Insulin glargine U300 (Toujeo ) and insulin glargine biosimilar (Abasaglar )

Insulin glargine U300 (Toujeo ) and insulin glargine biosimilar (Abasaglar ) Lead author: Stephen Erhorn Regional Drug & Therapeutics Centre (Newcastle) November 2015 2015

Summary Toujeo uses the same insulin glargine molecule as Lantus, but is a higherstrength formulation (300 units/ml), than the existing insulin glargine product on the market (Lantus, 100 units/ml). Toujeo is intended to have a flatter and more prolonged pharmacodynamic profile than Lantus and offers the benefit of a smaller volume of subcutaneous injection. Toujeo is licensed for the treatment of diabetes mellitus in adults. Toujeo was shown to be non-inferior to Lantus in reducing HBA1c in both T1DM and T2DM. The incidence of nocturnal severe and/or confirmed hypoglycaemia was a significantly lower with Toujeo in T2DM, but showed no difference in T1DM. The overall safety profile of Toujeo was comparable to the well-established safety profile of Lantus. No new or unexpected safety signals were detected. Abasaglar is the first biosimilar insulin approved in the EU. It has an identical amino acid sequence to that of the active ingredient in the reference product Lantus. The licensed indication (treatment of diabetes mellitus in adults, adolescents and children aged two years and above), dosing regimen, pharmaceutical form, and strength of Abasaglar are identical to those of Lantus. In extensive comparability exercises all major physicochemical characteristics and biological activities of Abasaglar were comparable to those of Lantus. Abasaglar was shown to be non-inferior to Lantus in reducing HBA1c in both T1DM and T2DM. The overall safety profile of Abasaglar was comparable to Lantus and was in line with the documented safety profile of the reference product. No new or unexpected safety signals were detected. NICE NG17 (2015) recommends multiple daily insulin injection basal-bolus regimens, rather than twice-daily mixed insulin regimens as the insulin injection regimen of choice in T1DM. Twice daily insulin detemir should be offered as basal insulin therapy. If a twice-daily insulin regimen is not acceptable, once-daily insulin glargine or detemir should be considered. Once-daily insulin glargine should also be considered if insulin detemir is not tolerated. NICE CG87 (2009) recommends NPH insulin as the preferred insulin therapy in T2DM, although long-acting insulin analogues may have a role in treating specific patients. In the NETAG area more is spent on drugs for diabetes than any other BNF section, with 45.1 million spent between April 2014 and March 2015. A total of 425,392 insulin items were prescribed at a cost of around 19.1 million. Of these, insulin glargine accounted for 83,361 items (20%) at a cost of around 4.4 million. The per unit acquisition cost of Toujeo is lower than Lantus. However, Toujeo and Lantus are not bioequivalent and therefore are not interchangeable. On a unit to unit basis, Toujeo has a lower glucose lowering effect than Lantus, and therefore higher doses of Toujeo (10-18%) may be required to achieve similar levels of glucose control. The per unit acquisition cost of Abasaglar represents a discount of approximately 15% on the corresponding list price of Lantus. Although the dosing regimen, pharmaceutical form, and strength of Abasaglar are identical to those of Lantus, some patients may still need an adjustment in dose. Northern Treatment Advisory Group, November 2015 2

Introduction and background Diabetes mellitus (DM) is a chronic metabolic disorder, caused by defects in insulin secretion, insulin action, or both. In type 1 diabetes mellitus (T1DM) the pancreas is no longer able to produce sufficient insulin, due to destruction of the pancreatic islet cells most commonly by an autoimmune process. As a consequence, people with T1DM are prone to developing hyperglycaemia, and require life-long insulin replacement. Until recently, the two most commonly used treatment regimens for T1DM were twice daily injections of a meal-time and basal insulin together, or a basalbolus regimen, with meal-time insulin taken prior to main meals, with once or twice daily dosing of basal insulin. In type 2 diabetes mellitus (T2DM) a combination of impaired insulin secretion and insulin resistance results in elevated blood glucose levels. Treatment initially involves lifestyle changes, with oral antihyperglycaemic drugs added as necessary to maintain adequate blood glucose control. Due to progressive islet cells failure, many patients with T2DM will eventually require insulin replacement and will commence once daily insulin to supplement oral therapy before moving to more involved regimes such as twice daily insulin mixtures or basal bolus insulin therapy. 1-5 Insulin glargine (Lantus, Sanofi) is a long-acting recombinant analogue of human insulin. It was approved in 2006 for the treatment of DM in adults, adolescents and children aged two years and above. The efficacy and safety of insulin glargine are well established through extensive clinical and observational studies involving over 200,000 patients. 1,6 Toujeo (Sanofi) uses the same insulin glargine molecule as Lantus, but is a higher-strength formulation (300 units/ml), than the existing insulin glargine product on the market (Lantus, 100 units/ml). Toujeo is intended to have a flatter and more prolonged pharmacodynamic profile than Lantus and offers the benefit of a smaller volume of subcutaneous injection. Toujeo is licensed for the treatment of DM in adults. In T1DM, Toujeo must be combined with short-/rapid-acting insulin to cover mealtime insulin requirements. In patients with T2DM mellitus, it can also be given together with other anti-hyperglycaemic medicinal products. 1,7 Abasaglar is the first biosimilar insulin approved in the European Union. This longacting insulin analogue has an identical amino acid sequence to that of the active ingredient in the reference product Lantus. Abasaglar differs from Lantus with respect to excipients used, but the final quantitative formulation is the same. The licensed indication, dosing regimen, pharmaceutical form, and strength of Abasaglar are identical to those of the reference product Lantus. 2,8 Both products were launched in the UK in August 2015. The patent for Lantus expired in the EU in May 2015. This report will review the evidence for the use of high-strength insulin glargine (Toujeo ) and biosimilar insulin glargine (Abasaglar ) in the treatment of diabetes. Northern Treatment Advisory Group, November 2015 3

