C l i n i c a l C a r e / E d u c a t i o n / N u tr i t i o n / P s y c h o s o c i a l R e s e a r c h
`O R I G I N A L
`A R T I C L E
`
`Downloaded from http://diabetesjournals.org/care/article-pdf/36/3/498/615818/498.pdf by guest on 12 January 2024
`
`The Fate of Taspoglutide, a Weekly GLP-1
`Receptor Agonist, Versus Twice-Daily
`Exenatide for Type 2 Diabetes
`The T-emerge 2 trial
`
`1
`
`JULIO ROSENSTOCK, MD
`2
`BOGDAN BALAS, MD
`3
`BERNARD CHARBONNEL, MD
`4
`GEREMIA B. BOLLI, MD
`
`5
`MARK BOLDRIN, MS
`6
`ROBERT RATNER, MD
`2
`RAFFAELLA BALENA, MD
`FOR THE T-EMERGE 2 STUDY GROUP*
`
`OBJECTIVEdTaspoglutide is a long-acting glucagon-like peptide 1 receptor agonist devel-
`oped for treatment of type 2 diabetes. The efficacy and safety of once-weekly taspoglutide was
`compared with twice-daily exenatide.
`
`RESEARCH DESIGN AND METHODSdOverweight adults with inadequately con-
`trolled type 2 diabetes on metformin 6 a thiazolidinedione were randomized to subcutaneous
`taspoglutide 10 mg weekly (n = 399), taspoglutide 20 mg weekly (n = 398), or exenatide 10 mg
`twice daily (n = 392) in an open-label, multicenter trial. The primary end point was change in
`HbA1c after 24 weeks.
`
`RESULTSdMean baseline HbA1c was 8.1%. Both doses of taspoglutide reduced HbA1c sig-
`nificantly more than exenatide (taspoglutide 10 mg: –1.24% [SE 0.09], difference –0.26, 95% CI
`–0.37 to –0.15, P , 0.0001; taspoglutide 20 mg: –1.31% [0.08], difference –0.33, –0.44 to
`–0.22, P , 0.0001; exenatide: –0.98% [0.08]). Both taspoglutide doses reduced fasting plasma
`glucose significantly more than exenatide. Taspoglutide reduced body weight (taspoglutide
`10 mg, –1.6 kg; taspoglutide 20 mg, –2.3 kg) as did exenatide (–2.3 kg), which was greater
`than with taspoglutide 10 mg (P , 0.05). HbA1c and weight effects were maintained after 52 weeks.
`More adverse events with taspoglutide 10 and 20 mg than exenatide developed over time (nausea in 53,
`59, and 35% and vomiting in 33, 37, and 16%, respectively). Allergic and injection-site reactions were
`more common with taspoglutide. Discontinuations were greater with taspoglutide. Antitaspoglutide
`antibodies were detected in 49% of patients.
`
`CONCLUSIONSdOnce-weekly taspoglutide demonstrated greater glycemic control than
`twice-daily exenatide with comparable weight loss, but with unacceptable levels of nausea/vom-
`iting, injection-site reactions, and systemic allergic reactions.
`
`G lucagon-like peptide 1 (GLP-1) re-
`
`ceptor agonists have emerged as
`antihyperglycemic medications
`with added therapeutic value beyond
`glucose-lowering properties. Exenatide,
`a twice-daily GLP-1 mimetic, and
`
`Diabetes Care 36:498–504, 2013
`
`liraglutide, a once-daily GLP-1 analog,
`are currently licensed for the treatment of
`type 2 diabetes. In randomized clinical
`trials, these subcutaneously administered
`compounds have demonstrated antihy-
`perglycemic and weight loss effects with a
`
`c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c
`
`From the 1Dallas Diabetes and Endocrine Center at Medical City, Dallas, Texas; 2F. Hoffmann-La Roche Ltd.,
`Basel, Switzerland; the 3Department of Internal Medicine, Endocrinology, and Diabetes, University of
`Nantes, Nantes, France; the 4Department of Internal Medicine, University of Perugia, Perugia, Italy;
`5Roche, Nutley, New Jersey; and 6MedStar Health Research Institute, Hyattsville, Maryland.
`Corresponding author: Julio Rosenstock, juliorosenstock@dallasdiabetes.com.
`Received 13 April 2012 and accepted 12 August 2012.
`DOI: 10.2337/dc12-0709. Clinical trial reg. no. NCT00717457, clinicaltrials.gov.
`This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10
`.2337/dc12-0709/-/DC1.
`R.B. is currently affiliated with Eli Lilly, Erl Wood Manor, Windlesham Surry, U.K.
`*A complete list of the T-emerge 2 study investigators can be found in the Supplementary Data online.
`© 2013 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.
