Preserved Pharmacokinetic Exposure and Distinct Glycemic Effects of Insulin Degludec and Liraglutide in IDegLira, a Fixed-Ratio Combination Therapy

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1 Pharmacokinetics/Pharmacodynamics Preserved Pharmacokinetic Exposure and Distinct Glycemic Effects of Insulin Degludec and Liraglutide in IDegLira, a Fixed-Ratio Combination Therapy The Journal of Clinical Pharmacology 2015, 55(12) The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology DOI: /jcph.549 Christoph Kapitza, MD 1, Bruce Bode, MD 2, Steen Hvass Ingwersen, MSc 3, Lisbeth Vestergård Jacobsen, MSc 3, and Pernille Poulsen, MD 3 Abstract Insulin degludec/liraglutide (IDegLira) is a novel fixed-ratio combination of the basal insulin insulin degludec (IDeg) and liraglutide, a glucagon-like peptide-1 analog. The pharmacokinetics (PK) and pharmacodynamics of IDegLira were assessed versus its components. A single-dose, randomized, 4- period crossover clinical pharmacology study in healthy subjects compared the bioavailability of IDegLira with its monocomponents. Dose proportionality, covariate effects on exposure, and exposure response for change in glycated hemoglobin were analyzed based on data from a randomized treat-to-target phase 3 study in subjects with type 2 diabetes. Overall, the PK properties of IDeg and liraglutide were preserved for IDegLira. Liraglutide exposure was lower when dosed as IDegLira but met the criterion for equivalence. No relevant deviations from dose proportionality for the IDegLira components were observed. Covariate effects on exposure were consistent with previous results. Glycemic response to IDegLira was larger than with IDeg or liraglutide alone, reflecting their distinct glucose-lowering effects throughout the dose/exposure range. Keywords Clinical Pharmacology (CPH), Drug Interactions, Endocrinology (END), Pharmacodynamics (PDY), Population Pharmacokinetics Exposure Response Type 2 diabetes (T2D) is a progressive disease with an underlying complex pathophysiology involving multiple organs, necessitating a multitargeted approach to treatment. 1 Accordingly, there is a need for therapies that have complementary mechanisms of action to help achieve improved glycemic control with fewer side effects than the currently available treatment options. 2 IDegLira is a novel fixed-ratio combination of the basal insulin, insulin degludec (IDeg; 100 U/mL), and a once-daily glucagon-like peptide-1 (GLP-1) analog, liraglutide (3.6 mg/ml). IDegLira may be initiated and titrated, as performed with basal insulin, and administered in dose steps, in which 1 dose step is defined as 1 unit IDeg/0.036 mg liraglutide and can be titrated up to a maximum of 50 dose steps (50 units/1.8 mg). 3,4 IDeg is a new-generation basal insulin with an ultralong duration of action, providing a flat and stable glucose-lowering effect. 5 8 IDeg has been shown to be efficacious in lowering glycated hemoglobin (HbA 1c ) and fasting plasma glucose (FPG) levels in subjects with T2D, 9 11 with fewer hypoglycemic episodes, particularly nocturnal episodes, versus insulin glargine. 12 The molecular structure of IDeg and its solubility at neutral ph (7) allow it to be coformulated with liraglutide. Liraglutide is an injectable, once-daily GLP-1 analog 13,14 that mimics the effects of native GLP-1 in restoring the insulin response to glucose, 15 providing both fasting and postprandial glycemic control 16,17 in a glucose-dependent manner. Liraglutide reduces body weight and body fat mass through mechanisms involving reduced hunger and lowered energy intake Although GLP-1 receptor agonist treatment has been associated with a moderately increased risk of gastrointestinal adverse events such as nausea, liraglutide has generally been shown to be both well tolerated and effective in lowering HbA 1c levels in subjects with T2D in a number of clinical settings. 14,23 1 Profil, Neuss, Germany 2 Atlanta Diabetes Associates, Atlanta, GA, USA 3 Global Development, Novo Nordisk A/S, Sùborg, Denmark This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Submitted for publication 17 March 2015; accepted 18 May Corresponding Author: Christoph Kapitza, MD, Profil Institut f ur Stoffwechselforschung GmbH, Hellersbergstr. 9, Neuss D-41460, Germany christoph.kapitza@profil.com