Guidance and related advice NICE guideline (NG17, 2015) for the management of T1DM recommends multiple daily insulin injection basal-bolus regimens, rather than twice-daily mixed insulin regimens as the insulin injection regimen of choice for all adults with T1DM. 9 Patients should be provided with guidance on using multiple daily injection basal bolus insulin regimens. Newly diagnosed patients should not be offered non basal bolus insulin regimens. Twice daily insulin detemir should be offered as basal insulin therapy. As an alternative, consider using an existing insulin regimen that is achieving agreed glucose targets, or once-daily glargine or detemir, if twice daily insulin regimen is not acceptable to the patient. Once daily insulin glargine should be considered if insulin detemir is not tolerated. Other basal insulin regimens should only be considered if the above do not deliver agreed targets. The choice of alternative insulin regimen should take into account patient preferences and acquisition cost. The current NICE guideline on T2DM (CG87, 2009) recommends insulin therapy when glycaemic control becomes or remains inadequate with other measures. 10 Human NPH insulin (isophane) once or twice-daily is the preferred option for most patients. The guideline recommends that the long-acting insulin analogues, insulin glargine and insulin detemir can be considered in some people, in certain circumstances (e.g. patients with significant hypoglycaemia, those requiring assistance to administer, or a need to reduce the number of daily injections). NICE Evidence summary for Toujeo in T1DM was published in October 2015. 11 The publication date for the evidence summary in T2DM is to be confirmed. NICE will not review Abasaglar separately as part of their technology appraisal programme. A NICE Evidence Summary for Abasaglar is due to be published in November 2015. The SMC has accepted Toujeo for restricted use within NHS Scotland following an abbreviated submission. 12 Its use should be targeted on patients with T1DM who are at risk of or experience unacceptable frequency and/or severity of nocturnal hypoglycaemia on attempting to achieve better hypoglycaemic control during treatment with established insulins. It is also acceptable as a once daily insulin therapy for patients who require carer administration of their insulin. In T2DM it should be restricted to those who suffer from recurrent episodes of hypoglycaemia or require assistance with their insulin injections. The SMC will not review Abasaglar following their recent update to the SMC policy for biosimilar medicines. An AWMSG appraisal of Abasaglar is currently in process. No review of Toujeo is currently on the AWMSG workplan. Clinical evidence Toujeo Insulin glargine 300 units/ml 1,13-18 The clinical efficacy of Toujeo (insulin glargine 300 units/ml) given once-daily was compared to that of once-daily Lantus (insulin glargine 100 units/ml) in four openlabel, randomised, active-control, parallel group studies of up to 26 weeks duration in patients with T1DM (EDITION 4), and patients with T2DM (EDITION 1, 2 and 3). Each study comprised of a six-month main study period followed by a six-month comparative safety extension period. Adult patients aged 18 years of age with a screening HbA1c of 7.0% to 10.0% for insulin pre-treated patients, and 7.0% to Northern Treatment Advisory Group, November 2015 4