`
`low risk of hypoglycemia (1). The most
`common adverse events with exenatide
`and liraglutide are gastrointestinal distur-
`bances such as nausea (8–44 and 8–35%,
`respectively) and vomiting (4–13 and 7–
`12%, respectively), which have limited
`their use and adherence in clinical prac-
`tice (2–5).
`The investigational GLP-1 receptor ag-
`onist taspoglutide has 93% homology with
`endogenous GLP-1 and was considered to
`have potency equivalent to GLP-1 (6). In
`short-term phase 2 clinical studies, once-
`weekly taspoglutide demonstrated mean-
`ingful antihyperglycemic and weight loss
`effects (7,8). Conceivably, weekly adminis-
`tration of a GLP-1 receptor agonist, such as
`taspoglutide, could result in beneficial ef-
`fects on glycemic control as well as greater
`acceptability by patients, enhancing treat-
`ment compliance.
`The American Diabetes Association/
`European Association for the Study of
`Diabetes consensus statement, which in-
`cludes the use of GLP-1 receptor agonists
`as a secondary option to add to metfor-
`min, recommends head-to-head compar-
`ative studies to assess the value of new
`agents to achieve the currently recom-
`mended glycemic goals and their safety
`profiles (9). Accordingly, we designed a
`long-term study (T-emerge 2) to com-
`pare the efficacy and safety of once-
`weekly taspoglutide with twice-daily
`exenatide in patients with type 2 diabetes
`inadequately controlled with metformin,
`thiazolidinedione, or a combination of
`metformin and thiazolidinedione. Prior
`to the completion of the long-term exten-
`sion arm of this study, the taspoglutide
`phase 3 clinical trials were terminated
`because of a significantly increased rate
`of unwanted adverse events. Neverthe-
`less, we believe that transparent reporting
`of the T-emerge 2 study results will pro-
`vide important information to help put in
`perspective important
`safety issues
`related to current and future trials with
`GLP-1 receptor agonists. We report the
`key efficacy results from the 24-week,
`open-label, active-controlled core phase
`
`498
`
`DIABETES CARE, VOLUME 36, MARCH 2013
`
`care.diabetesjournals.org
`
`Novo Nordisk Exhibit 2060
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00001
`
`

`

`Downloaded from http://diabetesjournals.org/care/article-pdf/36/3/498/615818/498.pdf by guest on 12 January 2024
`
`Rosenstock and Associates
`
`point was determined using ANOVA,
`with treatment, region, and background
`antihyperglycemic treatment as variables
`and baseline value of the end point as co-
`variate. Missing values were imputed as the
`last observation carried forward. HbA1c
`was tested in each of the two active arms
`versus exenatide for noninferiority first (if
`the upper limit of the two-sided 95% CI for
`the treatment difference was ,0.4%, a pre-
`specified noninferiority margin). The
`Hochberg procedure was used to control
`for the two comparisons. Superiority (if
`the upper limit of the two-sided CI limit
`was ,0) was tested under a gatekeeping
`test procedure only if noninferiority was
`met in both arms. Changes in fasting plasma
`glucose and body weight were analyzed
`similarly with the testing sequence. The
`other continuous secondary and explor-
`atory end points were assessed using
`ANCOVA but were not part of the testing
`sequence. HbA1c response rates and related
`95% CIs were calculated according to
`Pearson–Clopper. Patients were included
`in the safety analysis if they received at least
`one dose of the study drug and had at least
`one safety follow-up (or reported an adverse
`event).
`
`RESULTSdThe first participant was
`enrolled on 25 July 2008, and the final
`visit for any subject was 22 December
`2010. Of the 1,189 patients randomized,
`1,173 patients were included in the safety
`population and 1,149 patients were in-
`cluded in the intention-to-treat popula-
`tion of the 24-week core phase. Baseline
`demographic and disease characteristics
`for the intention-to-treat population were
`well balanced between treatment groups
`(Table 1). Of the 784 patients who com-
`pleted the core and extension phases of
`the study up to 52 weeks, 664 patients
`entered the long-term extension phase
`of the study. During the first 24-week
`study period, withdrawal rates were sim-
`ilar between groups (16, 22, and 16% of
`patients receiving taspoglutide 10 mg,
`taspoglutide 20 mg, or exenatide, respec-
`tively), but were clearly higher in the
`taspoglutide groups at study end (26,
`34, and 16%, respectively) (see Supple-
`mentary Fig. 1 for complete description
`of patient disposition).
`
`Efficacy
`After 24 weeks of treatment, least squares
`mean change in HbA1c was –1.24% (SE
`0.09), –1.31% (0.08), and –0.98% (0.08)
`in the taspoglutide 10-mg, taspoglutide
`20-mg, and exenatide groups, respectively,
`
`and the 28-week, open-label extension
`phase. We are also presenting the cumu-
`lative safety data for the entire study up to
`the last dose administered (week 104).
