Takeda Development Centre Europe Ltd Research Articles

Long-Term Efficacy and Safety of Ertugliflozin in Patients (Pts) with Type 2 Diabetes Mellitus (T2DM) Inadequately Controlled with Metformin (MET) Monotherapy—104-Week VERTIS MET Trial

This Phase 3 randomized, double-blind study in adults with T2DM (A1C 7.0-10.5%) on MET monotherapy (≥1500 mg/day ≥8 weeks) included a 26 week placebo (PBO)-controlled period followed by a 78 week extension where non-rescued PBO pts with fasting finger-stick glucose ≥110 mg/dL received blinded glimepiride (GLIM). Efficacy, safety and effect on bone mineral density (BMD) of ertugliflozin (ERTU) 5 mg and 15 mg QD at week 104 are reported. Pts (N=621) had baseline mean ± SD: age 56.6 ± 8.8 y; T2DM duration 8.0 ± 6.0 y; BMI 31.1 ± 4.7 kg/m2; A1C 8.1 ± 0.9%. 41% were post-menopausal women. At week 104, ERTU 5 mg and ERTU 15 mg reduced A1C, FPG, body weight (BW) and blood pressure (BP) compared to baseline, and increased the proportion of pts with A1C <7% (Table). Incidence of female genital mycotic infections was higher in ERTU 5 mg (7.3%; p=0.017) and 15 mg (9.8%; p=0.003) vs. PBO/GLIM (0.9%). Symptomatic hypoglycemia was lower in ERTU 5 mg (5.8%; p=0.009) and 15 mg (5.9%; p=0.009) vs. PBO/GLIM (13.4%). ERTU had no impact on BMD vs. PBO/GLIM, except total hip where BMD reduction was greater for ERTU 15 mg (Table). Fractures occurred in 3, 2 and 7 pts in ERTU 5 mg, 15 mg and PBO/GLIM, respectively. ERTU added to MET in pts with inadequately controlled T2DM improved glycemic control, BW and BP over 104 weeks. ERTU was well tolerated with no clinically meaningful impact on BMD. Table: Change in efficacy (vs baseline) and bone mineral density (vs PBO/GLIM) endpointsERTU 5 mgERTU 15 mg Efficacy endpointsa (change vs baseline)Change from baseline at Wk 104: LS mean (95% CI)bA1C (%)-0.5 (-0.6, -0.4)-0.8 (-0.9, -0.6)FPG (mg/dL)-17.0 (-22.7, -11.3)-26.7 (-32.5, -21.0)Body weight (kg)-3.6 (-4.2, -3.0)-3.5 (-4.1, -2.9)SBP (mmHg)-3.9 (-5.8, -2.0)-2.8 (-4.8, -0.9)DBP (mmHg)-2.3 (-3.6, -1.1)-1.2 (-2.5, 0.0)Proportion of subjects with A1C <7%c27.1%36.6% BMD endpointsd (change vs PBO/GLIM)Percent change from baseline at Wk 104: Difference in LS mean (95% CI) vs PBO/GLIMbLumbar spine-0.3 (-1.1, 0.5)-0.2 (-1.0, 0.6)Femoral neck0.1 (-0.7, 0.9)0.3 (-0.6, 1.1)Total hip-0.5 (-1.1, 0.1)-0.8 (-1.4, -0.2)Distal forearm0.2 (-0.5, 0.9)-0.1 (-0.8, 0.7)a All efficacy analyses were based on the full analysis set and excluding data after initiation of glycemic rescue therapy. 23 (11.1%), 22 (10.7%) and 51 (24.4%) pts in the ERTU 5 mg, 15 mg and PBO/GLIM groups, respectively, received glycemic rescue through Wk 104 (out of all pts randomized and treated).b Based on constrained longitudinal data analysis (cLDA) model with fixed effects for treatment, time, prior antihyperglycemic medication (metformin monotherapy or metformin + another antihyperglycemic medication), baseline eGFR (continuous), menopausal status (men, premenopausal women, women perimenopausal or <3 years postmenopausal, women ≥3 years postmenopausal) and the interaction of time by treatment. Time was treated as a categorical variable.c Missing data imputed using the cLDA model fitted with fixed effects as in the primary analysis. Ten imputed values were created for each missing value. A pt with missing data was considered to have an A1C <7.0% if at least 6 of 10 imputed values were <7.0%.d BMD analyses were based on raw data, and excluding data after initiation of bone rescue therapy. 1 pt in the ERTU 5 mg group and 1 pt in the ERTU 15 mg group received bone rescue. Disclosure S. Gallo: Employee; Self; Pfizer Inc. B. Charbonnel: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Sanofi, Takeda Development Centre Europe Ltd. A. Goldman: Stock/Shareholder; Self; Merck & Co., Inc.. Employee; Self; Pfizer Inc.. Stock/Shareholder; Self; Pfizer Inc. H. Shi: Employee; Self; Pfizer Inc. S. Huyck: Employee; Self; Merck & Co., Inc. A. Darekar: Employee; Self; Pfizer Inc.. Stock/Shareholder; Self; Pfizer Inc. B. Lauring: Employee; Self; Merck & Co., Inc. S. Terra: Employee; Self; Pfizer Inc..

