Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other blood glucose lowering drugs, excl. insulins, ATC code: A10BX10.

Mechanism of action

Lixisenatide is a selective GLP-1 receptor agonist. The GLP-1 receptor is the target for native GLP-1, an endogenous incretin hormone that potentiates glucose-dependent insulin secretion from the pancreatic beta cells.

Lixisenatide action is mediated via a specific interaction with GLP-1 receptors, leading to an increase in intracellular cyclic adenosine monophosphate (cAMP). Lixisenatide stimulates insulin secretion when blood glucose is increased but not at normoglycaemia, which limits the risk of hypoglycemia. In parallel, glucagon secretion is suppressed. In case of hypoglycemia, the rescue mechanism of glucagon secretion is preserved.

Lixisenatide slows gastric emptying thereby reducing the rate at which meal-derived glucose appears in the circulation.

Pharmacodynamic effects

When administered once daily, lixisenatide improves glycemic control through the immediate and sustained effects of lowering both post-prandial and fasting glucose concentrations in patients with type 2 diabetes.

This effect on post-prandial glucose was confirmed in a 4-week study versus liraglutide 1.8 mg once a day in combination with metformin. Reduction from baseline in the AUC 0:30-4:30 h of plasma glucose after a test-meal was: -12.61 h*mmol/L (-227.25 h*mg/dl) in the lixisenatide group and -4.04 h*mmol/L (-72.83 h*mg/dl) in the liraglutide group. This was also confirmed in an 8-week study versus liraglutide, administered before breakfast, in combination with insulin glargine with or without metformin.

Clinical efficacy and safety

The effects of Lyxumia on glycemic control were evaluated in six randomised double-blind, placebo- 
controlled clinical studies and one randomised, open-label, active-controlled study versus exenatide.

These studies included 3,825 patients with type 2 diabetes (2,445 patients randomised to lixisenatide), 48.2% men and 51.8% women.

768 subjects (447 randomised to lixisenatide) were ≥65 years of age and 103 subjects (57 randomised to lixisenatide) were ≥75 years of age.

In the completed Phase III studies, it was observed that more than 90% of the patient population was able to remain on the once daily maintenance dose of 20 mcg Lyxumia at the end of the main 24- week treatment period.

• Glycemic control

Add-on combination therapy with oral antidiabetics

Lyxumia in combination with metformin, a sulphonylurea, pioglitazone or a combination of these agents showed statistically significant reductions in HbA 1c, in fasting plasma glucose and in 2-hour post-prandial glucose after a test-meal compared to placebo at the end of the main 24-week treatment period (tables 2 and 3). The HbA1c reduction was significant with once-daily administration, whether administered morning or evening.

This effect on HbA1c was sustained in long term studies for up to 76 weeks.

Add-on treatment to metformin alone
Table 2: Placebo-controlled studies in combination with metformin (24-week results).


Metformin as background therapy
Lixisenatide   Placebo         Lixisenatide 20 mcg            Placebo 20 mcg
Morning        Evening

(N= 160)       (N= 159)        (N= 255)       (N= 255)        (N= 170) Mean HbA1c (%)
Baseline                  7.99           8.03            8.07           8.07            8.02 LS mean change from       -0.92          -0.42           -0.87          -0.75           -0.38 baseline
Patients (%) achieving 47.4              24.1            43.0           40.6            22.0 HbA1c <7.0%
Mean body weight
(kg)
Baseline                  90.30          87.86           90.14          89.01           90.40 LS mean change from       -2.63          -1.63           -2.01          -2.02           -1.64 baseline

In an active-controlled study, Lyxumia once daily showed an HbA 1c reduction of -0.79% compared to - 0.96% with exenatide twice daily at the end of the main 24-week treatment period with a mean treatment difference of 0.17% (95% CI: 0.033, 0.297) and a similar percentage of patients achieved an HbA1c less than 7% in the lixisenatide group (48.5%) and in the exenatide group (49.8%).
The incidence of nausea was 24.5% in the lixisenatide group compared to35.1% in the exenatide twice daily group and the incidence of symptomatic hypoglycemia with lixisenatide was 2.5% during the 24-week main treatment period compared to 7.9% in the exenatide group.

In a 24-week open-label study, lixisenatide administered before the main meal of the day was non-inferior to lixisenatide administered before breakfast in terms of HbA 1c reduction (LS mean change from baseline: -0.65% versus -0.74%). Similar HbA 1c decreases were observed regardless of which meal was the main meal (breakfast, lunch or dinner). At the end of the study, 43.6% (main meal group) and 42.8% (breakfast group) of patients achieved an HbA 1c less than 7%, Nausea was reported in 14.7% and 15.5% of patients, and symptomatic hypoglycaemia in 5.8% and 2.2% of patients, main meal group and breakfast group, respectively.