11.0% in insulin naïve patients were eligible for the studies. Exclusion criteria were as unrestrictive as possible to reflect the general population with diabetes mellitus. All four studies were designed to show non-inferiority of Toujeo versus Lantus based on the primary endpoint of change in HbA 1c from baseline to month six, with a noninferiority margin of 0.4% HbA1c, and if met 0.3%. The primary efficacy analyses were based on a modified intent-to treat (mitt) population defined as all randomized patients who received at least one dose of Toujeo or Lantus study medication, and who had both a baseline assessment and at least one post-baseline assessment of any primary or secondary efficacy endpoint. The key secondary efficacy endpoints was the proportion of patients experiencing at least one severe and/or confirmed nocturnal hypoglycaemia ( 3.9 mmol/l) from week nine to month six. Other secondary endpoints included fasting plasma glucose (FPG), self-monitored plasma glucose (SMPG), change in body weight, and change in basal insulin dose. Patients with T1DM 1,14 In EDITION 4, patients with T1DM were randomised to once-daily Toujeo or Lantus in the morning or evening while continuing to use their mealtime insulin. Participants had to have been on basal insulin in combination with mealtime insulin for at least one year. The starting insulin glargine dose was based on total basal insulin dose and fasting SMPG at baseline. The mean age was 47.3 years, mean duration of diabetes 21.0 years, and BMI 27.6. At week 26, the change in HbA1c was comparable in the two treatment-groups. The upper bound of the 95% CI (0.19%) was within the predefined non-inferiority margin of 0.40%, and the more stringent criteria of 0.3% (Table 1). Similar reductions were observed for FPG and SMPG. No clinically meaningful differences in glycaemic control were observed when morning and evening injection time was compared, including overlapping 8-point SMPG profiles. The percentage of patients with severe and/or confirmed nocturnal hypoglycaemia was similar between groups. There were no clinically important differences in body weight between treatment groups. Table 1: Phase 3 clinical trial of Toujeo in adult patients with type 1 diabetes mellitus. EDITION 4 Population T1DM previously treated with basal insulin Treatment group Toujeo Lantus Treatment in combination with Meal-time insulin analogue Number of subjects treated (mitt) 273 273 HbA1c Baseline mean 8.13 8.12 Adjusted Mean change from baseline -0.40-0.44 Adjusted Mean difference 0.04 [95% CI] [-0.010 to 0.18] Severe and/or confirmed nocturnal hypoglycaemia Number (%) 162 (59.3%) 153 (56.05) Relative risk vs. Lantus 1.06 [95% CI] [0.92 to 1.23] p-value Northern Treatment Advisory Group, November 2015 5 n/a

Patients with T2DM 1,13,15-18 In EDITION 1, patients with T2DM were randomised to once-daily Toujeo or Lantus in the evening while continuing to use their mealtime insulin with or without metformin. Participants had to have been on basal insulin ( 42 units/day) in combination with a mealtime for at least one year. The starting insulin glargine dose was based on total basal insulin dose and fasting SMPG at baseline. The mean age was 60 years, mean duration of diabetes 15.8 years, and BMI 36.6. In EDITION 2 and 3, patients with T2DM were randomised to once-daily Toujeo or Lantus as part of a combination regimen with non-insulin anti-hyperglycaemic drugs. At the time of randomisation patients in EDITION 2 had to have been on basal insulin for at least six months. The mean age of patients in EDITION 2 was 58.2 years, mean duration of diabetes 12.6 years, and BMI 34.8. Patients in EDITION 3 were insulin naïve, and had mean age was 57.7 years, mean duration of diabetes 9.8 years, and BMI 33.0. At week 26 in all three studies, treatment with Toujeo resulted in a mean reduction in HbA1c that met the predefined inferiority margin of 0.4% and 0.3%, compared to Lantus (table 2.). Similar reductions were observed for FPG and SMPG profiles. Toujeo was associated with fewer participants experiencing one or more confirmed and/or severe nocturnal hypoglycaemic events compared to Lantus. There were no clinically important differences in body weight between treatment groups. However, patients receiving Toujeo used more basal insulin than patients treated with Lantus (115, 12% and 15% for EDITION 1, 2 and 3, respectively). Table 2: Phase 3 clinical trials of Toujeo in adult patients type 2 diabetes mellitus. Population EDITION 1 EDITION 2 EDITION 3 T2DM previously treated with basal insulin T2DM previously treated with basal insulin T2DM previously insulin naïve Treatment group Toujeo Lantus Toujeo Lantus Toujeo Lantus Treatment in combination with Number of subjects treated (mitt) HbA1c Meal-time insulin analogue +/- metformin Non-insulin antihyperglycaemic drugs Non-insulin antihyperglycaemic drugs 404 400 403 405 432 430 Baseline mean 8.13 8.14 8.27 8.22 8.49 8.58 Adjusted Mean change from baseline Adjusted Mean difference -0.90-0.87-0.73-0.70-1.42-1.46-0.03-0.03 0.04 [95% CI] [-0.14 to 0.08] [-0.17 to 0.10] [-0.09 to 0.17] Severe and/or confirmed nocturnal hypoglycaemia Number (%) 146 (36.1%) 184 (46.0%) 87 (21.6%) 113 (27.9%) 67 (15.5%) 75 (17.4%) Relative risk vs. Lantus 0.79 0.77 0.89 [95% CI] [0.67 to 0.93] [0.61 to 0.99] [0.66 to 1.20] p-value 0.0045 0.0380 0.4536 Northern Treatment Advisory Group, November 2015 6

