exenatide LAR had an acute
`exenatide sensitivity. Then, once-
`weekly subcutaneous injections of 0.8
`or 2.0 mg exenatide LAR or placebo LAR
`were administered at the study sites by
`study personnel for 15 weeks, with no
`changes in preexisting antidiabetes reg-
`imens. Subjects were monitored for ad-
`verse events and pharmacokinetics
`during a subsequent 12-week follow-up
`period during which time no study
`medications were administered. Gener-
`ally, visits were conducted at weekly in-
`tervals. Study recruitment began 16
`February 2005 and follow-up contin-
`ued through 17 October 2005.
`For self-monitored blood glucose
`profiles, subjects were given blood glu-
`cose meters and instructed to perform
`measurements by fingerstick at the finger-
`tip. Preprandial glucose was measured 15
`min before each meal, postprandial glu-
`cose was measured 1.5–2 h after each
`meal, and an additional glucose measure-
`ment was taken at 0300 h. Measurements
`were recorded on 3 separate days for both
`baseline and week 15.
`Exenatide LAR consists of micro-
`spheres composed of exenatide and a
`poly(lactide-coglycolide) polymeric ma-
`trix. Poly(lactide-coglycolide) is a com-
`mon biodegradable medical polymer with
`an extensive history of human use in ab-
`sorbable sutures and extended-release
`pharmaceuticals. After injection, ex-
`enatide is slowly released from the micro-
`spheres through diffusion and erosion.
`Placebo LAR contained 0.5% ammonium
`sulfate instead of exenatide.
`
`End points
`Objectives of this study were to evaluate
`the safety, tolerability, and pharmacoki-
`netics of exenatide LAR. Additional objec-
`tives were to evaluate pharmacodynamic
`(i.e., glucose), A1C, and weight effects of
`exenatide LAR. Safety was assessed by ad-
`verse events, clinical laboratory values,
`physical examination, and electrocardio-
`grams. Adverse events, as reported by the
`subjects or noted by study-site staff inci-
`dentally or as a result of nondirected
`questioning, were categorized as mild if
`transient, requiring no special treatment,
`and not interfering with daily activities
`and as moderate if causing a low level of
`inconvenience, possibly interfering with
`daily activities, and ameliorated by simple
`therapeutic measures. An adverse event
`was categorized as severe if it interrupted
`a subject’s usual daily activities and re-
`quired systemic drug therapy or other
`treatment.
`
`Laboratory values
`Blood to measure plasma exenatide was
`drawn before study medication injec-
`tion. Plasma exenatide concentrations
`were quantitated by a validated en-
`zyme-linked immunosorbent assay (25)
`at LINCO Diagnostic Services (St.
`Charles, MO). A1C was quantitated by
`Quintiles Laboratories (Smyrna, GA)
`using high-performance liquid chroma-
`tography (26,27). Anti-exenatide anti-
`bodies were measured in a fashion
`similar to that described previously (25)
`at LINCO Diagnostic Services.
`
`Statistical analysis
`A sample size of 36 subjects was estimated
`to provide 95% CIs of ⬃65–115 and
`170 –290 pg/ml for the mean exenatide
`concentrations at steady state for 0.8 and
`2.0 mg exenatide LAR, respectively. The
`intent-to-treat (ITT) population com-
`prised all randomized subjects who re-
`ceived at least one injection of lead-in
`medication (n ⫽ 45), whereas the evalu-
`able population consisted of subjects
`from the ITT population who completed
`the study procedures through week 15 in
`compliance with the protocol (n ⫽ 43).
