Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1    Pharmacodynamic properties
Pharmacotherapeutic group: Drugs used in diabetes, insulins and analogues for injection, long-acting.
ATC Code: A10A E04.

Mechanism of action
The primary activity of insulin, including insulin glargine, is regulation of glucose metabolism. Insulin and its analogues lower blood glucose levels by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis in the adipocyte, inhibits proteolysis and enhances protein synthesis.

Pharmacodynamic effects
Insulin glargine is a human insulin analogue designed to have a low solubility at neutral pH. At pH 4, insulin glargine is completely soluble. After injection into the subcutaneous tissue, the acidic solution is neutralised leading to formation of a precipitate from which small amounts of insulin glargine are continuously released.

As observed in euglycemic clamp studies in patients with type 1 diabetes, the glucose lowering effect of Toujeo was more stable and prolonged in comparison with insulin glargine 100 units/ml after subcutaneous injection. Figure 1 shows results from a cross-over study in 18 patients with type 1 diabetes conducted for a maximum of 36 hours after injection. The effect of Toujeo was beyond 24 hours (up to 36 hours) at clinically relevant doses.


The more sustained release of insulin glargine from the Toujeo precipitate compared to insulin glargine 100 units/ml is attributable to the reduction of the injection volume by two thirds that results in a smaller precipitate surface area.

Figure 1: Activity profile at steady state in patients with type 1 diabetes in a 36-hour euglycaemic clamp study



*GIR: Glucose infusion rate: determined as amount of glucose infused to maintain constant plasma glucose levels (hourly mean values). The end of the observation period was 36 hours.

Insulin glargine is metabolised into 2 active metabolites M1 and M2 (see section 5.2).

Insulin receptor binding: In vitro studies indicate that the affinity of insulin glargine and its metabolites M1 and M2 for the human insulin receptor is similar to the one of human insulin.

IGF-1 receptor binding: The affinity of insulin glargine for the human IGF-1 receptor is approximately 5 to 8-fold greater than that of human insulin (but approximately 70 to 80-fold lower than the one of IGF-1), whereas M1 and M2 bind the IGF-1 receptor with slightly lower affinity compared to human insulin.

The total therapeutic insulin concentration (insulin glargine and its metabolites) found in type 1 diabetic patients was markedly lower than what would be required for a half maximal occupation of the IGF-1 receptor and the subsequent activation of the mitogenic-proliferative pathway initiated by the IGF-1 receptor. Physiological concentrations of endogenous IGF-1 may activate the mitogenic-proliferative pathway; however, the therapeutic concentrations found in insulin therapy, including in Toujeo therapy, are considerably lower than the pharmacological concentrations required to activate the IGF-1 pathway.

In a clinical pharmacology study, intravenous insulin glargine and human insulin have been shown to be equipotent when given at the same doses.

As with all insulins, the time course of action of insulin glargine may be affected by physical activity and other variables.

Clinical efficacy and safety
The overall efficacy and safety of Toujeo (insulin glargine 300 units/ml) once-daily on glycaemic control was compared to that of once-daily insulin glargine 100 units/ml in open-label, randomised, active-control, parallel studies of up to 26 weeks of duration, including 546 patients with type 1 diabetes mellitus and 2,474 patients with type 2 diabetes mellitus (Table 1 and 2).
Results from all clinical trials with Toujeo indicated that reductions in HbA1c from baseline to end of trial were non-inferior to insulin glargine 100 units/ml. Plasma glucose reductions at the end of the trial with Toujeo were similar to insulin glargine 100 units/ml with a more gradual reduction during 
the titration period with Toujeo. Glycaemic control was similar when Toujeo was administered once daily in the morning or in the evening.
Improvement in HbA1C was not affected by, gender, ethnicity, age, diabetes duration (<10 years and ≥10 years), HbA1c value at baseline (<8% or ≥8%) or baseline body mass index (BMI).
At the end of these treat-to-target trials, depending on the patient population and concomitant therapy, a 10-18% higher dose was observed in the Toujeo group than in the comparator group (Table 1 and 2).