Abasaglar Insulin glargine biosimilar 100 units/ml 2,19,20 To gain approval in the EU, biosimilar medicines must demonstrate that they are as safe and as effective as the reference medicine, and have the same quality characteristics. The EU regulatory process demands an extensive comparability exercise is performed through a stepwise process that begins with structural, physicochemical and biological analysis, non-clinical, then pharmacokinetic (PK) and pharmacodynamic studies (PD), followed by clinical safety and efficacy trials. In the extensive comparability exercise it was shown that the PK and PD profiles, the relative bioavailability and the duration of action of Abasaglar are comparable to those of Lantus. The clinical efficacy of Abasaglar (biosimilar insulin glargine 100 units/ml) given oncedaily was compared to that of once-daily Lantus (insulin glargine 100 units/ml) in two similarly designed randomised, active-control, parallel group studies. ELEMENT 1 was a 52 week study (24-week treatment period and 28-week extension) in patients with T1DM, and ELEMENT 2 was a 24-week study in patients with T2DM. Adult patients aged 18 years of age with a screening HbA1c of 11.0% for insulin pretreated patients and 7.0% to 11.0% in insulin naïve patients were eligible for the studies. Exclusion criteria were largely unrestrictive and reflect the general population with diabetes mellitus. Both studies were designed to show non-inferiority of Abasaglar versus Lantus based on the primary endpoint of change in HbA1c from baseline to 24 weeks, with a non-inferiority margin of 0.4% HbA1c, and if met 0.3%. The primary efficacy analyses were based on full intent-to treat (ITT). Secondary efficacy endpoints included fasting blood glucose (FBG), self-monitored blood glucose (SMBG), change in body weight, and change in basal insulin dose. Patients with T1DM 2,19 In ELEMENT 1, patients who had T1DM for at least one year were randomised to once-daily Abasaglar or Lantus started on the same dose at the same time of day as their basal insulin. At randomization, all patients mealtime insulin was replaced with insulin lispro at doses equivalent to their mealtime insulin. Insulin dose adjustments were carried out in both treatment groups to help patients achieve glycaemic targets. The mean age was 41.2 years, mean duration of diabetes 16.4 years, and BMI 25.5. Both treatment groups achieved similar decreases in mean HbA1c values from baseline to 24 weeks and 52 weeks. Abasaglar was found to be non-inferior to Lantus at the predefined inferiority margin of 0.4%, and the more stringent criteria of 0.3% (table 3.). For 7-point SMBG, patients in the Abasaglar arm had statistically significantly lower mean BG values at bedtime and 3 am compared with the Lantus arm; however, the mean difference between treatment arms was small and unlikely to result in clinically meaningful differences. There were no significant differences in other efficacy measures, including FBG, insulin dose, and body weight at 24 and 52 weeks. Northern Treatment Advisory Group, November 2015 7

Table 3: Phase 3 clinical trial of Abasaglar in adult patients with type 1 diabetes mellitus. Population ELEMENT 1 24 weeks 52 weeks T1DM previously treated with basal insulin T1DM previously treated with basal insulin Treatment group Abasaglar Lantus Abasaglar Lantus Treatment in combination with Number of subjects treated (ITT) HbA1c Meal-time insulin analogue Meal-time insulin analogue 268 267 268 267 Baseline mean 7.75 7.79 NR NR Adjusted Mean change from baseline -0.35-0.46-0.26-0.28 Adjusted Mean difference -0.11-0.02 [95% CI] [-0.002 to 0.22] [-0.010 to 0.14] NR= Not reported Patients with T2DM 2,20 ELEMENT 2 enrolled patients with T2DM who were insulin naïve and had been treated with two or more oral antihyperglycaemic drugs at stable doses for 12 weeks. The starting dose for all insulin-naïve patients was 10 units/day. Patients entering the study on Lantus were randomized to either Abasaglar or Lantus at a dose equivalent to their pre-study Lantus dose. Insulin dose adjustments were carried out in both treatment groups to help patients achieve glycaemic targets. The mean age was 58.9 years, mean duration of diabetes 11.4 years, and BMI 31.9. At week 24, treatment with Abasaglar resulted in a mean reduction in HbA1c that met the predefined inferiority margin of 0.4% and 0.3%, compared to Lantus (table 4.). There were no clinically significant treatment differences in any secondary efficacy measures, including FBG, insulin dose, and body weight at 24 weeks. Table 4: Phase 3 clinical trial of Abasaglar in adult patients with type 2 diabetes mellitus. Population ELEMENT 2 T2DM previously treated with basal insulin Treatment group Abasaglar Lantus Treatment in combination with 2 oral antihyperglycaemic drugs Number of subjects treated (ITT) 369 375 HbA1c Baseline mean 8.31 8.34 Adjusted Mean change from baseline -1.29-1.34 Adjusted Mean difference 0.05 [95% CI] [-0.07 to 0.17] Northern Treatment Advisory Group, November 2015 8