`
`RESEARCH DESIGN AND
`METHODSdEligible participants were
`18–75 years of age with type 2 diabetes,
`HbA1c between 7 and 10%, and BMI $25
`kg/m2 (.23 kg/m2 for Asians) and #45
`kg/m2 (with stable body weight [65%] for
`3 months), and were receiving a stable dose
`of antihyperglycemic medication (metfor-
`min $1,500 mg/day, a thiazolidinedione
`[either rosiglitazone $4 mg/day or pioglita-
`zone $30 mg/day], or both) for $3 months
`prior to screening. Key exclusion criteria were
`advanced diabetes complications, gastroin-
`testinal disease, previous bariatric surgery,
`pancreatitis, cardiovascular disease, or previ-
`ous exposure to GLP-1 receptor agonists.
`The trial was conducted in accordance
`with the Declaration of Helsinki and national
`regulations, and the protocol was approved
`by local independent ethics committees or
`institutional review boards. All participants
`provided written consent prior to any pro-
`cedure.
`
`Study design and interventions
`T-emerge 2 was a randomized, open-
`label, active-comparator, parallel-group,
`phase 3 trial with a 24-week core
`phase, a 28-week extension phase, and
`an optional 104-week, long-term exten-
`sion phase; the trial was conducted at 189
`sites in 23 countries. Participants were
`randomly assigned (1:1:1) to receive sub-
`cutaneous injections of taspoglutide 10 mg
`weekly, taspoglutide 10 mg weekly for the
`initial 4 weeks followed by 20 mg weekly,
`or exenatide (Byetta; Amylin Pharmaceuti-
`cals, San Diego, CA) 5 mg twice daily for the
`initial 4 weeks followed by 10 mg twice
`daily. Participants who completed the initial
`24 weeks of treatment entered the 28-week
`extension phase. At week 52, patients were
`invited to participate in the 104-week, long-
`term extension phase maintaining the same
`randomized study agent.
`Taspoglutide was administered sub-
`cutaneously before breakfast once a week.
`Exenatide was injected as per prescribing
`information within a 60-min period be-
`fore the morning and evening meals. All
`patients received self blood glucose mon-
`itoring devices (ACCU-CHEK; Roche Di-
`agnostics, Indianapolis, IN). During the
`study, background antihyperglycemic
`treatment was maintained at prestudy
`doses. If glycemic control deteriorated
`(fasting plasma glucose .13.3 mmol/L
`
`[.240 mg/dL] between weeks 4 and 8,
`.12.2 mmol/L [.220 mg/dL] between
`weeks 8 and 12, and .11.1 mmol/L
`[.200 mg/dL] between weeks 12 and
`24), additional antihyperglycemic rescue
`medication was prescribed (first choice
`was a sulfonylurea), and patients contin-
`ued in the study.
`
`End points and assessments
`The primary efficacy end point was the
`absolute change from baseline in HbA1c
`(%) after 24 weeks of treatment. Second-
`ary efficacy end points included changes
`in HbA1c (%), fasting plasma glucose, and
`body weight during 52 weeks of treat-
`ment and changes in fasting proinsulin,
`fasting proinsulin/insulin ratio, and ho-
`meostasis model assessment of b-cell
`function after 52 weeks of treatment. Ex-
`ploratory end points included changes in
`lipid profile, high-sensitivity C-reactive
`protein, and blood pressure after 52
`weeks of treatment and the proportion
`of patients who received rescue medica-
`tion. Samples were assayed by a central
`laboratory (Covance Central Laboratory,
`Geneva, Switzerland).
`Safety assessments included adverse
`events, vital signs, physical examinations,
`clinical
`laboratory tests, electrocardio-
`grams, and testing for antitaspoglutide
`antibodies (only in patients receiving
`taspoglutide).