Results from clinical trials demonstrated that the incidence of confirmed hypoglycaemia (at any time of the day and nocturnal) was lower in patients treated with Toujeo compared to insulin glargine 100 units/ml-treated patients, in patients with type 2 diabetes treated in combination with either non-insulin anti-hyperglycaemic medicinal product or mealtime insulin.
The superiority of Toujeo over insulin glargine 100 units/ml in lowering the risk of confirmed nocturnal hypoglycemia was shown in patients with type 2 diabetes treated with basal insulin in combination with either non-insulin anti-hyperglycaemic medicinal product (18% risk reduction) or mealtime insulin (21% risk reduction) during the period from week 9 to end of study period.
Overall, these effects on hypoglycaemia risk were consistently observed whatever the age, gender, BMI and duration of diabetes (<10 years and ≥10 years) in Toujeo-treated patients compared to insulin glargine 100 units/ml-treated patients.

In patients with type 1 diabetes, the incidence of hypoglycaemia was similar in patients treated with Toujeo compared to insulin glargine 100 units/ml-treated patients (Table 3).

Table 1: Results from clinical trials in type 1 diabetes mellitus

26 weeks of treatment
Toujeo                   IGlar
Treatment in combination with                                         Meal-time insulin analogue a
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 differenceb                                                0.04 [-0.098 to 0.185] c
Basal insulin dose (U/kg)
Baseline mean                                                        0.32                    0.32 Mean change from baseline                                            0.15                    0.09 Body weightd (kg)
Baseline mean                                                        81.89                   81.80 Mean change from baseline                                            0.46                    1.02 IGlar: Insulin glargine 100 units/ml a mITT: Modified intention-to-treat b Treatment difference: Toujeo– insulin glargine 100 units/ml; [95% Confidence Interval] c Change from baseline to Month 6 (observed case) d Change from baseline to Last main 6-month on-treatment value




Table 2: Results from clinical trials in type 2 diabetes mellitus
26 weeks of treatment
Patients previously       Patients previously          Previously insulin treated with basal        treated with basal             naive patients insulin                   insulin
Meal-time insulin        Non-insulin anti-hyperglycaemic medicinal
Treatment in combination with analog+/-metformin                         products
Toujeo       IGlar        Toujeo           IGlar       Toujeo      IGlar Number of patients treateda             404         400          403             405           432        430 HbA1c
Baseline mean                           8.13        8.14          8.27            8.22         8.49      8.58 Adjusted mean change from              -0.90       -0.87         -0.73           -0.70        -1.42      -1.46 baseline
Adjusted mean differenceb                    -0.03                      -0.03                       0.04 [-0.144 to 0.083]          [-0.168 to 0.099]           [-0.090 to 0.174] Basal insulin dosec (U/kg)
Baseline mean                          0.67         0.67         0.64            0.66          0.19       0.19 Mean change from baseline              0.31         0.22         0.30            0.19          0.43       0.34 Body weightd (kg)
Baseline mean                         106.11       106.50        98.73           98.17        95.14      95.65 Mean change from baseline              0.93         0.90          0.08           0.66          0.50       0.71 IGlar: Insulin glargine 100 units/ml a mITT: Modified intention-to-treat b Treatment difference: Toujeo– insulin glargine 100 units/ml; [95% Confidence Interval] c Change from baseline to Month 6 (observed case) d Change from baseline to Last main 6-month on-treatment value


Table 3 - Summary of the hypoglycaemic episodes of the clinical study in patients with type 1 and type 2 diabetes mellitus

Diabetic            Type 1 diabetes mellitus    Type 2 diabetes mellitus            Type2 diabetes mellitus population             Patients previously         Patients previously                 Patients previously treated with basal          treated with basal               Insulin naive or on basal insulin                     insulin                             insulin Treatment in                                                                             Non-insulin anti- Meal-time insulin combination           Meal-time insulin analog                                           hyperglycaemic analog+/-metformin with                                                                                medicinal products Toujeo        IGlar        Toujeo              IGlar           Toujeo        IGlar a
Incidence (%) of severe hypoglycaemia (n/Total N)
6.6           9.5           5.0             5.7                1.0          1.2 Entire study          (18/274)      (26/275)      (20/404)        (23/402)            (8/838)      (10/844) periodd              RR*: 0.69 [0.39;1.23]       RR: 0.87 [0.48;1.55]               RR: 0.82 [0.33;2.00] 