Add-on treatment to a sulphonylurea alone or in combination with metformin 
Table 3: Placebo-controlled study in combination with a sulphonylurea (24-week results) 

Sulphonylurea as background therapy with or without metformin
Lixisenatide 20 mcg             Placebo
(N= 570)                        (N= 286)
Mean HbA1c (%)
Baseline                                    8.28                            8.22 LS mean change from baseline                -0.85                           -0.10 Patients (%) achieving HbA1c <7.0%          36.4                            13.5 Mean body weight (kg)
Baseline                                    82.58                           84.52 LS mean change from baseline                -1.76                           -0.93 

Add-on treatment to pioglitazone alone or in combination with metformin 
In a clinical study, the addition of lixisenatide to pioglitazone with or without metformin, in patients not adequately controlled with pioglitazone, resulted in an HbA1c decrease from baseline of 0.90%, compared to a decrease from baseline of 0.34% in the placebo group at the end of the 24-week main treatment period. At the end of the 24-week main treatment period, 52.3% of the lixisenatide patients achieved an HbA1c less than 7 % compared to 26.4% in the placebo group.
During the 24-week main treatment period, nausea was reported in 23.5% in the lixisenatide group compared to 10.6% in the placebo group and symptomatic hypoglycemia was reported in 3.4% of the lixisenatide patients compared to 1.2% in the placebo group.

Add-on combination therapy with a basal insulin

Lyxumia given with a basal insulin alone, or with a combination of a basal insulin and metformin, or a combination of a basal insulin and a sulphonylurea resulted in statistically significant reductions in HbA1c and in 2-hour post-prandial glucose after a test-meal compared to placebo.


Table 4: Placebo-controlled studies in combination with a basal insulin (24-week results) 

Basal insulin as background therapy       Basal insulin as background therapy 
Alone or in combination with metformin Alone or in combination with a sulphonylurea *
Lixisenatide 20      Placebo              Lixisenatide 20      Placebo mcg                                       mcg
(N= 327)             (N= 166)             (N= 154)             (N= 157) Mean HbA1c (%)
Baseline             8.39                 8.38                 8.53                 8.53 LS mean change       -0.74                -0.38                -0.77                0.11 from baseline
Patients (%)         28.3                 12.0                 35.6                 5.2 achieving HbA1c
<7.0%
Mean duration of 3.06                     3.2                  2.94                 3.01 treatment with basal insulin at baseline (years)
Mean change in basal insulin dose (U)
Baseline             53.62                57.65                24.87                24.11 LS mean change       -5.62                -1.93                -1.39                -0.11 from baseline
Mean body weight (kg)
Baseline             87.39                89.11                65.99                65.60 LS mean change       -1.80                -0.52                -0.38                0.06 from baseline


*performed in Asian population
A clinical study was conducted in insulin-naive patients insufficiently controlled on oral antidiabetic agents. This study consisted of a 12-week run-in period with introduction and titration of insulin glargine and of a 24-week treatment period during which patients receive either lixisenatide or placebo in combination with insulin glargine and metformin with or without thiazolidinediones. Insulin glargine was continuously titrated during this period.
During the 12-week run-in period, addition and titration of insulin glargine resulted approximately in an HbA1c decrease of 1%. The addition of lixisenatide led to a significantly greater HbA 1c decrease of 0.71% in the lixisenatide group compared to 0.40% in the placebo group. At the end of the 24-week treatment period, 56.3% of the lixisenatide patients achieved an HbA 1c less than 7 % compared to 38.5% in the placebo group.
During the 24-week treatment period, 22.4% lixisenatide patients reported at least one symptomatic hypoglycemic event compared to 13.5% in the placebo group. The incidence of hypoglycemia was mainly increased in the lixisenatide group during the first 6 weeks of treatment and thereafter, was similar to the placebo group.

• Fasting plasma glucose

The reductions in fasting plasma glucose obtained with Lyxumia treatment ranged from 0.42 mmol/L to 1.19 mmol/L (7.6 to 21.4 mg/dl) from baseline at the end of the main 24-week treatment period in 
placebo-controlled studies.

• Post-prandial glucose

Treatment with Lyxumia resulted in reductions in 2-hour post-prandial glucose after a test-meal statistically superior to placebo whatever the background treatment.

The reductions with Lyxumia ranged from 4.51 to 7.96 mmol/L (81.2 to 143.3 mg/dl) from baseline at the end of the main 24-week treatment period across all studies in which post-prandial glucose was measured; 26.2% to 46.8% of patients had a 2-hour post-prandial glucose value below 7.8 mmol/L (140.4 mg/dl).