`
`Randomization and statistical
`analysis
`Randomization was stratified by baseline
`HbA1c (,8.0 or $8.0%) and background
`antidiabetic treatment. Randomization
`was performed centrally using either a
`telephone- or web-based system. Investiga-
`tors and sponsor were masked to the re-
`sults of efficacy assessments during the
`study. Approximately 330 subjects per
`arm were needed to provide at least 80%
`power with an a = 0.05 for the noninferi-
`ority test of taspoglutide versus exenatide,
`assuming a noninferiority limit of 0.3%
`(this margin used for sample size calcula-
`tion only), a 0% difference from exenatide
`in HbA1c change from baseline, and a stan-
`dard deviation of 1.2. Analyses of efficacy
`outcomes at 24 and 52 weeks were based
`on the intention-to-treat population, which
`consisted of all randomized patients who
`received at least one dose of study drug
`and had an evaluable baseline and at least
`one evaluable postbaseline measurement of
`HbA1c. The per-protocol population was
`used as sensitivity analysis to check the ro-
`bustness of the results. The primary end
`
`care.diabetesjournals.org
`
`DIABETES CARE, VOLUME 36, MARCH 2013
`
`499
`
`Novo Nordisk Exhibit 2060
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00002
`
`

`

`Downloaded from http://diabetesjournals.org/care/article-pdf/36/3/498/615818/498.pdf by guest on 12 January 2024
`
`Taspoglutide compared with exenatide
`
`Table 1dBaseline demographic and disease characteristics (intention-to-treat population,
`n = 1,149)
`
`Taspoglutide 10 mg
`once weekly
`(n = 384)
`
`Taspoglutide 20 mg
`once weekly
`(n = 392)
`
`Exenatide 10 mg
`twice daily
`(n = 373)
`
`Men
`Age, years
`Race/ethnicity
`White
`Nonwhite
`Hispanic
`Weight, kg
`BMI, kg/m2
`HbA1c
`Fasting plasma glucose,
`mmol/L
`Duration of diabetes, years
`HbA1c baseline category
`,8.0%
`$8.0%
`Background therapy
`Metformin only
`Thiazolidinedione only
`Metformin and
`thiazolidinedione
`
`Data are mean (SD) or number (%).
`
`221 (58%)
`56 (9.6)
`
`326 (85%)
`58 (15%)
`71 (18%)
`95.5 (20.0)
`33.5 (5.2)
`8.1% (0.9%)
`
`9.9 (2.6)
`6.3 (5.2)
`
`187 (49%)
`197 (51%)
`
`205 (52%)
`56 (10.0)
`
`334 (85%)
`58 (15%)
`82 (21%)
`93.2 (18.9)
`33.1 (5.3)
`8.1% (0.9%)
`
`9.8 (2.4)
`7.0 (5.7)
`
`193 (49%)
`199 (51%)
`
`182 (49%)
`55 (9.9)
`
`316 (85%)
`57 (15%)
`73 (20%)
`94.5 (18.6)
`33.8 (5.2)
`8.1% (0.9%)
`
`9.9 (2.7)
`6.5 (5.4)
`
`197 (53%)
`176 (47%)
`
`338 (88.0%)
`3 (0.8%)
`
`345 (88.0%)
`4 (1.0%)
`
`322 (86.3%)
`7 (1.9%)
`
`43 (11.2%)
`
`43 (11.0%)
`
`44 (11.8%)
`
`from a mean baseline HbA1c of 8.1% (0.9).
`Reduction in HbA1c with both doses of
`taspoglutide was significantly greater than
`with exenatide (estimated treatment differ-
`ence of –0.26 [95% CI –0.37 to –0.15], P ,
`0.0001, and –0.33 [–0.44 to –0.22], P ,
`0.0001, for taspoglutide 10 and 20 mg, re-
`spectively), which met noninferiority and
`then superiority criteria. These reductions
`in HbA1c persisted through 52 weeks of
`treatment, with a change in HbA1c of
`–1.16% (SE 0.09), –1.18% (0.09), and
`–0.94% (0.09) in the taspoglutide 10-mg,
`taspoglutide 20-mg, and exenatide groups,
`respectively (Fig. 1A and B). Reduction in
`HbA1c with both doses of taspoglutide was
`significantly greater than with exenatide
`(estimated treatment difference of –0.22
`[95% CI –0.34 to –0.11], P , 0.0005,
`and –0.25 [–0.37 to –0.13], P , 0.0001,
`for taspoglutide 10 and 20 mg, respec-
`tively), sustaining the superiority criterion.
`Taspoglutide reduced fasting plasma
`glucose significantly more than exenatide
`at 24 weeks, with changes of –2.18 (0.2)
`mmol/L, –2.48 (0.2) mmol/L, and –1.81
`(0.19) mmol/L from baseline 9.9 (0.13)
`mmol/L, 9.8 (0.13) mmol/L, and 9.0
`(0.13) mmol/L in the taspoglutide 10-mg,
`taspoglutide 20-mg, and exenatide groups,
`respectively (estimated treatment difference
`vs. exenatide of –0.37 [95% CI –0.63 to
`
`–0.11], P , 0.01, and –0.67 [–0.94 to
`–0.41], P , 0.0001, for taspoglutide
`10 and 20 mg, respectively). Reductions
`persisted after 52 weeks of treatment, and
`taspoglutide reduced fasting plasma glucose
`more than exenatide (estimated treatment
`difference vs. exenatide of –0.31 [–0.62 to
`–0.01], P = 0.054, and –0.34 [–0.64 to
`–0.03], P = 0.034, for taspoglutide 10 and
`20 mg, respectively) (Fig. 1C and D). Tas-
`poglutide reduced body weight in a dose-
`dependent manner at week 24, with
`changes from baseline of –1.6 (0.4) kg,
`–2.3 (0.4) kg, and –2.3 (0.4) kg in patients
`receiving taspoglutide 10 mg, taspoglutide
`20 mg, or exenatide, respectively. At week
`52, weight loss was maintained in all
`groups and met the prespecified criteria
`for noninferiority versus exenatide (limit
`of 3 kg) in the taspoglutide 10- and
`20-mg groups; however, weight loss with
`taspoglutide 10 mg was significantly less
`than with exenatide (P = 0.01) (Fig. 1E and F).