2 1370 The Journal of Clinical Pharmacology / Vol 55 No 12 (2015) The pathophysiology of T2D and the complementary effects of the 2 treatments provide the clinical rationale for combining IDeg and liraglutide in a single treatment. Clinical benefits of IDegLira have been confirmed in 2 phase 3 clinical trials. 3,4 IDegLira is designed to be titrated according to individual glycemic control and not intended for direct substitution of its monocomponents. Nevertheless, to leverage the clinical experience with IDeg and liraglutide and in accordance with the European Medicines Agency guidelines for fixed-combination medicinal products, 24 the 2 studies discussed in this article provide a comparison of the pharmacokinetics (PK) of IDegLira versus the monocomponents. Overall, the current analysis assessed the extent to which combining IDeg and liraglutide in the same formulation affected the PK profiles of the 2 components. We also evaluated the effect of selected demographic and treatment-related covariates on exposure, dose exposure proportionality, and the contributions to glycemic control made by each of the individual components across the dose and exposure range. PK data were derived from 2 clinical studies: a clinical pharmacology single-dose study in healthy male subjects and population analyses based on data from the phase 3 DUAL TM I trial in subjects with T2D. Methods Both the clinical pharmacology single-dose study and the phase 3 DUAL TM I trial were registered with clinicaltrials.gov (NCT and NCT , respectively), and the protocols were approved by independent ethics committees or institutional review boards at all participating institutions. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2000 and The studies were performed in accordance with Good Clinical Practice as defined by the International Conference on Harmonisation. Subjects were fully informed of the study risks and were made aware that they could withdraw from the study at any time for any reason. Subjects were informed, and written consent was obtained before any trial-related procedures were initiated. Single-Dose Pharmacokinetics The clinical pharmacology study was a single-center, single-dose, randomized, double-blind, double-dummy, 4-period crossover study in 24 healthy male subjects. The primary objective of the study was to investigate the safety and tolerability of IDegLira (17 dose steps, equivalent to 17 units IDeg/0.6 mg liraglutide) compared with IDeg (17 units) alone, liraglutide (0.6 mg) alone, and separate but simultaneous administration of IDeg and liraglutide. The 4 treatments were given in a randomized order. Eligible subjects were aged between 18 and 55 years and had a body mass index (BMI) of kg/m 2 and a FPG level 6.1 mmol/l. Strenuous exercise was not permitted within 48 hours of the study, and the subjects were not allowed to consume alcohol within 24 hours of dosing or methylxanthinecontaining beverages (tea, coffee, cola) within 48 hours of dosing. Concomitant medications were not permitted during the study, except for paracetamol, acetylsalicylic acid, and vitamins. The trial included 4 in-house dosing visits (with 7 15 days between dose administrations to allow for washout). PK end points were derived from the 96-hour concentration time profile of IDeg and the 72-hour concentration time curves of liraglutide following single doses of IDegLira or of the monocomponents. Blood samples for IDeg and liraglutide measurements were obtained before dose administration and then at regular points postdosing. For IDeg, blood samples were obtained 1, 2, 4, 6, and 8 hours postdosing, hourly between 10 and 16 hours, every 2 hours between 18 and 24 hours, at the 30-hour point, every 12 hours between 36 and 72 hours, and at the 96-hour point postdosing. For liraglutide, blood samples were obtained at 2 and 4 hours, hourly between 6 and 14 hours, and 16, 20, 24, 30, 36, 48, 60, and 72 hours postdosing. IDeg concentration in serum was determined using a validated IDeg-specific enzyme-linked immunoabsorbent assay (ELISA) with a lower limit of quantification (LLOQ) of 20 pmol/l. Liraglutide concentration in plasma was determined using a validated ELISA with a LLOQ of 30 pmol/l. The same methods were also used in the phase 3 study described below. The key PK end point was exposure to IDeg and liraglutide, defined as the AUC 0 1,IDeg and AUC 0 1,lira, respectively. Additional secondary PK end points included C max,ideg, C max,lira, and time to maximum concentration for IDeg (t max,ideg ) and liraglutide (t max,lira ). PK end points for IDeg and liraglutide were estimated using a noncompartmental method (SAS version 9.3, SAS Institute Inc., Cary, North Carolina). For the statistical analysis, AUC 0 1,IDeg, AUC 0 1,lira, C max,ideg, and C max,lira were transformed using the natural logarithm and analyzed using a linear normal mixed model with treatment and period as fixed effects, with subject as a random effect and an error term. The estimated treatment differences were transformed back to the original scale and presented as ratios with 95% confidence intervals (CIs). As part of a post-hoc evaluation presented in this article and in accordance with the guideline for fixedcombination medicinal products, 24 the ratios for AUC 0 1 and C max were also presented with 90%CIs, and equivalence was confirmed if the 90%CIs were within the range for bioequivalence ( ).