Safety Toujeo Insulin glargine 300 units/ml 1,13-18 Data supporting the safety of Toujeo are based on the results from the EDITION 4 study plus an exploratory phase 2 study (PDY12777) in patients with T1DM, and the EDITION 1, 2 and 3 studies in patients with T2DM. During the main 24 week ontreatment period, the overall number and pattern of treatment-emergent adverse events (TEAEs) were comparable between Toujeo and Lantus treated patients. TEAEs were reported in 62.8% and 58.9% of patients, respectively in T1DM studies, and in 57.3% and 53.7% of patients, respectively in T2DM studies. In both treatment groups the most commonly reported TEAEs were infections and infestations, with nasopharyngitis and upper respiratory tract infection the most common in both T1DM and T2DM (Table 5.). Overall, serious TEAEs were reported by 5.4% of the patients in both the Abasaglar and Lantus groups, and by a comparable number of patients in the T1DM (5.9% vs.7.2%, respectively) and T2DM studies (5.2% vs. 5.0%, respectively), with no single event driving the results. The most common serious TEAE in the T1DM studies was hypoglycaemia (3.0% vs. 3.9%, respectively; T2DM: <0.1% vs. 0.2%, respectively) and the most common in the T2DM studies was coronary artery disease (0.2% vs. <0.1%, respectively); T1DM: one event, no events, respectively). Table 5. Summary of TEAEs in 3% of all pooled Abasaglar and Lantus patients (EDITION 1, 2, 3, 4 and PDY12777). Preferred Term N, (%) Abasaglar (n=304) T1DM T2DM All studies Lantus (n=304) Abasaglar (n=1,242) Lantus (n=1,246) Abasaglar (n=1,546) Lantus (n=1,550) Any TEAE 191 (62.8%) 179 (58.9%) 712 (57.3%) 669 (53.7%) 903 (58.4%) 848 (54.7%) Nasopharyngitis 39 (12.8%) 33 (10.9%) 88 (7.1%) 72 (5.8%) 127 (8.2%) 105 (6.8%) URTI 29 (9.5%) 23 (7.6%) 71 (5.7%) 67 (5.4%) 100 (6.5%) 90 (5.8%) Headache 14 (4.6%) 14 (4.6%) 61 (4.9%) 47 (3.8%) 75 (4.9%) 61 (3.9%) Diarrhoea 7 (2.3%) 6 (2.0%) 47 (3.8%) 38 (3.0%) 54 (3.5%) 44 (2.8%) Nausea 8 (2.6%) 5 (1.6%) 40 (3.2%) 27 (2.2%) 48 (3.1%) 32 (2.1%) Bronchitis 6 (2.0%) 6 (2.0%) 41 (3.3%) 42 (3.4%) 47 (3.0%) 48 (3.1%) There were no clinically important differences in hypoglycaemia between Toujeo and Lantus among T1DM patients. In EDITION 4, the incidence of severe hypoglycaemia at week 26 was lower in the Toujeo group compared with the Lantus group (6.6% vs. 9.5%, respectively). This difference was largely driven by daytime events. However, annualized rates were comparable between two groups (0.24 vs. 0.34 events/person year at any time of day). The incidence of documented symptomatic hypoglycaemia Northern Treatment Advisory Group, November 2015 9

was comparable at 69% and 69.8%, respectively. In all three studies in T2DM, the cumulative incidence of hypoglycaemia was lower in the Toujeo group than in the Lantus group. The incidence of severe hypoglycaemia was 5% vs. 5.7% at 26 weeks in patients receiving Toujeo and Lantus in combination with mealtime insulin. In the two studies where patients received treatment in combination with non-insulin antihyperglycaemic drugs the corresponding figures were1.0% vs. 1.5% and 0.9% vs. 0.9%, respectively. The incidence of documented symptomatic hypoglycaemia ranged from 7.6% to 37.4% in patients receiving Toujeo vs. 13.9% to 41.5%, and the highest risk was again seen in patients receiving treatment in combination with mealtime insulin. There were no differences in the insulin antibody response and in the clinical effects associated with antibody formation in either treatment group. No new or unexpected safety signals were detected with respect to injection site reactions, hypersensitivity reactions and cardiovascular safety. Abasaglar Insulin glargine biosimilar 100 units/ml 2,19,20 The safety profile of Abasaglar has been well characterised in the context of the extensive comparability exercise, in which it appeared comparable to the established and documented safety profile of the reference product, Lantus. The clinical data supporting the safety of Toujeo are based on the results from the ELEMET 1 and 2 studies in which a total of 446 patients were exposed to Abasaglar for at least six months. In addition 52-week safety data from ELEMENT 1 have been reported. Overall, the incidence and pattern of adverse events (AEs) reported with Abasaglar were comparable to those of Lantus, with no statistically significant differences observed between the two groups (table 6.). In both T1DM and T2DM, the most frequently reported AEs were nasopharyngitis, upper respiratory tract infection and diarrhoea (comparative data have not been reported). Table 6. Overall summary of adverse events in ELEMENT 1 and 2. Preferred Term N, (%) Abasaglar (n=268) Any Adverse Event 167 (62%) Serious Adverse Event 20 (8%) T1DM (52 weeks) Lantus (n=267) 166 (62%) 24 (9%) Abasaglar (n=376) 196 (52%) 15 (4%) T2DM (24 weeks) Lantus (n=380) 184 (84%) 18 (5%) AEs possibly related to study drug 17 (6%) 14 (5%) 26 (7%) 23 (6%) Discontinuations due to an AE 2 (1%) 6 (2%) 6 (2%) 11 (3%) Allergic reactions 20 (8%) 11 (4%) 21 (6%) 27 (7%) Injection site reactions (patient questionnaires) 7 (3%) All treatment comparisons p<0.05, with the exception of injection site reactions (patient questionnaires), and events experienced by <4 patients, where treatment comparisons were not performed. 3 (1%) 13 (4%) 11 (3%) Northern Treatment Advisory Group, November 2015 10