`Only taspoglutide (both doses) sig-
`nificantly increased homeostasis model
`assessment of b-cell function from base-
`line; the differences were significantly
`better than with exenatide. No significant
`differences were observed in fasting insu-
`lin from baseline or between treatment
`groups. All treatments significantly de-
`creased the proinsulin/insulin ratio to a
`
`similar degree (see Supplementary Table 1
`for changes in indices of islet function and
`cardiovascular risk).
`
`Safety and tolerability
`During the entire study (core, extension,
`and long-term extension phases), adverse
`events were reported among 92, 94, and
`89% of patients treated with taspoglutide
`10 mg, taspoglutide 20 mg, and exenatide,
`respectively (Table 2). Among taspoglutide-
`treated patients experiencing severe adverse
`events, 34% were gastrointestinal disor-
`ders, 6% were injection-site reactions,
`and 4% were hypersensitivity reactions. In
`the exenatide group, nausea (9%) and
`nephrolithiasis (5%) were the most com-
`mon severe adverse events. A total of 121
`patients experienced serious adverse events.
`Those attributed to study treatment by the
`investigators included anaphylactic reaction
`(n = 2), anaphylactoid reaction (n = 1), hy-
`persensitivity (n = 1), and dyspepsia (n = 1)
`for taspoglutide 10 mg; hypersensitivity
`(n = 3), anaphylactoid reaction (n = 2), ab-
`dominal pain (n = 1), pancreatitis (n = 1),
`and acute myocardial infarction (n = 1) for
`taspoglutide 20 mg; and hypoglycemia (n =
`1) for exenatide. Four patients died during
`the study. Causes of death were completed
`suicide (n = 1) and hemorrhagic stroke (n =
`1) in the taspoglutide 10-mg group, myo-
`cardial infarction (n = 1) in the taspoglutide
`20-mg group, and bleeding varicose vein
`(n = 1) in the exenatide group. These deaths
`occurred during the extension phase (n = 3)
`and the long-term extension phase (n = 1)
`and were deemed not related to treatment
`by the investigators.
`Withdrawal due to adverse events was
`most commonly due to nausea and vomit-
`ing (taspoglutide 10 mg [6.3 and 4.8%,
`respectively], taspoglutide 20 mg [10.2 and
`6.6%], and exenatide [5.7 and 2.1%])
`(Table 2). Immune system disorders (in-
`cluding hypersensitivity, anaphylactoid, or
`anaphylactic reactions) and injection-site
`adverse events were also reasons for with-
`drawal more often in the taspoglutide
`groups than in the exenatide group. One
`case of pancreatitis of severe intensity was
`reported in the taspoglutide 20-mg group
`during the long-term extension phase of the
`study. Although it resolved without se-
`quelae, it led to study withdrawal.
`The most frequent adverse events
`were gastrointestinal disorders, with higher
`incidences in the taspoglutide 10-mg
`(68%) and 20-mg (72%) groups than in
`the exenatide (57%) group (Table 2).
`Injection-site reactions were more fre-
`quently reported with taspoglutide 10 mg
`
`500
`
`DIABETES CARE, VOLUME 36, MARCH 2013
`
`care.diabetesjournals.org
`
`Novo Nordisk Exhibit 2060
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00003
`
`

`

`Downloaded from http://diabetesjournals.org/care/article-pdf/36/3/498/615818/498.pdf by guest on 12 January 2024
`
`Rosenstock and Associates
`
`Figure 1dGlycemic control and body weight. A: HbA1c values from baseline to week 52. B: Change in HbA1c values from baseline to weeks 24 and
`52. C: Fasting plasma glucose concentrations from baseline to week 52. D: Change in fasting plasma glucose concentrations from baseline to weeks
`24 and 52. E: Body weight from baseline to week 52. F: Change in body weight from baseline to weeks 24 and 52. A, C, and E: Open circle, tas-
`poglutide 10 mg once weekly (n = 384), baseline 8.1%; closed circle, taspoglutide 20 mg once weekly (n = 392), baseline 8.1%; open square, exenatide
`10 mg twice daily (n = 373), baseline 8.1%. B, D, and F: White bar, taspoglutide 10 mg; black bar, taspoglutide 20 mg; striped bar, exenatide.
`
`(35%) and taspoglutide 20 mg (41%) than
`with exenatide (6%) (Table 2).