`Descriptive statistics on demographics,
`safety, glycemic end points, and weight
`(i.e., mean values with either SE or SD, as
`appropriate) were provided for the ITT
`population. Descriptive statistics for self-
`monitored blood glucose measurements,
`which contained week 15 measurements,
`were performed for the evaluable popula-
`tion. The proportion of subjects achieving
`
`DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007
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`Kim and Associates
`
`Assessed for
`eligibility (N = 104)
`
`Randomized/
`Intent to Treat
`( = 45)
`
`Excluded (N = 59)
`Did not meet inclusion criteria (N = 49)
`Refused to participate (N = 3)
`Other reasons ( = 7)
`
`( Placebo LAR )
`
`( 0.8 mg exenatide LAR )
`
`( 2.0 mg exenatide LAR)
`
`Sex(%)
`Male
`Female
`Race(%)
`Caucasian
`Black
`Hispani c
`Other
`
`36%
`64%
`
`64%
`14%
`21%
`0%
`
`Sex(%)
`Male
`Female
`Race(%)
`Caucasian
`Black
`Hispan ic
`Other
`
`75%
`25%
`
`56%
`13%
`19%
`13%
`
`Sex(%)
`Male
`Female
`Race(%)
`Caucasian
`Black
`Hispanic
`Other
`
`67%
`33%
`
`60%
`20%
`20%
`0%
`
`55±9
`101 ±20
`36±6
`8.6±1.4
`
`Age (y)
`Weight (kg)
`Body Mass Index (kglm')
`AIC(¾)
`Fasting Plasma Gl ucose
`(mmol/L)
`10.2±2 .3
`Duration of Dia betes (y)
`4±4
`Diabetes treatment, metformin/ 64/36
`diet and exercise (%)
`
`55±12
`107±24
`35±6
`8.6± 1.1
`
`Age (y)
`Weight (kg)
`Body Mass Index (kglm')
`A IC (%)
`Fasting Plasma Glucose
`(mmol/L)
`10.3±2.7
`Duration of Diabetes (y)
`5±3
`Diabetes treatment, me.tformi n/ 63/38
`diet and exercise(%)
`
`51 ±1 1
`110±1 7
`36±6
`8.3± 1.1
`
`Age (y)
`Weight (kg)
`Body Mass Index (kg/nl)
`AIC(¾)
`Fasting Plasma Glucose
`(mmol/L)
`9.3± 1.6
`4±5
`Duration of Diabetes (y)
`Diabetes treatment, metformin/ 53/47
`diet and exercise(%)
`
`Received interven ti on (N = 14)
`Discontinued due to:
`Adverse event (N = I)
`Loss of glucose control (N = l)
`Completed (N = 12)
`
`Received inte1vention (N = 16)
`Compl eted (N = 16)
`
`Received i11te1ventioo (N = 15)
`Completed (N = 15)
`
`Figure 1— Study flowchart. Disposition of patients throughout the study, with baseline demographics. Demographic data are means ⫾ SD, except
`for sex, race, and diabetes treatment. Percentages may not add up to 100 because of rounding.
`
`A1C ⱕ7.0% also depended on week 15
`measurements. The A1C target analysis was
`performed on the subset of evaluable pa-
`tients with baseline A1C ⬎7% (n ⫽ 41).
`Plasma exenatide concentrations by
`treatment and time were provided for
`those subjects who received exenatide
`LAR and completed the study. Exenatide
`pharmacokinetics were analyzed by stan-
`dard noncompartmental methods and
`summarized descriptively. Post hoc anal-
`yses were performed to compare the 0.8-
`
`DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007
`
`and 2.0-mg exenatide LAR groups to the
`placebo LAR group with respect to the
`change from baseline for A1C, fasting
`plasma glucose, and body weight. Statis-
`tical significance was set at P ⬍ 0.05.
`
`RESULTS
`
`Subject demographics and
`disposition
`Study subjects (n ⫽ 45) were 40% female
`and had the following mean ⫾ SD base-
`
`line characteristics: A1C 8.5 ⫾ 1.2%, fast-
`ing plasma glucose 9.9 ⫾ 2.3 mmol/l,
`weight 106 ⫾ 20 kg, and diabetes dura-
`tion 5 ⫾ 4 years. The different groups
`(Fig. 1) varied in their sex, with more
`women in the placebo LAR group and
`more men in the exenatide LAR groups,
`and glycemia, with lower A1C and fasting
`plasma glucose in the 2.0-mg exenatide
`LAR group. Most subjects in this study
`were receiving metformin (n ⫽ 27),
`whereas the remaining 18 subjects were
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`Exenatide LAR in subjects with type 2 diabetes
`
`Cl.
`
`"O
`
`'.:j'
`E
`oi 550
`C: 500
`.Q ro 450
`....
`"E
`<I> 400
`u
`C:
`0 350
`(.)
`<I> 300
`~ 250
`C:
`<I>
`X 200
`w
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`E 150
`ro a: 100
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`50
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`C:
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`
`ti)
`
`(f)
`
`Last Injection +
`
`Active Treatment Period
`
`Follow-U Period
`
`• = 2.0 rrg exenatide LAR, N = 15
`■ = 0.8 rrg exenatide LAR, N = 16
`
`0
`
`4
`
`8
`
`12
`16
`Time (weeks)
`
`20
`
`24
`
`28
`
`Figure 2— Plasma exenatide concentrations (means ⫾ SD) over time in subjects receiving exenatide LAR (n ⫽ 31). Note that the last injection was
`administered at week 14.