Diabetic            Type 1 diabetes mellitus    Type 2 diabetes mellitus       Type2 diabetes mellitus population             Patients previously         Patients previously            Patients previously treated with basal          treated with basal          Insulin naive or on basal insulin                     insulin                        insulin
Treatment in                                                                         Non-insulin anti- Meal-time insulin combination           Meal-time insulin analog                                       hyperglycaemic analog+/-metformin with                                                                            medicinal products Toujeo        IGlar         Toujeo          IGlar          Toujeo          IGlar Incidence (%) of confirmedb hypoglycaemia (n/Total N)
93.1          93.5           81.9           87.8           57.6            64.5 Entire study         (255/274)     (257/275)      (331/404)      (353/402)      (483/838)       (544/844) period
RR: 1.00 [0.95;1.04]        RR: 0.93 [0.88; 0.99]          RR: 0.89 [0.83; 0.96] Incidence (%) of confirmed nocturnalc hypoglycaemia (n/Total N)

From week 9 to            59.3          56.0           36.1           46.0           18.4            22.5 end of study          (162/273)     (153/273)      (146/404)      (184/400)      (154/835)       (188/835) period               RR: 1.06 [0.92;1.23]        RR: 0.79 [0.67;0.93]           RR: 0.82 [0.68;0.99] IGlar: Insulin glargine 100 units/ml a
Severe hypoglycaemia: Episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.
b
Confirmed hypoglycaemia: Any severe hypoglycaemia and/or hypoglycaemia confirmed by plasma glucose value ≤3.9 mmol/l.
c
Nocturnal hypoglycaemia: Episode that occurred between 00:00 and 05:59 hours d
6-month treatment period
*RR: estimated risk ratio; [95% Confidence Interval]

Flexibility in dosing time

The safety and efficacy of Toujeo administered with a fixed or flexible dosing time were also evaluated in 2 randomized, open-label clinical studies for 3 months. Type 2 diabetic patients (n=194) received Toujeo once daily in the evening, either at the same time of the day (fixed time of administration) or within 3 hours before or after the usual time of administration (flexible dosing time). Administration with a flexible dosing time had no effect on glycaemic control and the incidence of hypoglycaemia.

Antibodies

Results from studies comparing Toujeo and insulin glargine 100 units/ml did not indicate any difference in term of development of anti-insulin antibodies, on efficacy, safety or dose of basal insulin between Toujeo and insulin glargine 100 units/ml.

Body weight

Mean change in body weight of less than 1 kg at the end of the 6-month period was observed in Toujeo-treated patients (see Table 1 and 2).

Results from a study on progression of diabetic retinopathy

Effects of insulin glargine 100 units/ml (once daily) on diabetic retinopathy were evaluated in an open-label 5 year NPH-controlled study (NPH given bid) in 1024 type 2 diabetic patients in which progression of retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale was investigated by fundus photography. No significant difference was seen in the progression of diabetic retinopathy when insulin glargine100 units/ml was compared to NPH insulin.


Long term efficacy and safety outcome study
The ORIGIN (Outcome Reduction with Initial Glargine INtervention) study was a multicenter, randomized, 2x2 factorial design study conducted in 12,537 participants at high cardiovascular (CV) risk with impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) (12% of participants) or type 2 diabetes mellitus (treated with ≤1 antidiabetic oral agent) (88% of participants). Participants were randomized (1:1) to receive insulin glargine 100 units/ml (n=6264), titrated to reach FPG ≤95 mg/dl (5.3 mM), or standard care (n=6273).
The first co-primary efficacy outcome was the time to the first occurrence of CV death, nonfatal myocardial infarction (MI), or nonfatal stroke, and the second co-primary efficacy outcome was the time to the first occurrence of any of the first co-primary events, or revascularisation procedure (coronary, carotid, or peripheral), or hospitalisation for heart failure.

Secondary endpoints included all-cause mortality and a composite microvascular outcome.