`Systemic allergic reactions were re-
`ported in 51 patients, occurring in 25 and
`23 patients treated with taspoglutide 10
`and 20 mg (each 6%), respectively, versus
`3 (1%) with exenatide. Hypersensitivity
`was the most common systemic allergic
`
`reaction reported in 19 (5%) and 16 (4%)
`patients in the taspoglutide 10- and 20-mg
`groups, respectively, and in 3 (1%) pa-
`tients in the exenatide group. Seri-
`ous systemic allergic reaction adverse
`events occurred in four patients treated
`with taspoglutide 10 mg (anaphylactic
`reaction [n = 2], anaphylactoid reaction
`
`[n = 1], and hypersensitivity [n = 1]) and
`five patients treated with taspoglutide 20
`mg (hypersensitivity [n = 2], anaphylac-
`toid reaction [n = 2], and type I hypersen-
`sitivity [n = 1]). Study withdrawal due
`to systemic allergic reaction adverse
`events occurred in 18 (5%) patients in
`the taspoglutide 10-mg group, 13 (3%)
`
`care.diabetesjournals.org
`
`DIABETES CARE, VOLUME 36, MARCH 2013
`
`501
`
`Novo Nordisk Exhibit 2060
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00004
`
`

`

`Downloaded from http://diabetesjournals.org/care/article-pdf/36/3/498/615818/498.pdf by guest on 12 January 2024
`
`was reported for 31% of patients. The
`proportion of patients with a confirmed
`positive antitaspoglutide antibody test in-
`creased from 16% at week 12 to 39% at
`week 24, with no further increase noted
`at week 52. As a result of the implemented
`risk-mitigation plan, patients with con-
`firmed positive antitaspoglutide antibody
`test .230 ng-eq/mL were discontinued
`during the long-term extension phase of
`the study, resulting in a substantial with-
`drawal rate. Consequently, no interpreta-
`tion of the data can be made for week
`104 results.
`Confirmed hypoglycemia (plasma glu-
`cose ,3.1 mmol/L [,55 mg/dL]) occurred
`in 5 (1.3%), 14 (3.6%), and 15 (3.9%) of the
`taspoglutide 10-mg, taspoglutide 20-mg,
`and exenatide groups by week 52, respec-
`tively. There were no cases of severe hypo-
`glycemia.
`Thyroid neoplasm–related adverse
`events were reported in 22 patients (7
`[2%], taspoglutide 10 mg; 9 [2%], taspoglu-
`tide 20 mg; and 6 [2%], exenatide). These
`data were based on a Roche-selected list of
`Medical Dictionary for Regulatory Activities
`preferred terms that were reported. No cases
`of medullary thyroid hyperplasia or carci-
`noma were detected.
`
`CONCLUSIONSdThis head-to-head
`study demonstrated that both once-weekly
`taspoglutide and the twice-daily exenatide
`significantly reduced HbA1c, fasting plasma
`glucose, and body weight from baseline af-
`ter 24 weeks of treatment, with no severe
`hypoglycemia. Noninferiority and superior
`HbA1c reductions with both taspoglutide
`10 and 20 mg compared with exenatide
`were demonstrated at 24 weeks. The re-
`ductions in HbA1c were observed at as early
`as 4 weeks, continued to decrease until 16
`weeks, and were maintained up to 52
`weeks.
`Despite a nonsignificant difference in
`HbA1c reduction between the two doses of
`taspoglutide, greater weight loss was seen
`with the 20-mg dose; this suggests that
`doses higher than necessary for glycemic
`control may further reduce body weight,
`as has been seen with liraglutide (10).