`
`treated with diet modification and exer-
`cise. Two subjects withdrew from the
`study, both from the placebo LAR group.
`One subject withdrew during the lead-in
`period because of an adverse event, and
`one subject withdrew during the treat-
`ment period because of loss of glucose
`control (Fig. 1).
`
`Pharmacokinetics
`With once-weekly exenatide LAR injec-
`tions, mean plasma exenatide concentra-
`tions rose steadily. By week 2, treatment
`with 2.0 mg exenatide LAR reached 50
`pg/ml, a concentration previously shown
`to significantly reduce plasma glucose
`(Fig. 2) (28). After ⬃6 weeks of treatment
`with 2.0 mg exenatide LAR, plasma ex-
`enatide concentrations were maintained
`at concentrations similar to the maximum
`concentration achieved with a single in-
`jection of 10 ␮g exenatide (steady-state
`concentration of 232 pg/ml with 2.0 mg
`exenatide LAR compared with 211 pg/ml
`after a single injection of 10 ␮g exenatide)
`(16). The steady-state concentration with
`0.8 mg exenatide LAR was 111 pg/ml. Af-
`ter completion of the treatment phase at
`week 15, exenatide concentrations de-
`creased steadily to below those consid-
`ered to have a therapeutic effect by week
`21.
`
`Glycemic end points
`Fasting plasma glucose was reduced rap-
`idly, with significant mean ⫾ SE changes
`
`1490
`
`from baseline to week 15 of ⫺2.4 ⫾ 0.9
`and ⫺2.2 ⫾ 0.5 mmol/l for the 0.8- and
`2.0-mg exenatide LAR groups, respec-
`tively, compared with ⫹1.0 ⫾ 0.7 mmol/l
`for the placebo LAR group (P ⬍ 0.001 for
`both 0.8 and 2.0 mg vs. placebo LAR)
`(Fig. 3A).
`All three groups had similar self-
`monitored blood glucose profiles and
`mean average daily blood glucose con-
`centrations at baseline (placebo LAR 11.3
`mmol/l, 0.8 mg exenatide LAR 11.4
`mmol/l, and 2.0 mg exenatide LAR 10.8
`mmol/l) (Fig. 3B). By week 15, the mean
`average daily blood glucose concentration
`decreased for both LAR treatment groups
`(week 15 values 9.2 mmol/l [0.8 mg] and
`8.3 mmol/l [2.0 mg]) and rose for the pla-
`cebo LAR group (12.2 mmol/l). Prepran-
`dial and postprandial plasma glucose
`concentrations decreased for both ex-
`enatide LAR groups, with the magnitude
`of postprandial excursions decreased by
`as much as fourfold with 2.0 mg ex-
`enatide LAR compared with placebo LAR.
`A1C was reduced at the first postex-
`enatide LAR measurement (week 3) for
`both exenatide LAR groups and progres-
`sively decreased throughout the treat-
`ment period (Fig. 3C). At week 15,
`significant mean ⫾ SE A1C changes from
`baseline of ⫺1.4 ⫾ 0.3 and ⫺1.7 ⫾ 0.3%
`were observed for the 0.8- and 2.0-mg
`exenatide LAR groups, respectively, com-
`pared with ⫹0.4 ⫾ 0.3% for the placebo
`LAR group (P ⬍ 0.0001 for both 0.8 and
`
`2.0 mg vs. placebo LAR), resulting in
`mean A1C values of 7.2 and 6.6% in the
`0.8- and 2.0-mg exenatide LAR groups,
`respectively, compared with 9.0% for the
`placebo LAR group. Of evaluable subjects
`with baseline A1C ⬎7% (n ⫽ 41), 86% in
`the 2.0-mg group and 36% of subjects in
`the 0.8-mg group achieved an A1C of
`ⱕ7% at week 15, compared with 0% of
`subjects in the placebo LAR group.
`
`Weight
`Body weight decreased progressively in
`the 2.0-mg exenatide LAR group, with a
`significant mean ⫾ SE change from base-
`line at week 15 of ⫺3.8 ⫾ 1.4 kg (3.5% of
`total baseline body weight) (Fig. 3D) (P ⬍
`0.05 for 2.0 mg exenatide LAR vs. placebo
`LAR). Body weight was unchanged for the
`0.8-mg exenatide LAR and placebo LAR
`groups.