Insulin glargine 100 units/ml did not alter the relative risk for CV disease and CV mortality when compared to standard of care. There were no differences between insulin glargine and standard care for the two co-primary outcomes; for any component endpoint comprising these outcomes; for all-cause mortality; or for the composite microvascular outcome.
Mean dose of insulin glargine 100 units/ml by study end was 0.42 U/kg. At baseline, participants had a median HbA1c value of 6.4% and median on-treatment HbA1c values ranged from 5.9 to 6.4% in the insulin glargine 100 units/ml group, and 6.2% to 6.6% in the standard care group throughout the duration of follow-up.
The rates of severe hypoglycaemia (affected participants per 100 participant years of exposure) were 1.05 for insulin glargine 100 units/ml and 0.30 for standard care group and the rates of confirmed non-severe hypoglycaemia were 7.71 for insulin glargine 100 units/ml and 2.44 for standard care group. Over the course of this 6-year study, 42% of the insulin glargine 100 units/ml group did not experience any hypoglycaemia.

At the last on-treatment visit, there was a mean increase in body weight from baseline of 1.4 kg in the insulin glargine 100 units/ml group and a mean decrease of 0.8 kg in the standard care group.

Pediatric population
The efficacy and safety of Toujeo have been studied in a 1:1 randomized controlled open label clinical trial in children and adolescents with type 1 diabetes mellitus for a period of 26 weeks (n=463).
Patients in the Toujeo arm included 73 children aged < 12 years and 160 children aged ≥12 years.
Toujeo dosed once daily showed similar reduction in HbA1c and FPG from baseline to week 26 compared to insulin glargine 100 units/mL.

The dose-response analysis showed that following the initial titration phase, the body weight adjusted doses in pediatric patients are higher than in adult patients at steady state.

Overall the incidence of hypoglycaemia in patients in any category was similar in both treatment groups, with 97.9% of patients in the Toujeo group and 98.2% in the insulin glargine 100 units/mL group reporting at least one event. Similarly, nocturnal hypoglycaemia was comparable in the Toujeo and insulin glargine 100 units/mL treatment groups. The percentage of patients reporting severe hypoglycaemia was lower in patients in the Toujeo group as compared to patients in the insulin glargine 100 units/mL group, 6% and 8.8% respectively. The percentage of patients with hyperglycaemic episodes with ketosis was lower for Toujeo versus insulin glargine 100 units/mL, 6.4% and 11.8%, respectively. No safety issues were identified with Toujeo with respect to adverse events and standard safety parameters. Antibody development was sparse and had no clinical impact.
Efficacy and safety data for paediatric patients with type 2 diabetes mellitus have been extrapolated from data for adolescent and adult patients with type 1 diabetes mellitus and adult patients with type 2 diabetes mellitus. Results support the use of Toujeo in paediatric patients with type 2 diabetes mellitus.



Pharmacokinetic Properties

5.2    Pharmacokinetic properties

Absorption and distribution
In healthy subjects and diabetic patients, insulin serum concentrations indicated a slower and more prolonged absorption resulting in a flatter time-concentration profile after subcutaneous injection of Toujeo in comparison to insulin glargine 100 units/ml.

Pharmacokinetic profiles were consistent with the pharmacodynamic activity of Toujeo.

Steady state level within the therapeutic range is reached after 3-4 days of daily Toujeo administration.
After subcutaneous injection of Toujeo, the intra-subject variability, defined as the coefficient of variation for the insulin exposure during 24 hours was low at steady state (17.4%).

Biotransformation
After subcutaneous injection of insulin glargine, insulin glargine is rapidly metabolized at the carboxyl terminus of the Beta chain with formation of two active metabolites M1 (21A-Gly-insulin) and M2 (21A-Gly-des-30B-Thr-insulin). In plasma, the principal circulating compound is the metabolite M1.
The exposure to M1 increases with the administered dose of insulin glargine. The pharmacokinetic and pharmacodynamic findings indicate that the effect of the subcutaneous injection with insulin glargine is principally based on exposure to M1. Insulin glargine and the metabolite M2 were not detectable in the vast majority of subjects and, when they were detectable their concentration was independent of the administered dose and formulation of insulin glargine.

Elimination
When given intravenously the elimination half-life of insulin glargine and human insulin were comparable.

The half-life after subcutaneous administration of Toujeo is determined by the rate of absorption from the subcutaneous tissue. The half-life of Toujeo after subcutaneous injection is 18-19 hours independent of dose.