`However, the overall safety profile of
`taspoglutide was clearly worse than
`exenatide with respect to gastrointestinal
`tolerability, systemic allergic reactions,
`and injection-site reactions. The greater
`proportion of taspoglutide-treated pa-
`tients who experienced nausea and/or
`vomiting compared with exenatide may
`reflect pharmacokinetic differences be-
`tween once-weekly and twice-daily
`
`Taspoglutide compared with exenatide
`
`Table 2dSummary of adverse events and withdrawals during the entire study (up to
`104 weeks)
`
`Patients with at least
`one adverse event
`Serious adverse events
`Treatment-related
`serious adverse events*
`Adverse events leading to death
`Adverse events leading to
`withdrawal in .1%
`Total patients with at least
`one adverse event
`Serious adverse events
`Gastrointestinal disorders
`Nausea
`Vomiting
`Diarrhea
`General disorders and
`administration-site conditions
`Immune system disorders
`Hypersensitivity
`Adverse events reported
`by .5% of patients
`Nausea
`Vomiting
`Diarrhea
`Dyspepsia
`Constipation
`Abdominal pain upper
`Injection-site pruritus
`Injection-site nodule
`Injection-site induration
`Injection-site erythema
`Hypersensitivity
`Asthenia
`Nasopharyngitis
`Bronchitis
`Urinary tract infection
`Influenza
`Upper respiratory tract
`infection
`Gastroenteritis
`Hypoglycemia
`Decreased appetite
`Headache
`Dizziness
`Back pain
`Arthralgia
`Hypertension
`
`Taspoglutide 10 mg
`once weekly
`(n =394)
`
`Taspoglutide 20 mg
`once weekly
`(n =394)
`
`Exenatide 10 mg
`twice daily
`(n = 385)
`
`363 (92.1)
`50 (12.7)
`
`5/62 (8.1)
`2 (0.5)
`
`370 (93.9)
`33 (8.4)
`
`8/38 (21.1)
`1 (0.3)
`
`343 (89.1)
`38 (9.9)
`
`1/41 (2.4)
`1 (0.3)
`
`103 (26.1)
`11 (2.8)
`55 (14.0)
`25 (6.3)
`19 (4.8)
`3 (0.8)
`
`11 (2.8)
`15 (3.8)
`12 (3.0)
`
`209 (53.0)
`131 (33.2)
`53 (13.5)
`33 (8.4)
`24 (6.1)
`24 (6.1)
`37 (9.4)
`35 (8.9)
`20 (5.1)
`22 (5.6)
`19 (4.8)
`19 (4.8)
`53 (13.5)
`21 (5.3)
`14 (3.6)
`17 (4.3)
`
`16 (4.1)
`17 (4.3)
`59 (15.0)
`34 (8.6)
`42 (10.7)
`22 (5.6)
`21 (5.3)
`8 (2.0)
`33 (8.4)
`
`135 (34.3)
`11 (2.8)
`85 (21.6)
`40 (10.2)
`26 (6.6)
`6 (1.5)
`
`9 (2.3)
`12 (3.0)
`8 (2.0)
`
`233 (59.1)
`144 (36.5)
`66 (16.8)
`43 (10.9)
`40 (10.2)
`17 (4.3)
`43 (10.9)
`39 (9.9)
`34 (8.6)
`31 (7.9)
`16 (4.1)
`23 (5.8)
`50 (12.7)
`24 (6.1)
`25 (6.3)
`16 (4.1)
`
`15 (3.8)
`11 (2.8)
`60 (15.2)
`38 (9.6)
`32 (8.1)
`36 (9.1)
`23 (5.8)
`14 (3.6)
`25 (6.3)
`
`60 (15.6)
`5 (1.3)
`39 (10.1)
`22 (5.7)
`8 (2.1)
`3 (0.8)
`
`2 (0.5)
`3 (0.8)
`3 (0.8)
`
`135 (35.1)
`60 (15.6)
`53 (13.8)
`27 (7.0)
`14 (3.6)
`15 (3.9)
`3 (0.8)
`2 (0.5)
`1 (0.3)
`1 (0.3)
`3 (0.8)
`6 (1.6)
`61 (15.8)
`15 (3.9)
`20 (5.2)
`23 (6.0)
`
`21 (5.5)
`20 (5.2)
`79 (20.5)
`28 (7.3)
`22 (5.7)
`26 (6.8)
`18 (4.7)
`23 (6.0)
`18 (4.7)
`
`Data are number (%) of patients in the safety population (n = 1,173). Adverse events are reported as system
`organ class or preferred terms (Medical Dictionary for Regulatory Activities, version 12.0). *Data are number
`(%) of serious adverse events.
`
`patients in the taspoglutide 20-mg group,
`and 2 (0.5%) patients in the exenatide group.
`Among those patients with a postbase-
`line antitaspoglutide antibody test result,
`
`43% in the taspoglutide 10-mg group and
`55% in the taspoglutide 20-mg group had
`at least one positive test result (Table 3). A
`confirmed positive result .230 ng-eq/mL
`
`502
`
`DIABETES CARE, VOLUME 36, MARCH 2013
`
`care.diabetesjournals.org
`
`Novo Nordisk Exhibit 2060
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00005
`
`

`

`Downloaded from http://diabetesjournals.org/care/article-pdf/36/3/498/615818/498.pdf by guest on 12 January 2024
`
`Rosenstock and Associates
`
`patients with type 2 diabetes (14), making
`any assessment of causality difficult in this
`relatively small study.