Treatment Effects of Once-Weekly Dulaglutide vs. Insulin Glargine in Patients with Different Baseline Glycemic Patterns (Based on High/Low Fasting or High/Low Postprandial Glucose)—A Post-Hoc Analysis of the AWARD-2 Clinical Trial

Insulin glargine (Glar) exerts its action primarily through a decrease in fasting plasma glucose (FPG), whereas dulaglutide (DU), a once-weekly GLP-1RA, targets both fasting and postprandial glucose (PPG). This post-hoc analysis of the AWARD-2 study assessed the efficacy of DU vs. Glar in patients with type 2 diabetes with different glycemic patterns at baseline determined by self-monitoring of blood glucose (fasting glucose [FG] vs. PPG). Patients were categorized into 4 groups based on combinations of low and high FG and PPG, with median baseline values of FG (151 mg/dL) and PPG (182 mg/dL) being used as threshold for low and high, respectively. Analyses were conducted using analysis of covariance. DU showed a statistically significantly greater reduction in A1c compared with Glar for all of the subgroups, except for low FG/high PPG, where the numerical difference was in favor of DU but did not reach statistical significance (Table). Total hypoglycemia was numerically lower for DU vs. Glar in all subgroups. DU showed efficacy on A1c reductions across different baseline glycemic patterns vs. Glar (with the exception of low FG/high PPG), indicating a clinical benefit of targeting both FG and PPG, irrespective of the baseline glycemic phenotype. Disclosure F. Giorgino: Consultant; Self; Abbott, AstraZeneca, Boehringer Ingelheim GmbH. Research Support; Self; Eli Lilly and Company, Johnson & Johnson Services, Inc.. Consultant; Self; MedImmune, Merck Sharp & Dohme Corp., Roche Diabetes Care Health and Digital Solutions, Sanofi. Research Support; Self; Takeda Development Centre Europe Ltd. M. Yu: Employee; Self; Eli Lilly and Company. A. Haupt: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. Z. Milicevic: Employee; Self; Eli Lilly and Company. L. Garcia-Perez: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company.

The Cost-Effectiveness of Alogliptin Versus Sulfonylurea as Add-on Therapy to Metformin in Patients with Uncontrolled Type 2 Diabetes Mellitus.