During the main 24 week on-treatment period, the total number of hypoglycaemic events was numerically lower with Abasaglar compared to Lantus in both studies, including the number of severe hypoglycaemic events. However, the estimated difference in the 52-week update of ELEMENT was approximately three events per year, which is not considered clinically meaningful. Likewise in ELEMENT 2, the estimated difference at 24 weeks was around one event per year, with no difference in documented symptomatic hypoglycaemia reported. The proportion of patients with detectable anti-insulin antibodies was comparable throughout both studies. There was no evidence that the antibody response had any impact on efficacy and safety outcomes in either treatment group. No new or unexpected safety signals were detected with respect to injection site reactions, hypersensitivity reactions and cardiovascular safety. Risk minimisation strategy for high strength and biosimilar insulin products Several new insulin products have come to market recently, and healthcare professionals and patients need to understand the insulin strength of these products and how to use them correctly to minimise the risk of medication errors such as the wrong insulin dose being administered. The European Medicines Agency is currently consulting on guidance to minimise the risk of medication error. 21 This draft guidance summarises ways to minimise the risk of medication errors with the high strength, fixed combination and biosimilar insulin products already on the market. Dosage and administration Trade name Formulation/strength Indication Posology and administration Toujeo 7 (Sanofi) Insulin glargine 300 units/ml in 1.5 ml prefilled SoloStar pen. These units are exclusive to Toujeo and are not the same as IU or the units used to express the potency of other insulin analogues. Treatment of diabetes mellitus in adults. Injected once daily subcutaneously. The dose and timing should be adjusted according to individual response In T1DM, Toujeo must be combined with short-/rapid acting insulin to cover mealtime insulin requirements. In T2DM, Toujeo can be given in combination with other antihyperglycaemic drugs Abasaglar 8 (Eli Lilly) Insulin glargine 100 units/ml in a 3 ml prefilled KwikPen, or 3 ml cartridge for use in Lilly reusable pen. These units are exclusive to insulin glargine and are not the same as IU or the units used to express the potency of other insulin analogues. Treatment of diabetes mellitus in adults, adolescents and children aged 2 years and above. Injected once daily subcutaneously. The dose and timing should be adjusted according to individual response. In T2DM, Abasaglar can be given in combination with oral antihyperglycaemic drugs. Northern Treatment Advisory Group, November 2015 11

Cost analysis No published economic analyses on the use of Toujeo or Abasaglar were identified. In the area more is spent on drugs for diabetes than any other BNF section, with 45.1 million spent between April 2014 and March 2015. A total of 425,392 insulin items were prescribed at a cost of around 19.1 million. Of these, insulin glargine accounted for 83,361 items (20%) at a cost of around 4.4 million. The comparative cost of all currently available insulin glargine products is shown in table 7. The per unit acquisition cost of Toujeo is lower than Lantus. However, Toujeo and Lantus are not bioequivalent and therefore are not interchangeable. On a unit to unit basis, Toujeo has a lower glucose lowering effect than Lantus, and therefore higher doses of Toujeo (approximately 10-18%) may be required to achieve similar levels of glucose control. The dosing regimen, pharmaceutical form, and strength of the biosimilar Abasaglar are identical to those of the reference product Lantus. However, some patients may still need an adjustment in dose. The per unit acquisition cost of Abasaglar represents a discount of approximately 15% on the corresponding list price of Lantus. Table 7. Comparative cost of insulin glargine products (dm+d and emims, November 2015). Product Toujeo (300 units/ml) Abasaglar (100 units/ml) Lantus (100 units/ml) Cost 33.13 per pack of 3 x 1.5ml SoloStar prefilled pen. (1,350 units) 35.28 per pack of 5 x 3ml prefilled KwikPens. (1,500 units) 41.50 per pack of 5 x 3ml SoloStar prefilled pen. (1,500 units) 35.28 per pack of 5 x 3ml cartridges for use in reusable Savvio pen. (1,500 units) 41.50 per pack of 5 x 3mL cartridges for Autopen 24 and ClikSTAR. (1,500 units) Annual cost per patient (20 units daily)* Annual cost per patient (40 units daily)* Annual cost per patient (60 units daily)* 179.15 171.70 201.97 358.29 343.39 403.93 537.44 515.09 605.90 30.68 for 1 x 10ml vial. (1,000 units) * On a unit to unit basis, Toujeo has a lower glucose lowering effect than Lantus, and therefore higher doses of Toujeo (approximately 10-18%) may be required to achieve similar levels of glucose control. Northern Treatment Advisory Group, November 2015 12