`Once-weekly taspoglutide was supe-
`rior to twice-daily exenatide for glycemic
`control, while offering similar weight loss
`but an increased rate of nausea or vomit-
`ing, injection-site reactions, and hyper-
`sensitivity reactions. Clearly, GLP-1
`receptor agonists may not be appropriate
`for all patients with type 2 diabetes, as
`they are limited by gastrointestinal
`in-
`tolerance with rates of nausea in the 25–
`45% range and vomiting in the 8–15%
`range with different compounds, depend-
`ing on study populations; however, the
`greater frequency of vomiting seen with
`the taspoglutide formulation tested in
`phase 3, compounded by the allergic re-
`actions and high discontinuation rate,
`made this formulation clinically unac-
`ceptable. (In September 2010, Roche de-
`cided to stop dosing patients in the
`taspoglutide phase 3 trials because higher
`than expected discontinuation rates of
`taspoglutide-treated patients were ob-
`served, mainly due to gastrointestinal tol-
`erability and the implementation of the
`risk-mitigation plan to address serious
`hypersensitivity reactions. Since this
`time, Roche has worked on the root cause
`analysis and on the modified taspoglutide
`formulations with the input of Ipsen. Af-
`ter further analysis, Roche has now made
`the decision to stop the development of
`taspoglutide and to return the product to
`the originator, Ipsen, which is currently
`pursuing further investigations.) Al-
`though there are no head-to-head com-
`parisons between taspoglutide and other
`weekly GLP-1 agonists,
`the efficacy
`and safety profile of taspoglutide as re-
`vealed by this study could be of relevance
`for other long-acting GLP-1 agonists,
`such as the currently available weekly
`exenatide and the other weekly GLP-1 re-
`ceptor agonists in development (e.g., al-
`biglutide and dulaglutide).
`There seems to be a wide range of
`individual responses to GLP-1 receptor
`agonists. Not all patients have satisfactory
`glucose-lowering responses with mean-
`ingful weight loss, but some have robust
`efficacy responses with good tolerance;
`more research is clearly needed to help
`identify those responders in future trials.
`
`AcknowledgmentsdThe T-emerge 2 study
`was funded by F. Hoffmann-La Roche Ltd.
`Support for third-party writing assistance for
`the manuscript, furnished by Giles Brooke and
`
`Table 3dSummary of confirmed antitaspoglutide antibody results (safety population,
`n = 788)
`
`Taspoglutide 10 mg
`once weekly (n =394)
`
`Taspoglutide 20 mg
`once weekly (n = 394)
`
`Baseline, n
`Confirmed positive
`Week 12, n
`Confirmed positive
`Week 24, n
`Confirmed positive
`Week 52, n
`Confirmed positive
`Week 104, n
`Confirmed positive
`Postbaseline, n
`$1 confirmed positive
`
`374
`1 (0%)
`357
`45 (13%)
`307
`99 (32%)
`288
`105 (36%)
`132
`4 (3%)
`382
`166 (43%)
`
`368
`0
`361
`73 (20%)
`292
`136 (47%)
`265
`122 (46%)
`115
`11 (10%)
`382
`209 (55%)
`
`Pooled
`(n = 788)
`
`742
`1 (0%)
`718
`118 (16%)
`599
`235 (39%)
`553
`227 (41%)
`247
`15 (6%)
`764
`375 (49%)
`
`n, the number of patients who had at least one antibody test during the time windows for the scheduled time.
`All percentages are calculated using n from the associated scheduled time as the denominator. If a patient had
`antibody results from more than 1 day in the scheduled time of baseline, weeks 12, 24, 52, and 104, the worst
`result is summarized. A confirmed (positive) antibody response necessitated additional antibody testing at all
`subsequent planned study visits until the antibody test result returned to pretreatment values.
`
`formulations, as episodes tended to occur
`more frequently on the day of injection
`for taspoglutide, which is probably re-
`lated to the initial higher maximum
`plasma concentration of taspoglutide, an
`effect that may be related to the specific
`nature of the taspoglutide formulation
`tested (data not shown).
`As a consequence of the higher in-
`cidence of adverse events observed in both
`taspoglutide groups, almost twice as many
`patients receiving taspoglutide (34%) with-
`drew from the study than patients taking
`exenatide (16%). The higher than expected
`discontinuation rates primarily due to gas-
`trointestinal tolerability observed in the
`analyses of the 52-week data factored into
`the decision to terminate the clinical study.
`The withdrawal rate was further increased
`during the long-term extension phase of
`the study as a result of the risk-mitigation
`plan requiring discontinuation of patients
`with confirmed positive antitaspoglutide
`antibody test .230 ng-eq/mL regardless of
`the presence or absence of allergic adverse
`events.
`Systemic allergic reactions were more
`common in the taspoglutide-treated pa-
`tients than in exenatide-treated patients
`and resulted in withdrawal from the study
`of 31 of the 51 patients having a reaction
`in the taspoglutide groups. Most cases
`occurred after the 24-week core study
`period. Although allergic reactions are
`possible with protein-based therapies,
`the rate of this adverse event with taspo-
`glutide was higher than anticipated and
`
`has rarely been reported with other GLP-1
`receptor agonists (11).
`Antitaspoglutide antibodies were con-
`firmed positive in 49% of taspoglutide-
`treated patients.