3 Kapitza et al 1371 Population Pharmacokinetic Analysis (Phase 3 Study) Study Design. The phase 3 study was a 26-week, randomized, open-label, multicenter, parallel, 3-arm, treat-to-target trial comparing IDegLira versus IDeg or liraglutide alone in subjects with T2D treated with metformin pioglitazone. 4 The full analysis set included a total of 1660 randomized subjects, with 833 subjects randomized to the IDegLira treatment arm, and 414 and 413 to the IDeg and liraglutide treatment arms, respectively. A population PK analysis was carried out with the phase 3 data to assess dose proportionality and covariate effects for the exposure in patients with T2D during steady state throughout the full dose range. Data from 1549 patients were available for population PK analysis. The data set for the IDeg analysis contained 7892 concentration values from 1173 patients dosed with either IDegLira or IDeg. The data set for the liraglutide analysis contained 6888 observations from 1141 subjects dosed with either IDegLira or liraglutide. Eligible subjects were male or female adults, aged 18 years with a BMI 40 kg/m 2 and an HbA 1c level in the range of 7.0% 10.0%. Subjects were randomized using a 2:1:1 randomization scheme for the treatments IDegLira, IDeg, and liraglutide. IDegLira treatment (starting dose: 10 dose steps, equivalent to 10 U IDeg/0.36 mg liraglutide) was titrated to the fasting glycemic target of mmol/l (72 90 mg/dl), and subcutaneously administered with a maximum planned dose of 50 dose steps (50 units of IDeg and 1.8 mg of liraglutide). IDeg treatment was titrated to the same fasting glycemic target with no maximum dose. All subjects in the liraglutide group were dose-escalated from 0.6 to 1.8 mg/day, with weekly dose increases of 0.6 mg/day. The primary clinical end point was the change from baseline in HbA 1c. The study also compared the PK of IDegLira versus the monocomponents at clinically relevant doses. Population Pharmacokinetic Analysis. During the 26-week study, single blood samples for serum concentrations of IDeg and/or plasma concentrations of liraglutide were drawn at weeks 1, 2, 4, 8, 12, 16, 20, and 26. The investigator recorded the actual clock time of sampling on the case report form. Samples from the IDegLira and IDeg treatment groups were assayed for serum concentrations of IDeg, and samples from the IDegLira and liraglutide treatment groups were assayed for plasma concentrations of liraglutide. Dosing information (dose level, injection site, and time and day of dosing) was recorded for 3 4 doses prior to blood sampling. The population PK analysis of phase 3 data included analysis of dose proportionality based on data for the IDegLira treatment only and analysis of covariate effects on apparent clearance (CL/F), and hence exposure, based on data from IDegLira and the monocomponents dosed alone. In each analysis, effects were deemed as being pharmacokinetically relevant if 90%CIs for relative exposure were outside the criterion for bioequivalence (90%CI, ). For the analysis of dose proportionality, models including effects of body weight and dose on CL/F for IDeg, and effects of body weight, sex, and dose on CL/F for liraglutide, were estimated using data from the IDegLira treatment. To evaluate dose proportionality, the exposure-versus-dose relationships in these models were compared with the relationship for otherwise identical models assuming dose proportionality. Body weight was included in the models used for assessing dose proportionality to eliminate possible bias because of the likely increase in titrated IDegLira doses with increasing body weight. For liraglutide, sex was also included in the model, as sex has previously been shown to have an effect on CL/F for liraglutide. 25 Further methodological details are available in the Appendix. The covariate effects on exposure for IDeg and liraglutide were analyzed separately using a prespecified full model approach 26,27 and data from all treatment groups. The covariate analysis included effects of time, treatment type (IDegLira, IDeg, and liraglutide), injection site, ethnicity, race, age, sex, and body weight on exposure in terms of dose-normalized area under the curve (AUC) in the 24-hour dosing interval. The population PK analysis was conducted according to a prospective analysis plan. The models were validated and found to be suitable using standard goodness-of-fit plots, evaluation of PK parameter estimates, assessment of shrinkage and sensitivity toward influential outliers, and a simplified visual predictive check. Furthermore, the results of the covariate analysis were found to be in accordance with results obtained from a time-independent analysis of dose-normalized concentrations. 