• Body weight

Treatment with Lyxumia in combination with metformin and/or a sulphonylurea resulted in a sustained body weight change from baseline in all controlled studies in a range from -1.76 kg to -2.96 kg at the end of the main 24-week treatment period.

Body weight change from baseline in a range from -0.38 kg to -1.80 kg was also observed in lixisenatide patients receiving stable basal insulin dose, alone or in combination with metformin or a sulphonylurea.

In patients newly started on insulin, body weight remained almost unchanged in the lixisenatide group while an increase was shown in the placebo group.

Body weight reduction was sustained in long term studies up to 76 weeks.

The body weight reduction is independent from the occurrence of nausea and vomiting.

• Beta cell function
Clinical studies with Lyxumia indicate improved beta-cell function as measured by the homeostasis model assessment for beta-cell function (HOMA-β).

Restoration of first phase insulin secretion and improved second phase insulin secretion in response to an intravenous bolus of glucose were demonstrated in patients with type 2 diabetes (n=20) after a single dose of Lyxumia.

• Cardiovascular evaluation

No increase in mean heart rate in patients with type 2 diabetes was seen in all placebo controlled phase III studies.

Mean systolic and diastolic blood pressure reductions up to 2.1 mmHg and up to 1.5 mmHg respectively were observed in phase III placebo-controlled studies.

A meta-analysis of all independently adjudicated cardiovascular events (CV death, non-fatal myocardial infarction, non-fatal stroke, hospitalization for unstable angina, hospitalization for heart failure and coronary revascularization procedure) from 8 phase III placebo-controlled studies which included 2673 type 2 diabetes patients treated with lixisenatide and 1448 patients treated with placebo showed a hazard ratio of 1.03 (95% confidence interval 0.64, 1.66) for lixisenatide versus placebo. The number of events in the clinical studies was low (1.9% in lixisenatide treated patients and 1.8% in placebo treated patients), precluding firm conclusions. The incidence of the individual CV events (lixisenatide vs placebo) was: CV death (0.3% vs 0.3%), non-fatal myocardial infarction (0.4% vs 0.4%), non-fatal stroke (0.7% vs 0.4%), hospitalization for unstable angina (zero vs 0.1%), 
hospitalization for heart failure (0.1% vs zero), and coronary revascularization procedure (0.7% vs 1.0%).

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Absorption
Following subcutaneous administration to patients with type 2 diabetes, the rate of lixisenatide absorption is rapid and not influenced by the dose administered. Irrespective of the dose and whether lixisenatide was administered as single or multiple doses, the median t max is 1 to 3.5 hours in patients with type 2 diabetes. There are no clinically relevant differences in the rate of absorption when lixisenatide is administered subcutaneously in the abdomen, thigh, or arm.

Distribution

Lixisenatide has a moderate level of binding (55%) to human proteins.
The apparent volume of distribution after subcutaneous administration of lixisenatide (Vz/F) is approximately 100 L.

Biotransformation and elimination

As a peptide, lixisenatide is eliminated through glomerular filtration, followed by tubular reabsorption and subsequent metabolic degradation, resulting in smaller peptides and amino acids, which are reintroduced in the protein metabolism.

After multiple dose administration in patients with type 2 diabetes, mean terminal half-life was approximately 3 hours and the mean apparent clearance (CL/F) about 35 L/h.

Special populations

Patients with renal impairment
There were no relevant differences in mean Cmax and AUC of lixisenatide between subjects with normal renal function and subjects with mild impaired renal function (creatinine clearance calculated by the Cockcroft-Gault formula 50-80 ml/min). In subjects with moderate renal impairment (creatinine clearance 30-50 ml/min) AUC was increased by 24% and in subjects with severe renal impairment (creatinine clearance 15-30 ml/min) AUC was increased by 46%.

Patients with hepatic impairment

As lixisenatide is cleared primarily by the kidney, no pharmacokinetic study has been performed in patients with acute or chronic hepatic impairment. Hepatic dysfunction is not expected to affect the pharmacokinetics of lixisenatide.

Gender

Gender has no clinically relevant effect on the pharmacokinetics of lixisenatide.
Race

Ethnic origin had no clinically relevant effect on the pharmacokinetics of lixisenatide based on the results of pharmacokinetic studies in Caucasian, Japanese and Chinese subjects.


  Elderly

Age has no clinically relevant effect on the pharmacokinetics of lixisenatide. In a pharmacokinetic study in elderly non-diabetic subjects, administration of lixisenatide 20 mcg resulted in a mean increase of lixisenatide AUC by 29% in the elderly population (11 subjects aged 65 to 74 years and 7 subjects aged ≥75 years) compared to 18 subjects aged 18 to 45 years, likely related to reduced renal function in the older age group.

Body weight

Body weight has no clinically relevant effect on lixisenatide AUC.