EPERZAN Powder and solvent for solution for injection Ref.[27937] Active ingredients: Albiglutide

Pharmacotherapeutic group: Drugs used in diabetes. Other blood glucose lowering drugs excl. insulins. Glucagon-like peptide-1 (GLP-1) analogues
ATC code: A10BJ04

Mechanism of action

Albiglutide is an agonist of the GLP-1 receptor and augments glucose-dependent insulin secretion. Albiglutide also slows gastric emptying.

Pharmacodynamic effects

Glucose control

Eperzan lowers fasting glucose and reduces postprandial glucose excursions. The majority of the observed reduction in fasting plasma glucose occurs after a single dose, consistent with the pharmacokinetic profile of albiglutide.

In patients with type 2 diabetes who received 2 doses of albiglutide 32 mg (Day 1 and 8), a statistically significant reduction (24%) in postprandial glucose AUC_(0.5-4.5h) was observed compared to placebo following a standardised breakfast meal on Day 9.

A single dose of albiglutide 50 mg did not impair the glucagon, epinephrine, norepinephrine, cortisol or growth hormone counter-regulatory hormone response to hypoglycaemia.

Gastric motility

Albiglutide slowed gastric emptying compared with placebo for both solids and liquids when 100 mg was administered as a single dose in healthy subjects. For solids, gastric emptying t_1/2 increased from 1.14 h to 2.23 h (p=0.0112). For liquids, gastric emptying t_1/2 increased from 0.28 h to 0.69 h (p=0.0018).

Clinical efficacy and safety

A total of 2,365 patients with type 2 diabetes were treated with Eperzan and 2,530 received other study medications in 8 active and placebo-controlled phase III clinical trials. Studies evaluated the use of Eperzan 30 mg and 50 mg once weekly, allowing for optional titration of Eperzan from 30 mg to 50 mg once weekly in 5 of the 8 studies. Across the 8 clinical trials, and including subjects in all treatment groups, a total of 19% of patients (N = 937) were 65 years of age and older, and 2% (N = 112) were 75 years of age and older, 52% were male, with a mean body mass index (BMI) of 33 kg/m². Sixty seven percent of patients were Caucasian, 15% African American/African heritage and 11% Asian; 26% of patients were Hispanic/Latino.

No overall differences in glycaemic effectiveness or body weight were observed across demographic subgroups (age, gender, race/ethnicity, duration of diabetes).

Monotherapy

The efficacy of Eperzan was evaluated in a 3-year randomised, double-blind, placebo-controlled, multicentre study (n = 296) in patients inadequately controlled on diet and exercise. Patients were randomised (1:1:1) to Eperzan 30 mg once weekly, Eperzan 30 mg once weekly uptitrated to 50 mg once weekly at week 12, or placebo. The primary endpoint was change in HbA_1c from baseline at 52 weeks. Compared to placebo, treatment with Eperzan 30 mg and 50 mg SC weekly resulted in statistically significant reductions in HbA_1c from baseline at Week 52. The change from baseline in HbA_1c at the 6 month timepoint was also statistically significant for the 30 mg (0.9%) and 50 mg (1.1%) weekly doses of Eperzan (see Table 2).

Table 2. Results at 52 weeks in a placebo-controlled study with two doses of Eperzan (30 vs. 50 mg SC weekly) as monotherapy:

^a Intent to treat population – last observation carried forward
^b Adjusted mean
^c P <0.05 for treatment difference

Combination Therapy

Add-on to metformin

The efficacy of Eperzan was evaluated in a 3-year, randomised, double-blind, multicentre study (n = 999). On background therapy of metformin ≥1,500 mg daily, Eperzan 30 mg SC weekly (with optional uptitration to 50 mg weekly after a minimum of 4 weeks) was compared to sitagliptin 100 mg daily, glimepiride 2 mg daily (with optional titration to 4 mg daily), or placebo. The primary endpoint was change in HbA_1c from baseline at 2 years compared to placebo. Results at 104 weeks are presented in Table 3. Eperzan demonstrated glycaemic lowering and was statistically superior in reduction in HbA_1c from baseline compared to placebo, sitagliptin, or glimepiride (see Table 3).

Table 3. Results at 104 weeks in a placebo-controlled study comparing Eperzan 30 mg SC weekly (with optional uptitration to 50 mg weekly) to sitagliptin 100 mg daily and glimepiride 2 to 4 mg daily as add-on therapy in patients inadequately controlled on metformin ≥1,500 mg daily:

^a Intent to treat population – last observation carried forward
^b Adjusted mean
^c P <0.05 for treatment difference

Add-on to pioglitazone

The efficacy of Eperzan was evaluated in a 3-year, randomised, double-blind, multicentre study (n = 299). Eperzan 30 mg SC weekly was compared to placebo in patients inadequately controlled on pioglitazone ≥30 mg daily (with or without metformin ≥1,500 mg daily).

Compared to placebo, treatment with Eperzan resulted in statistically significant reductions from baseline in HbA_1c (-0.8% for Eperzan versus -0.1% for placebo, p <0.05) and FPG (-1.3 mmol/l for Eperzan versus +0.4 mmol/l for placebo, p <0.05) at 52 weeks. The change from baseline in weight did not differ significantly between treatment groups (see Table 4).