26 Details on the models used for assessing dose proportionality and covariate effects on exposure are provided in the Appendix. Dose Response and Exposure Response Analyses The exposure response relationship for IDegLira in subjects with T2D was assessed using data from the phase 3 trial. This was performed by comparing dose and exposure with HbA 1c response for IDegLira with each of its components. The purpose of this was to establish the contribution of both components of IDegLira to the overall glycemic response across its dose and exposure range. Data sets used for the exposure response analysis of HbA 1c were derived from the PK data set used for the population PK analysis. Subjects without recorded values of HbA 1c at week 26 were excluded to avoid bias originating from imputed values. Exposure was expressed as model-derived AUC within a dosing interval at steady state for IDeg and liraglutide following doses of IDegLira or its individual components. The exposure response

4 1372 The Journal of Clinical Pharmacology / Vol 55 No 12 (2015) relationship for HbA 1c at week 26 was described graphically using baseline-adjusted values for change in HbA 1c from baseline. Baseline adjustment was achieved by subtracting the effect of baseline HbA 1c as determined from a linear model with HbA 1c change from baseline as the response, baseline HbA 1c as a covariate and treatment as a fixed effect. Safety Assessments Safety assessments were recorded during the clinical pharmacology study and the phase 3 study. These included adverse events, hypoglycemia, physical examination, electrocardiogram, IDeg- and liraglutide-specific antibodies, and other laboratory tests. Results Baseline Demographics Baseline characteristics of the patient populations are briefly described as follows. In the clinical pharmacology study, 24 healthy male subjects were randomized and exposed to treatment. Mean age was 36 years (range, years), mean (standard deviation [SD]) body weight was 79.6 (7.2) kg, and mean (SD) BMI was 24.7 (1.9) kg/m 2. The phase 3 trial included 1663 randomized subjects with T2D on metformin pioglitazone. Across the three treatment groups, mean (SD) age was 55.1 (9.9) years, mean (SD) body weight was 87.2 (19.0) kg, and mean (SD) BMI was 31.2 (5.2) kg/m 2. Single-Dose Pharmacokinetics The mean IDeg and liraglutide concentrations over time following each of the 4 dose administrations are presented in Figure 1A,B. The relative bioavailability of IDeg namely, the ratio of the AUC for IDeg (AUC 0 1, IDeg) between administration as part of IDegLira and administration of IDeg alone was 1.03, with the 90% CIs within the limits for bioequivalence. For the maximum concentration of IDeg (C max,ideg ), the ratio was 1.12, with the 90%CI just exceeding the upper limit for bioequivalence (Table 1). The relative bioavailability of liraglutide that is, the ratio of AUC for liraglutide (AUC 0 1,lira ) between administration as part of IDegLira and liraglutide alone was 0.89, with the 90%CI within the limits for bioequivalence (Table 1). The C max,lira ratio for liraglutide between administration as part of IDegLira and liraglutide was 0.77; however, the 90%CI was outside the lower limit for bioequivalence. Similar results were obtained when comparing exposure of IDegLira with those following concomitant but separate administrations of IDeg and liraglutide (Table S1), and equivalence was shown for all comparisons between separate (concomitant) administrations compared with IDeg alone and liraglutide alone, respectively. A summary of PK end points derived after 4 singledose administrations (IDegLira, IDeg, liraglutide, and separate simultaneous administration of IDeg and liraglutide) in healthy subjects is available in Table S2. The mean time to reach maximum concentration (t max ) Figure 1. Concentration time profiles and model-derived steady-state profiles. Concentration time profiles (A) for insulin degludec (IDeg) following single doses of 17 units of IDeg and (B) following 0.6 mg of liraglutide when dosed as IDegLira and separately, either alone or concomitantly with the other monocomponent. Model-derived steady-state pharmacokinetics profiles for (C) IDeg and (D) liraglutide when dosed as IDegLira (50 units/1.8 mg) and IDeg (50 units) or liraglutide (1.8 mg) alone for a reference subject with type 2 diabetes.