IntroductionENDURE (ClinicalTrials.gov identifier, NCT00856284), a multicenter, double-blind, active-controlled study of 2639 patients with uncontrolled type 2 diabetes mellitus (T2DM), found that metformin in combination with alogliptin (12.5 and 25 mg doses), when compared to standard add-on therapy (sulfonylurea, SU), exerted sustained antihyperglycemic effects over 2 years. This economic analysis of ENDURE aimed to quantify the relationship between increased glycemic durability and cost-effectiveness of alogliptin in the UK clinical setting, and communicate its sustained glycemic benefit in economic terms.MethodsUsing baseline characteristics and treatment effects from the ENDURE trial population, between-group cost-effectiveness analyses compared the combined use of metformin and alogliptin (MET + ALO12.5/25) in patients with inadequately controlled T2DM, as an alternative to metformin and SU (MET + SU). In scenario analyses, an intragroup cost-effectiveness analysis compared MET + ALO12.5/25 with MET + SU; a between-group cost-effectiveness analysis also compared MET + ALO12.5/25 versus MET + SU within a subpopulation of patients who achieved HbA1c control (<7.5%) at 2 years on study drug.ResultsCompared with baseline profiles of patients, combination therapies with alogliptin or SU were associated with improvements in length and quality of life and were cost-effective at established norms. Despite increased drug acquisition costs, alogliptin at 12.5 mg and 25 mg doses resulted in greater predicted lifetime quality-adjusted life year (QALY) gains with associated incremental cost-effectiveness ratios (ICERs) of £10,959/QALY and £7217/QALY compared to SU, respectively.ConclusionThe ENDURE trial and the present cost-effectiveness analysis found that the glycemic durability of alogliptin therapy was associated with improved long-term patient outcomes, QALY gains, and ICERs that were cost-effective when evaluated against standard threshold values. Alogliptin therefore represents a cost-effective treatment alternative to SU as add-on therapy to metformin in patients with poorly managed T2DM.FundingTakeda Development Centre Europe Ltd.Electronic supplementary materialThe online version of this article (doi:10.1007/s13300-016-0206-7) contains supplementary material, which is available to authorized users.

PTH-084 Cost-Effectiveness of Vedolizumab Compared with Infliximab, Adalimumab, and Golimumab for Treatment of Moderately-to-Severely Active Ulcerative Colitis in The United Kingdom

Introduction The objective of this analysis was to examine the clinical and economic impact of vedolizumab (VDZ) compared with infliximab (IFX), adalimumab (ADA), and golimumab (GOL) in the treatment of moderately to severely active ulcerative colitis (UC) in the UK (UK). Methods A Markov decision analytic model in Microsoft Excel was used to compare VDZ with IFX, ADA, and GOL for the treatment of UC patients in the UK. Due to a lack of data in comparable patient populations, this analysis was conducted in anti-tumour necrosis factor (TNF)-naive patients only. Efficacy data were obtained from a network meta-analysis of Phase III clinical trials, using placebo as the common comparator. Other inputs (e.g., unit costs, adverse event disutilities, probability of surgery, mortality) were obtained from published literature. Costs are presented in 2014 British pounds. Outcomes included quality-adjusted life-years (QALY), time spent in clinical response, and time spent in clinical remission. Time horizons included 10 year (base case) and lifetime (scenario) horizons, with costs and outcomes discounted by 3.5% per year. Incremental cost-effectiveness ratios (ICER) were presented for VDZ compared with other biologics. Univariate and multivariate probabilistic sensitivity analyses were conducted to assess model robustness to parameter uncertainty. Results Over the base-case (10 year) time horizon, the model predicted that anti-TNF-naive patients on VDZ accrued more QALY than patients on other biologics: 5.898 QALY vs 5.818, 5.760, and 5.790 QALY for IFX, ADA, and GOL, respectively. The incremental results over a 10 year horizon suggests that VDZ is a cost-effective treatment compared with ADA (ICER of £6,634/QALY), and VDZ is dominant compared with IFX and GOL. Patients on VDZ spent more time in clinical response (2.93 years vs 2.55 years for ADA, IFX and GOL) and clinical remission (1.38 years vs 1.08, 0.99, and 1.04 years for IFX, ADA and GOL respectively). VDZ was found to be dominant compared with all other biologics over a lifetime horizon. Sensitivity analyses suggest that results are most sensitive to treatment response and transition probabilities. However, VDZ remained cost-effective irrespective of variation in any of the input parameters. Conclusion Our model predicted that treatment with VDZ improves QALY, increases time in remission and response, and is a cost-effective treatment option for anti-TNF-naive patients with moderately to severely active UC compared with all other biologics tested. VDZ may also be a cost-saving treatment strategy as well. Disclosure of Interest M. Wilson Conflict with: Employee of RTI Health Solutions, a company hired to conduct the study by Takeda Pharmaceuticals, M. Kerrigan Conflict with: Employee of PHMR Ltd, a company hired to conduct the study by Takeda Pharmaceuticals, M. Smyth Employee of: Takeda Development Centre Europe Ltd, London, UK, H. Chevrou-Severac Employee of: Takeda Pharmaceuticals GmbH, Zurich, Switzerland, A. Bergman Employee of: Takeda Pharmaceuticals GmbH, Zurich, Switzerland, R. Selby Employee of: Takeda UK Ltd., Bucks, UK