Table 4. Results at 52 weeks in a placebo-controlled study comparing Eperzan 30 mg SC weekly as add-on therapy in patients inadequately controlled on pioglitazone ≥30 mg daily metformin ≥1,500 mg daily:

^a Intent to treat population – last observation carried forward
^b Adjusted mean
^c P <0.05 for treatment difference

Add-on to metformin plus sulphonylurea

The efficacy of Eperzan was evaluated in a 3-year, randomised, double-blind, multicentre study (n = 657). On background therapy of metformin ≥1,500 mg daily plus glimepiride 4 mg daily, Eperzan 30 mg SC weekly (with optional uptitration to 50 mg weekly after a minimum of 4 weeks) was compared to placebo or pioglitazone 30 mg daily (with optional titration to 45 mg/day). The primary endpoint was change in HbA_1c from baseline at 52 weeks compared to placebo. At 52 weeks, treatment with Eperzan resulted in statistically significant reductions from baseline in HbA_1c compared to placebo. Treatment with Eperzan did not meet the pre-specified noninferiority margin (0.3%) against pioglitazone for HbA_1c. The change from baseline in weight for Eperzan did not differ significantly from placebo but was significantly less compared to pioglitazone (see Table 5).

Table 5. Results at 52 weeks in a placebo-controlled study comparing Eperzan 30 mg SC weekly (with optional uptitration to 50 mg weekly) to pioglitazone 30 mg daily (with optional titration to 45 mg/day) as add-on therapy in patients inadequately controlled on metformin + sulphonylurea (glimepiride 4 mg daily):

^a Intent to treat population – last observation carried forward
^b Adjusted mean
^c P <0.05 for treatment difference

Add-on to insulin glargine

The efficacy of Eperzan was evaluated in a 52 week, randomised, open-label, multicentre noninferiority study (n = 563). On background therapy of insulin glargine (started at 10 units and titrated to ≥20 units per day), Eperzan 30 mg SC once weekly (with uptitration to 50 mg if inadequately controlled after Week 8) was compared to prandial insulin lispro (administered daily at mealtimes, started according to standard of care and titrated to effect). The primary endpoint was change in HbA_1c from baseline at 26 weeks. At Week 26, the mean daily dose of insulin glargine was 53 IU for Eperzan and 51 IU for lispro. The mean daily dose of insulin lispro at Week 26 was 31 IU, and at Week 52, 69% of patients treated with Eperzan were on 50 mg weekly. At 26 weeks, the between-treatment difference in HbA_1c of 0.2% for Eperzan and insulin lispro met the pre-specified noninferiority margin (0.4%). Treatment with Eperzan resulted in a mean weight loss for Eperzan (-0.7 kg) compared to a mean weight gain for insulin lispro (+0.8 kg) and the difference between treatment groups was statistically significant (see Table 6).

Table 6. Results at 26 weeks in a study comparing Eperzan 30 mg SC weekly (with optional uptitration to 50 mg weekly) to prandial insulin lispro as add-on therapy in patients inadequately controlled on insulin glargine alone:

^a Intent to treat population – last observation carried forward
^b Adjusted mean
^c P <0.05 for treatment difference

In patients who completed the study (52 weeks), the adjusted mean change in baseline in HbA_1c was -1.0% for Eperzan (N = 121) and -0.9% for insulin lispro (N = 141). The adjusted mean change in body weight from baseline at 52 weeks was -1.0 kg for Eperzan (N = 122) and +1.7 kg for insulin lispro (N = 141). These data exclude the use of antidiabetic therapies permitted after the efficacy assessment if glycaemic thresholds were exceeded.

Active-controlled study versus insulin glargine as add-on to metformin sulphonylurea

The efficacy of Eperzan was evaluated in a 3-year, randomised (2:1), open-label, insulin glargine-controlled noninferiority study (n = 735). On background therapy of metformin ≥1,500 mg daily (with or without sulphonylurea), Eperzan 30 mg SC weekly (with optional uptitration to 50 mg weekly) was compared to insulin glargine (started at 10 units and titrated weekly per prescribing information). The primary endpoint was change in HbA_1c from baseline at 52 weeks. The starting total daily dose of insulin glargine ranged between 2 and 40 units (median daily dose of 10 units) and ranged between 3 and 230 units (median daily dose of 30 units) at Week 52. The median daily dose of insulin glargine used prior to hyperglycaemic rescue was 10 units (range 2 to 40 units) at study start and 30 units (range 3 to 230 units) at Week 52. At Week 156, 77% of patients treated with Eperzan were uptitrated to 50 mg SC weekly. The between-treatment difference in HbA_1c of 0.1% (-0.04, 0.27) from baseline at 52 weeks for Eperzan and insulin glargine met the prespecified noninferiority margin (0.3%). A statistically significant decrease in body weight was observed for Eperzan compared to an increase in body weight for insulin glargine and the difference in weight change was statistically significant (see Table 7). Medicinal product no longer authorised