5 Kapitza et al 1373 Table 1. Analysis of AUC 0 1 and C max ; Treatment Ratios for Insulin Degludec (IDeg) and Liraglutide From a Single-Dose Study in Healthy Male Subjects Treatment/Comparison Estimate 90%CI AUC 0 1,IDeg ; treatment ratio IDegLira/IDeg C max,ideg ; treatment ratio IDegLira/IDeg AUC 0 1,lira ; treatment ratio IDegLira/liraglutide C max,lira ; treatment ratio IDegLira/liraglutide AUC, area under the curve; C max, maximum serum concentration; CI, confidence interval; IDeg, insulin degludec; IDegLira, insulin degludec/ liraglutide. The data shown above are from a post-hoc analysis. The estimates are from an ANCOVA model with treatment and period as fixed effects and subject as random effect and an error term. was comparable for IDeg and liraglutide when dosed as IDegLira compared with separate administrations, either alone or concomitantly with the other monocomponent (Table S2). Population Pharmacokinetic Analyses Analyses to evaluate dose proportionality were performed using a population PK model. Plots of IDeg and liraglutide exposure expressed as AUC 0 24 h at steady state versus dose for the model, with dose effects on clearance included, are shown in Figure 2. The 90%CIs for both the IDeg model and the liraglutide model with dose effects were within the 80% 125% CI of the reference dose-proportional model (Figure 2), indicating that there were no pharmacokinetically relevant deviations from dose proportionality for IDeg or liraglutide when dosed in combination as IDegLira. The covariate analysis for IDeg revealed no difference in exposure (dose-normalized AUC) when dosed as IDegLira compared with IDeg dosed alone (estimated mean ratio, 1.02; 90%CI, ; Figure 3A). This is in agreement with the PK parameters observed after single-dose administration in healthy subjects (Table 1). The covariate analysis for liraglutide showed a mean reduction of 14% in exposure (dose-normalized AUC) when dosed as IDegLira compared with liraglutide dosed alone, with the 90%CI within the limits for equivalence (Figure 3B), which is in accordance with the results seen in healthy subjects in the single-dose study (Table 1). Given that no relevant deviations from dose proportionality of AUC 0 24 h,ss were observed for liraglutide following administration of IDegLira (Figure 2B), it can be inferred that the reduced liraglutide exposure for IDegLira compared with liraglutide dosed alone is consistent across the dose range. Furthermore, the analysis of covariate effects on exposure to IDeg and liraglutide established that the exposure of IDeg was dependent on body weight (Figure 3A); similar results with respect to body weight were also seen with liraglutide (Figure 3B). There were no pharmacokinetically relevant effects for IDeg or liraglutide with respect to time (since the start of treatment), injection site, race, ethnicity, age, or sex (Figure 3). Taken together, these findings are consistent with previous results obtained for covariate effects for IDeg (data on file) and liraglutide. 25 The modeled concentration time profile of IDeg at steady state following IDegLira administration was similar to the profile for IDeg dosed alone (Figure 1C). The PK profile demonstrated that exposure is distributed evenly across the 24-hour dosing interval. Similar data were also observed with liraglutide (Figure 1D). These data are consistent with the results obtained in the singledose clinical pharmacology study (Figure 1A,B). Figure 2. Dose-proportionality plots for (A) insulin degludec (IDeg) and (B) liraglutide following steady-state doses of IDegLira. The solid lines represent means, whereas broken lines indicate 90%CIs of AUC 0 24 h,ss versus dose, from a model with dose effect included. The shaded areas represent the 80% 125% CI from a model with dose proportionality. The symbols indicate means and 95%CIs for individual model-derived estimates for percentiles of dose values.