Points to consider Toujeo is a higher-strength formulation (300 units/ml), than the existing insulin glargine product on the market (Lantus, 100 units/ml), Toujeo is intended to have a flatter and more prolonged pharmacodynamic profile than Lantus and offers the benefit of a smaller volume of subcutaneous injection. It is licensed for the treatment of DM in adults. Toujeo was shown to be non-inferior to Lantus in reducing HBA1c in both T1DM and T2DM. The incidence of nocturnal severe and/or confirmed hypoglycaemia was a significantly lower with Toujeo in T2DM, but showed no difference in T1DM. The overall safety profile of Toujeo was comparable to the well-established safety profile of Lantus. No new or unexpected safety signals were detected. Abasaglar is the first biosimilar insulin approved in the EU. The licensed indication (treatment of diabetes mellitus in adults, adolescents and children aged two years and above), dosing regimen, pharmaceutical form, and strength of Abasaglar are identical to those of the reference product Lantus. In extensive comparability exercises all major physicochemical characteristics and biological activities of Abasaglar were comparable to Lantus. Abasaglar was shown to be non-inferior to Lantus in reducing HBA1c in both T1DM and T2DM. In the comparability exercise and clinical studies the overall safety profile of Abasaglar was comparable to Lantus and in line with the documented safety profile of Lantus. No new or unexpected safety signals were detected NICE NG17 (2015) recommends multiple daily insulin injection basal-bolus regimens, rather than twice-daily mixed insulin regimens as the insulin injection regimen of choice in T1DM. Twice daily insulin detemir should be offered as basal insulin therapy. If a twice-daily insulin regimen is not acceptable, once-daily insulin glargine or detemir should be considered. Oncedaily insulin glargine should also be considered if insulin detemir is not tolerated. NICE CG87 (2009) recommends NPH insulin as the preferred insulin therapy in T2DM, although longacting insulin analogues may have a role in treating specific patients. Toujeo represent an additional treatment option for patients that require a long-acting insulin analogue who are not currently able to achieve optimal glycaemic control. Due to a flatter and more prolonged pharmacodynamic profile Toujeo allows patients greater flexibility in the timing of their once-daily injection compared with Lantus. However, switching from Lantus to Toujeo is not straightforward, as the drugs are not bioequivalent and are not directly interchangeable. A switch can be done on a unit-to-unit basis, but higher doses of Toujeo (approximately 10-18%) may be required to achieve similar levels of glucose control. Abasaglar may be considered as an option for new patients requiring insulin glargine in line with NICE guidelines. However, individual Trusts may wish to consider a managed therapeutic switch between products. Abasaglar has been shown to be bioequivalent to Lantus and the efficacy of the two products are comparable. Nevertheless, as with other biosimilar medicines, some patients may still need an adjustment in dose. In the NETAG area more is spent on drugs for diabetes than any other BNF section, with 45.1 million spent between April 2014 and March 2015. A total of 425,392 insulin items were prescribed at a cost of around 19.1 million. Of these, insulin glargine accounted for 83,361 items (20%) at a cost of around 4.4 million. The per unit acquisition cost of Toujeo is lower than Lantus. However, Toujeo and Lantus are not bioequivalent and therefore are not interchangeable. On a unit to unit basis, Toujeo has a lower glucose lowering effect than Lantus, and therefore higher doses of Toujeo (10-18%) may be required to achieve similar levels of glucose control. The per unit acquisition cost of Abasaglar represents a discount of approximately 15% on the corresponding list price of Lantus. Although the dosing regimen, pharmaceutical form, and strength of the biosimilar Abasaglar are identical to those of the reference product Lantus, some patients may still need an adjustment in dose. Northern Treatment Advisory Group, November 2015 13