`
`Safety and tolerability
`All adverse events were mild to moderate
`in intensity, except for one severe adverse
`event of urticaria and pruritus, which was
`considered to be related to shellfish inges-
`tion not to exenatide treatment. Nausea
`was the most frequently reported adverse
`event among exenatide LAR-treated sub-
`jects (exenatide LAR 0.8 mg 19% and 2.0
`mg 27% vs. placebo LAR 15%), followed
`by gastroenteritis (exenatide LAR 0.8 mg
`19% and 2.0 mg 13% vs. placebo LAR
`0%), and hypoglycemia (exenatide LAR
`0.8 mg 25% and 2.0 mg 0% vs. placebo
`
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`;;l 13
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`Figure 3— Glycemic and weight parameters. Unless otherwise indicated: E, placebo LAR, n ⫽ 14; f, 0.8 mg exenatide LAR, n ⫽ 16; F, 2.0 mg
`exenatide LAR, n ⫽ 15. *Statistically significant results: P ⬍ 0.05 compared with placebo LAR (A, C, and D). A: Fasting plasma glucose
`concentrations over time (ITT, n ⫽ 45; mean ⫾ SE). B: Self-monitored blood glucose concentration profiles at baseline and week 15 (evaluable, n ⫽
`43; mean ⫾ SE). E, placebo LAR, n ⫽ 12; f, 0.8 mg exenatide LAR, n ⫽ 16; F, 2.0 mg exenatide LAR, n ⫽ 15. C: A1C (%) over time (ITT, n ⫽
`45; mean ⫾ SE). D: Change in body weight from baseline over time (ITT, n ⫽ 45; mean ⫾ SE).
`
`LAR 0%). All episodes of nausea were
`mild, with no reports of vomiting. Hy-
`poglycemic episodes, only one of which
`was confirmed with a blood glucose
`concentration (3.1 mmol/l), were mild
`in intensity and were not related to the
`dose of exenatide LAR (as all occurred in
`the 0.8-mg group). Injection site bruising
`
`occurred more frequently in exenatide
`LAR-treated patients (exenatide LAR 0.8
`mg 13% and 2.0 mg 7% vs. placebo LAR
`0%).
`There were no withdrawals because
`of adverse events during exenatide LAR
`treatment. There were no clinically signif-
`icant abnormal hematologic, chemistry,
`
`or urinalysis values reported during the
`study. Further, there were no clinically
`significant abnormalities in vital signs and
`electrocardiogram interpretations.
`At week 15, 67% of subjects in the
`exenatide LAR treatment groups were
`positive for anti-exenatide antibodies. In-
`dividual subject profiles did not reveal a
`
`DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007
`
`1491
`
`MPI EXHIBIT 1030 PAGE 5
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1030-0005
`
`

`

`Exenatide LAR in subjects with type 2 diabetes
`
`clear association between antibody re-
`sponse and effects on safety or efficacy.
`
`CONCLUSIONS — Development of
`an exenatide formulation with once-
`weekly dosing that reduces A1C and
`weight could provide patients and clini-
`cians with a novel tool with which to treat
`type 2 diabetes. In this study, once-
`weekly exenatide LAR for 15 weeks had
`multiple metabolic effects, including sig-
`nificant reductions of A1C, weight, and
`fasting glucose and marked reduction of
`self-monitored postprandial glucose.
`Treatment with 2.0 mg exenatide LAR but
`not with 0.8 mg reduced body weight,
`indicating that higher exenatide concen-
`trations are required for effects on weight.
`This dose dependence in weight effects is
`in keeping with the observed results of
`30-week placebo-controlled studies of
`exenatide on a background of metformin
`or sulfonylurea treatment (18,19). Like-
`wise, the magnitude of postprandial glu-
`cose excursions decreased as much as
`fourfold with 2.0 mg exenatide LAR
`(compared with placebo LAR), which
`may account for the greater magnitude of
`A1C reduction with the 2.0-mg dose.