6 1374 The Journal of Clinical Pharmacology / Vol 55 No 12 (2015) Figure 3. Forest plot of covariate analysis for (A) insulin degludec (IDeg) and (B) liraglutide from a phase 3 study of IDegLira and its individual components in subjects with type 2 diabetes. Data points and 90%CIs are expressed as dose-normalized steady-state exposure (AUC 0 24 h ) relative to a median body weight (85.8 kg), non-hispanic, white female subject aged <65 years dosed weeks 1 11 in the thigh by IDeg or liraglutide, respectively. Dotted lines indicate the acceptance interval used for bioequivalence testing, for comparison. The column to the right provides the geometric mean relative exposures with 90%CIs obtained by likelihood profiling. Dose Response and Exposure Response Analyses The effects of IDegLira and IDeg on the change in HbA 1c from baseline are shown in Figure 4. At all doses (Figure 4A) and exposure levels (Figure 4B), the effect of IDegLira on HbA 1c response was larger than the effect of IDeg dosed alone. These data confirm that liraglutide contributed to the HbA 1c -lowering effect of IDegLira across the entire dose/exposure range. A similar analysis was performed for IDegLira versus liraglutide given alone. Figure 4C, shows the effects on HbA 1c change from baseline versus liraglutide dose for IDegLira and for separate liraglutide (1.8 mg) administration. The effect of IDegLira on HbA 1c was larger than that of liraglutide (1.8 mg) dosed alone (Figure 4C), owing to the contribution of the IDeg component in IDegLira. Similarly, the effect of IDegLira was larger than the effect of liraglutide dosed alone at all exposure levels (Figure 4D), confirming that IDeg contributed to the effect of IDegLira throughout the range of exposures analyzed. Safety Overall, single-dose administration of IDegLira did not give rise to any safety or tolerability issues of concern in healthy male subjects. The incidence of adverse events was comparable between treatment with IDegLira (7 events in 6 subjects), IDeg (9 events in 6 subjects), and liraglutide (7 events in 6 subjects). Adverse events were mild or moderate in severity. The rate of gastrointestinal disorders was also low, with 1 event of nausea reported with IDeg and 2 events of vomiting reported in 2 subjects with liraglutide treatment. Similarly, treatment with IDegLira, IDeg, and liraglutide was well tolerated in the phase 3 study (discussed in further detail in Gough et al, 4 ). Discussion The main objectives of these analyses were to evaluate PK exposure, including dose proportionality, for IDegLira compared with its monocomponents and to demonstrate

7 Kapitza et al 1375 Figure 4. Change in HbA 1c from baseline to week 26. For IDegLira and IDeg (A) versus dose and (B) versus exposure (AUC) for IDeg at steady state. For IDegLira and liraglutide (C) versus dose and (D) versus exposure (AUC) for liraglutide at steady state. IDegLira, IDeg, and liraglutide are represented by green circles, blue triangles, and red squares, respectively. Data for HbA 1c (%) are expressed as baseline-adjusted mean with 95%CI versus percentiles of dose or exposure of IDeg (A and B) or liraglutide (C and D). the contribution from each component to overall glycemic control. Consistent with the single-dose study in healthy male subjects, the exposure, assessed as AUC, for IDeg was similar when administered as part of IDegLira compared with administration as IDeg alone. Liraglutide exposure was lower when dosed as IDegLira but met the criterion for equivalence. However, the C max,ideg was higher (by 12%) following IDegLira dosing, whereas C max,lira was lower (by 23%) for liraglutide when administered as part of IDegLira. Based on the population PK analysis, there were no relevant deviations from dose proportionality for either of the components of IDegLira across the recommended dose range, as previously documented for IDeg and liraglutide. 