Author s declaration: The author has no relevant interests to declare. References 1. European Medicines Agency. European public assessment report - Toujeo (insulin glargine). February 2015. http://www.ema.europa.eu/docs/en_gb/document_library/epar_- _Public_assessment_report/human/002835/WC500175383.pdf 2. European Medicines Agency. European public assessment report - Abasaglar (insulin glargine). June 2014. http://www.ema.europa.eu/docs/en_gb/document_library/epar_- _Public_assessment_report/human/002835/WC500175383.pdf. 3. National Institute for Health and Care Excellence. Clinical Knowledge Summaries. Diabetes - type 1. Last revised in June 2015. 4. National Institute for Health and Care Excellence. Clinical Knowledge Summaries. Diabetes - type 2. Last revised in July 2015. 5. Holt et al., (Eds.), International Textbook of Diabetes Mellitus: 4th Edition. United Kingdom: Wiley-Blackwell Publishing. 2010. 6. Sanofi. Summary Product Characteristics. Lantus 100 units/ml solution for injection in a vial, cartridge and SoloStar pre-filled pen. Date of revision of text: August 2015. 7. Sanofi. Summary Product Characteristics. Toujeo 300 units/ml solution for injection in a pre-filled pen. Date of revision of text: July 2015. 8. Eli Lilly. Summary Product Characteristics. ABASAGLAR 100 units/ml solution for injection in cartridge & pre-filled pen. Date of revision of text: July 2015. 9. National Institute for Health and Care Excellence. Type 1 diabetes in adults: diagnosis and management (NG 17). August 2105. https://www.nice.org.uk/guidance/ng17. 10. National Institute for Health and Care Excellence. Type 2 diabetes: The management of type 2 diabetes (CG 87). May 2009. https://www.nice.org.uk/guidance/cg87 11. National Institute for Health and Care Excellence. Evidence Summary-New Medicine [ESNM62]. Type 1 diabetes mellitus in adults: high-strength insulin glargine 300 units/ml (Toujeo). October 2015.. 12. Scottish Medicines Consortium. insulin glargine 300 units/ml solution for injection in a pre-filled pen (Toujeo). SMC No. (1078/15). July 2015. 13. Bolli GB, Riddle MC, Bergenstal RM et al. New insulin glargine 300 U/ml compared with glargine 100 U/ml in insulin-naive people with type 2 diabetes on oral glucose-lowering drugs: a randomized controlled trial (EDITION 3). Diabetes Obes Metab 2015;17:386-94. 14. Home PD, Bergenstal RM, Bolli GB et al. New Insulin Glargine 300 Units/mL Versus Glargine 100 Units/mL in People With Type 1 Diabetes: A Randomized, Phase 3a, Open-Label Clinical Trial (EDITION 4). Diabetes Care 2015. 15. Riddle MC, Bolli GB, Ziemen M et al. New insulin glargine 300 units/ml versus glargine 100 units/ml in people with type 2 diabetes using basal and mealtime insulin: glucose control and hypoglycemia in a 6-month randomized controlled trial (EDITION 1). Diabetes Care 2014;37:2755-62. 16. Yki-Jarvinen H, Bergenstal R, Ziemen M et al. New insulin glargine 300 units/ml versus glargine 100 units/ml in people with type 2 diabetes using oral agents and basal insulin: glucose control and hypoglycemia in a 6-month randomized controlled trial (EDITION 2). Diabetes Care 2014;37:3235-43. 17. Yki-Jarvinen H, Bergenstal RM, Bolli GB et al. Glycaemic control and hypoglycaemia with new insulin glargine 300 U/mL versus glargine 100 U/mL in people with type 2 diabetes using basal insulin and oral antihyperglycaemic drugs Northern Treatment Advisory Group, November 2015 14

(EDITION 2 randomised 12-month trial including 6-month extension). Diabetes Obes Metab 2015. 18. Riddle MC, Yki-Jarvinen H, Bolli GB et al. One-year sustained glycaemic control and less hypoglycaemia with new insulin glargine 300 U/ml compared with 100 U/ml in people with type 2 diabetes using basal plus meal-time insulin: the EDITION 1 12- month randomized trial, including 6-month extension. Diabetes Obes Metab 2015;17:835-42. 19. Blevins TC, Dahl D, Rosenstock J et al. Efficacy and safety of LY2963016 insulin glargine compared with insulin glargine (Lantus(R)) in patients with type 1 diabetes in a randomized controlled trial: the ELEMENT 1 study. Diabetes Obes Metab 2015;17:726-33. 20. Rosenstock J, Hollander P, Bhargava A et al. Similar efficacy and safety of LY2963016 insulin glargine and insulin glargine (Lantus(R)) in patients with type 2 diabetes who were insulin-naive or previously treated with insulin glargine: a randomized, double-blind controlled trial (the ELEMENT 2 study). Diabetes Obes Metab 2015;17:734-41. 21. Medicines and Healthcare products Regulatory Agency. Drug Safety Update: High strength, fixed combination and biosimilar insulin products: minimising the risk of medication error. April 2015. Northern Treatment Advisory Group, November 2015 15