Table 7. Results at 52 weeks in an active-controlled study comparing Eperzan 30 mg SC weekly (with optional uptitration to 50 mg weekly) to insulin glargine (titrated weekly per prescribing information) as addon therapy in patients inadequately controlled on metformin sulfonylurea:

^a Intent to treat population – last observation carried forward
^b Adjusted mean
^c P <0.05 for treatment difference

In patients who were treated for at least 104 weeks, the adjusted mean change in baseline in HbA_1c was -0.97% for Eperzan (N = 182) and -1.04% for insulin glargine (N = 102). The adjusted mean change in body weight from baseline at 104 weeks was -2.6 kg for Eperzan (N = 184) and +1.4 kg for insulin glargine (N = 104). These data exclude the use of antidiabetic therapies permitted after the efficacy assessment if glycaemic thresholds were exceeded.

Active-controlled study versus liraglutide in combination with metformin, thiazolidinedione, or sulphonylurea (as monotherapy or dual therapy)

The efficacy of Eperzan was evaluated in a 32-week, randomised, open-label, liraglutide-controlled noninferiority study (N = 805). Eperzan 30 mg SC weekly (with uptitration to 50 mg weekly at Week 6) was compared to liraglutide 1.8 mg daily (titrated up from 0.6 mg at Week 1 and 1.2 mg at Week 1 to Week 2) in patients inadequately controlled on monotherapy or combination oral antidiabetic therapy (metformin, thiazolidinedione, or sulphonylureas). The primary endpoint was change in HbA_1c from baseline at 32 weeks. Treatment with Eperzan did not meet the pre-specified noninferiority margin (0.3%) against liraglutide for HbA_1c (see Table 8).

Table 8. Results of an active-controlled trial of Eperzan 30 mg SC weekly (with uptitration to 50 mg weekly) versus liraglutide 1.8 mg daily at 32 weeks^a:

^a Intent to treat population – last observation carried forward
^b Adjusted mean
^c P <0.05 for treatment difference

Active-controlled study versus sitagliptin in patients with type 2 diabetes and different degrees of renal impairment

The efficacy of Eperzan was evaluated in a randomised, double-blind, active-controlled 52-week study in 486 patients with mild, moderate, and severe renal impairment inadequately controlled on a current regimen of diet and exercise or other antidiabetic therapy. Eperzan 30 mg SC weekly (with uptitration to 50 mg weekly if needed) was compared to sitagliptin. Sitagliptin was dosed according to creatinine clearance estimated by Cockcroft-Gault formula (100 mg daily in mild, 50 mg daily in moderate, and 25 mg daily in severe renal impairment) The primary endpoint was change in HbA_1c from baseline at 26 weeks. Treatment with Eperzan resulted in statistically significant reductions in HbA_1c from baseline at Week 26 compared to sitagliptin. The model-adjusted mean decrease in HbA_1c from baseline with Eperzan was -0.80 (n = 125), -0.83 (n = 98), and -1.08 (n = 19) in patients with mild (eGFR 60 to 89 ml/min/1.73m²), moderate (eGFR 30 to 59 ml/min/1.73m²), and severe (eGFR <30 ml/min/1.73m²) renal impairment, respectively (see Table 9).

Table 9. Results at 26 weeks in a study of Eperzan 30 mg SC weekly (with uptitration to 50 mg weekly if needed) versus sitagliptin (dosed according to renal function) in patients with different degrees of renal impairment:

^a Intent to treat population – Last Observation Carried Forward (ITT-LOCF)
^b Adjusted mean
^c P <0.05 for treatment difference

Durability of glycaemic control

The durability of glycaemic control for Eperzan over time relative to other classes of type 2 antidiabetic agents and placebo is shown in Figure 1 as add-on to metformin.

Figure 1. Kaplan-Meier curve showing durability of glycaemic control (measured by time to rescue) for Eperzan, relative to two active controls (sitagliptin and glimepiride) and placebo:

x axis; Weeks (Rescue free), y axis; Probability of event

Fasting plasma glucose

Treatment with Eperzan alone or in combination with one or two oral antidiabetic medicinal products resulted in a reduction in fasting plasma glucose from baseline as compared to placebo of 1.3 to 2.4 mmol/l. Most of this reduction was observed within the first two weeks of treatment.

Cardiovascular Evaluation:

A meta-analysis of 9 clinical studies (8 major effectiveness studies and 1 phase II dose finding study) of up to 3 years duration was conducted to assess the cardiovascular safety of Eperzan (N=2,524) compared to all comparators (N=2,583) within these trials. An endpoint called MACE+ (major adverse cardiac events plus) included hospitalisation for unstable angina in addition to the MACE endpoints (acute myocardial infarction, stroke, and CV death). The hazard ratio for Eperzan versus comparators for MACE+ was 1.0 (95% CI 0.68, 1.49). The incidence rates observed for first MACE+ were 1.2 and 1.1 events per 100 person-years for Eperzan versus all comparators, respectively.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Eperzan in one or more subsets of the paediatric population in the treatment of type 2 diabetes mellitus (see section 4.2 for information on paediatric use).