6,25,28 Furthermore, covariate analysis demonstrated that there was no difference in IDeg dose-normalized exposure (AUC) with IDegLira compared with IDeg alone, supporting the findings of the single-dose PK study. A lower mean steady-state liraglutide exposure was observed consistently across the 2 studies (including in healthy subjects and those with T2D), when dosed as part of IDegLira compared with liraglutide alone and was within the criterion set for bioequivalence. Thus, the pharmacokinetics in the single-dose trial were maintained at steady state across the entire therapeutic dose range. The minor difference in exposures following IDegLira compared with the monocomponents was not considered to be clinically relevant as IDegLira was intended to be titrated in a similar manner as for a basal insulin product, based on the individual needs of the patient. As expected, exposure to both components of IDegLira was inversely correlated with body weight, but other covariates (time since start of treatment, treatment type [IDegLira, IDeg, or liraglutide], injection site, race, age group, and sex) were shown to have little or no effect on exposure. These results were largely consistent with the results seen in the individual IDeg and liraglutide clinical development programs. 25,29 31 Dose/exposure response analyses showed that across the entire range of doses and exposures, the effect of IDegLira on HbA 1c levels was larger than the effect of both IDeg and liraglutide administered alone. It can therefore be concluded that the IDeg and liraglutide components contribute distinctly to the glycemic effect of IDegLira throughout the studied dose and exposure ranges. The complex pathophysiology of T2D necessitates a multitargeted therapeutic approach for which the use of combination therapies for improved glycemic control is an appropriate treatment option. 1,2 The results presented here demonstrated that the PK properties of IDeg and liraglutide were largely preserved in the fixed-dose ratio combination product IDegLira, with no pharmacokinetically relevant deviations from dose proportionality for IDeg or for liraglutide when dosed as IDegLira across the therapeutic dose range. Moreover, the dose/exposure response analyses showed that both monocomponents of IDegLira distinctly contribute to overall glycemic control,

8 1376 The Journal of Clinical Pharmacology / Vol 55 No 12 (2015) supporting efficacy data from the clinical trial program for IDegLira. 3,4 As such, it can be concluded that by combining 2 complementary modes of action, IDegLira is a valuable addition to the treatment options available in T2D, offering a convenient, well-tolerated, and multitargeted once-daily therapeutic option with the potential for improved glycemic control. Acknowledgments This study was funded by Novo Nordisk A/S. Medical writing support was provided by apothecom scopemedical ltd and funded by Novo Nordisk A/S. Declaration of Conflicting Interests C. K. has received research funds from Adocia, Boehringer Ingelheim, Dance Pharmaceuticals, Gr unenthal, Hoffmann LaRoche, Johnson & Johnson, Eli Lilly, Mars, Marvel, Novo Nordisk, Novartis, Perosphere, Pfizer, Sanofi, and Senseonics and received speaker and travel grants from Sanofi and Novo Nordisk. B.B. has served on speakers bureaus for DexCom, GlaxoSmithKline, Janssen, Insulet, Eli Lilly, Medtronic, Merck, Novo Nordisk, Sanofi, and Valeritas; performed consultancy for Halozyme, Janssen, Medtronic, Novo Nordisk, Sanofi, and Valeritas; received research and grant support to employer from Abbott, Biodel, DexCom, GlaxoSmithKline, Halozyme, Janssen, Lexicon, Eli Lilly, MannKind, Medtronic, Novo Nordisk, Pfizer, Sanofi, and Valeritas. S.H.I., L.V.J., and P.P. are employees and shareholders of Novo Nordisk A/S. No other potential conflicts of interest relevant to this article were reported. The data discussed in this article were presented in a poster (No. 826) at the 50th EASD annual meeting on September 15 19, Author Contributions C.K. designed the clinical pharmacology study in healthy subjects, performed the research, and edited the article. B.B. performed the research and edited the article. S.H.I. and L.V.J. analyzed the data and contributed to and edited the article. P.P. designed the studies and contributed to and edited the article. C.K. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. References 1. Lin Y, Sun Z. Current views on type 2 diabetes. J Endocrinol. 2010;204(1): Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35(6): Buse JB, Vilsbùll T, Thurman J, et al. Contribution of liraglutide in the fixed-ratio combination of insulin degludec and liraglutide (IDegLira). Diabetes Care. 2014;37(11): Gough SCL, Bode B, Woo V, et al. 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