`A single dose of the BID formulation
`of exenatide has a half-life of 2.4 h after
`subcutaneous injection, predominantly
`because of renal clearance, and is admin-
`istered before the two main meals of the
`day, ⱖ6 hours apart (16). Improvements
`in postprandial glycemia with exenatide
`BID have been most pronounced at
`breakfast and dinner, the meals before
`which exenatide is typically given, with
`some residual beneficial effects after
`lunch and during fasting. In contrast,
`treatment with exenatide LAR provides
`24-h exposure to therapeutic exenatide
`concentrations. This continuous expo-
`sure may account for the reduction in
`fasting glucose observed with 15 weeks of
`exenatide LAR being fourfold greater than
`that reported in 30-week studies with 10
`␮g exenatide BID (18 –20). In addition,
`exenatide LAR provides postprandial
`glycemic control with all meals. This
`combination of daylong fasting and post-
`prandial effects may explain why the A1C
`reduction was approximately twice as
`large with 2.0 mg exenatide LAR com-
`pared with exenatide BID and why the
`majority of subjects (86%) achieved target
`A1C values of ⱕ7%. Similarly, it is possi-
`ble that the twofold greater weight reduc-
`tion could reflect effects on food intake
`throughout the day with 2.0 mg exenatide
`
`1492
`
`LAR, as opposed to presumably only at
`breakfast and dinner with exenatide BID.
`Continuous GLP-1 infusion improves
`glycemic control, weight, insulin sensitiv-
`ity, and ␤-cell function (8,29). However,
`whereas GLP-1, with a half-life of ⬍2 min
`(6), is administered as a continuous infu-
`sion, exenatide LAR, with a median half-
`life of 2 weeks (data on file; Amylin
`Pharmaceuticals, San Diego, CA), can be
`administered as a once-weekly subcuta-
`neous injection. Exenatide acts in a glu-
`cose-dependent manner, affecting insulin
`and glucagon secretion during hypergly-
`cemia but not euglycemia or hypoglyce-
`mia. Therefore, continuous exenatide
`concentrations can potentially improve
`glycemic control and other metabolic
`measures without increasing the risk of
`clinically significant hypoglycemia.
`Exenatide LAR was well tolerated,
`with almost exclusively mild-to-moderate
`adverse events. The relatively mild nausea
`profile with exenatide LAR compared
`with that observed with exenatide BID
`(18 –20) may be due to the more gradual
`increase in plasma exenatide concentra-
`tions upon initiation of treatment. In sup-
`port of
`this hypothesis, stepwise
`introduction of exenatide has been shown
`to reduce the incidence of nausea by ap-
`proximately half (30). The formation of
`anti-exenatide antibodies with exenatide
`LAR treatment was not predictive of end
`point response or adverse safety outcome,
`consistent with exenatide BID studies
`(18 –20). Longer-term studies are needed
`to examine the safety profile of exenatide
`LAR. Thus far, exenatide BID has been on
`the market for ⬃2 years and has been
`studied in clinical trials of up to 3 years in
`duration (31) without significant changes
`to its safety profile.
`Although these findings are encour-
`aging, the relatively modest size (45 sub-
`jects) and short duration (15 weeks) of
`the study and administration of exenatide
`LAR by study staff must all be considered
`when interpreting these findings. The re-
`ductions in A1C and weight did not ap-
`pear to plateau by week 15, so the full
`potential for and sustainability of glyce-
`mic improvement and weight reduction
`were not determined by this study. Addi-
`tionally, the administration of injections
`by study staff at study sites ensured high
`compliance and a uniform injection tech-
`nique, which may not reflect real-world
`clinical use.
`In this early study, the data suggest
`that a convenient, once-weekly exenatide
`formulation shows promise in the treat-
`
`ment of type 2 diabetes. The combined
`potential benefits of improved glycemic
`control and reduced weight in a novel
`once-weekly treatment regimen for pa-
`tients with type 2 diabetes merits longer-
`term large-scale studies to gain further
`insight into treatment with exenatide
`LAR.
`
`Acknowledgments — This work was sup-
`ported by Amylin Pharmaceuticals, San Diego,
`CA, Eli Lilly and Company, Indianapolis, IN,
`and Alkermes, Cambridge, MA.
`The authors thank the exenatide LAR clinical
`team for their assistance in the conduct, report-
`ing, and quality control of the study and devel-
`opment of the manuscript; the investigators
`Andrew Ahmann, Bruce Berwald, Eric Klein,
`Sam D. Miller, John Pullman, and Richard Wein-
`stein and the study site staffs for conducting the
`study; the study subjects for their participation;
`and Susanna Mac for writing of the manuscript.