PTH-083 Cost-Effectiveness of Vedolizumab Compared with Conventional Therapy for Treatment of Moderately-to-Severely Active Ulcerative Colitis in The United Kingdom

Introduction The objective of this analysis was to examine the clinical and economic impact of vedolizumab (VDZ) compared with conventional therapy (CT) in the treatment of moderately to severely active ulcerative colitis (UC) in the UK (UK). Methods A Markov decision analytic model in Microsoft Excel was used to compare VDZ with CT (aminosalicylates, corticosteroids, immunomodulators) for the treatment of UC patients in the UK. We considered three populations: the overall intent-to-treat (ITT) population; anti-tumour necrosis factor (TNF)-naive patients; and patients who previously failed anti-TNF therapy from the GEMINI 1 trial. Population characteristics, efficacy data, and UC health-state utility data were obtained from the GEMINI 1 trial. Other inputs (e.g., unit costs, adverse event disutilities, probability of surgery, mortality) were obtained from published literature. Costs are presented in 2014 British pounds. Outcomes included quality-adjusted life-years (QALY), time spent in clinical response, and time spent in clinical remission. Time horizons included 10 year (base-case) and lifetime (scenario) horizons, with costs and outcomes discounted by 3.5% per year. Incremental cost-effectiveness ratios (ICER) were presented for VDZ compared with CT. Univariate and multivariate probabilistic sensitivity analyses were conducted to assess model robustness to parameter uncertainty, and a scenario analysis was explored using efficacy data from a network meta-analysis. Results Over the base-case (10 year) time horizon, the model predicted that patients on VDZ accrued more QALY than patients on CT: 5.551 QALY vs 5.397 QALY in the ITT population (ICER=£33,297/QALY); 5.597 vs 5.403 QALY for anti-TNF-naive patients (ICER=£24,657/QALY; network meta-analysis results: utilities 5.898 for VDZ vs 5.555 for CT and ICER=£4,862/QALY); and 5.463 vs 5.373 QALY for anti-TNF-failure patients (£64,999/QALY). Patients on VDZ spent more time in clinical response (0.99 years vs 0.27 years for the ITT population) and clinical remission (0.64 years vs 0.13 years) than patients on CT. Scenario analyses with a lifetime horizon showed VDZ to be even more cost-effective (ITT population ICER=£20,599/QALY). Sensitivity analyses suggest that results are most sensitive to treatment response and transition probabilities. Conclusion Our model predicted that treatment with VDZ improves QALY, increases time in remission and response, and is a cost-effective treatment option for both anti-TNF naive and anti-TNF failure patients with moderately to severely active UC compared with CT over 10 year and lifetime horizons. Disclosure of Interest M. Wilson Conflict with: Employee of RTI Health Solutions, a company hired to conduct the study by Takeda Pharmaceuticals, M. Kerrigan Conflict with: Employee of PHMR Ltd, a company hired to conduct the study by Takeda Pharmaceuticals, M. Smyth Employee of: Takeda Development Centre Europe Ltd, London, UK, H. Chevrou-Severac Employee of: Takeda Pharmaceuticals GmbH, Zurich, Switzerland, A. Bergman Employee of: Takeda Pharmaceuticals GmbH, Zurich, Switzerland, R. Selby Employee of: Takeda UK Ltd., Bucks, UK