`We thank Alkermes for leading the development
`of and for manufacturing the long-acting release
`formulation of exenatide.
`
`References
`1. National Diabetes Information Clear-
`inghouse. National diabetes statistics
`[article online], 2005. Available from
`http://diabetes.niddk.nih.gov/dm/pubs/
`statistics/index.htm#7. Accessed 5 Sep-
`tember 2006
`2. Koro CE, Bowlin SJ, Bourgeois N, Fedder
`DO: Glycemic control from 1988 to 2000
`among U.S. adults diagnosed with type 2
`diabetes: a preliminary report. Diabetes
`Care 27:17–20, 2004
`3. Mokdad AH, Ford ES, Bowman BA, Dietz
`WH, Vinicor F, Bales VS, Marks JS: Prev-
`alence of obesity, diabetes, and obesity-
`related health risk factors, 2001. JAMA
`289:76 –79, 2003
`4. Maggio CA, Pi-Sunyer FX: The prevention
`and treatment of obesity: application to
`type 2 diabetes. Diabetes Care 20:1744 –
`1766, 1997
`5. Purnell JQ, Weyer C: Weight effect of cur-
`rent and experimental drugs for diabetes
`mellitus: from promotion to alleviation of
`obesity. Treat Endocrinol 2:33– 47, 2003
`6. Drucker DJ: Enhancing incretin action for
`the treatment of type 2 diabetes. Diabetes
`Care 26:2929 –2940, 2003
`7. Parkes D, Jodka C, Smith P, Nayak S,
`Rinehart L, Gingerich R, Chen K, Young
`A: Pharmacokinetic actions of exendin-4
`in the rat: comparison with glucagon-like
`peptide-1. Drug Dev Res 53:260 –267,
`2001
`8. Zander M, Madsbad S, Madsen JL, Holst
`JJ: Effect of 6-week course of glucagon-
`like peptide 1 on glycaemic control, insu-
`lin sensitivity, and ␤-cell function in type
`2 diabetes: a parallel-group study. Lancet
`
`DIABETES CARE, VOLUME 30, NUMBER 6, JUNE 2007
`
`MPI EXHIBIT 1030 PAGE 6
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1030-0006
`
`

`

`359:824 – 830, 2002
`9. Parkes DG, Pittner R, Jodka C, Smith P,
`Young A: Insulinotropic actions of ex-
`endin-4 and glucagon-like peptide-1 in
`vivo and in vitro. Metabolism 50:583–589,
`2001
`10. Toft-Nielsen MB, Damholt MB, Madsbad
`S, Hilsted LM, Hughes TE, Michelsen BK,
`Holst JJ: Determinants of the impaired se-
`cretion of glucagon-like peptide-1 in type
`2 diabetic patients. J Clin Endocrinol Metab
`86:3717–3723, 2001
`11. Egan JM, Clocquet AR, Elahi D: The insu-
`linotropic effect of acute exendin-4 ad-
`ministered to humans: comparison of
`nondiabetic state to type 2 diabetes. J Clin
`Endocrinol Metab 87:1282–1290, 2002
`12. Kolterman OG, Buse JB, Fineman MS,
`Gaines E, Heintz S, Bicsak TA, Taylor K,
`Kim D, Aisporna M, Wang Y, Baron AD:
`Synthetic exendin-4 (exenatide) signifi-
`cantly reduces postprandial and fasting
`plasma glucose in subjects with type 2 di-
`abetes. J Clin Endocrinol Metab 88:3082–
`3089, 2003
`13. Nielsen LL, Young AA, Parkes DG: Phar-
`macology of exenatide (synthetic ex-
`endin-4): a potential
`therapeutic for
`improved glycemic control of type 2 dia-
`betes. Regul Pept 117:77– 88, 2004
`14. Edwards CM, Stanley SA, Davis R, Brynes
`AE, Frost GS, Seal LJ, Ghatei MA, Bloom
`SR: Exendin-4 reduces fasting and post-
`prandial glucose and decreases energy in-
`take in healthy volunteers. Am J Physiol
`Endocrinol Metab 281:E155–E161, 2001
`15. Triplitt C, DeFronzo RA: Exenatide: first-
`in-class incretin mimetic for the treatment
`of type 2 diabetes mellitus. Expert Rev En-
`docrinol Metab 1:329 –341, 2006
`16. BYETTA prescribing information [article
`online], 2006. Available from http://pi.
`lilly.com/us/byetta-pi.pdf. Acc