Tanzeum (Albiglutide) - Description and Clinical Pharmacology

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Summary Description and Clinical Pharmacology Indications and Dosage Warnings and Precautions Side Effects and Adverse Reactions Drug Interactions, Overdosage, Contraindications, Other Rx Info

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Published Studies Curr't Clinical Trials

DESCRIPTION

TANZEUM is a GLP-1 receptor agonist, a recombinant fusion protein comprised of 2 tandem copies of modified human GLP-1 genetically fused in tandem to human albumin. The human GLP-1 fragment sequence 7 – 36 has been modified with a glycine substituted for the naturally-occurring alanine at position 8 in order to confer resistance to dipeptidylpeptidase IV (DPP-IV) mediated proteolysis. The human albumin moiety of the recombinant fusion protein, together with the DPP-IV resistance, extends the half-life allowing once-weekly dosing. TANZEUM has a molecular weight of 72,970 Daltons.

TANZEUM is produced by a strain of Saccharomyces cerevisiae modified to express the therapeutic protein.

TANZEUM 30-mg Pen for injection (for subcutaneous use) contains 40.3 mg lyophilized albiglutide and 0.65 mL Water for Injection diluent designed to deliver a dose of 30 mg in a volume of 0.5 mL after reconstitution.

TANZEUM 50-mg Pen for injection (for subcutaneous use) contains 67 mg lyophilized albiglutide and 0.65 mL Water for Injection diluent designed to deliver a dose of 50 mg in a volume of 0.5 mL after reconstitution.

The lyophilized powder of both dose strengths is white to yellow in color and the solvent is a clear and colorless solution. The reconstituted solution is yellow in color.

Inactive ingredients include 153 mM mannitol, 0.01% (w/w) polysorbate 80, 10 mM sodium phosphate, and 117 mM trehalose dihydrate. TANZEUM does not contain a preservative.

CLINICAL PHARMACOLOGY

Mechanism of Action

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

Pharmacodynamics

TANZEUM lowers fasting glucose and reduces postprandial glucose excursions in patients with type 2 diabetes mellitus. The majority of the observed reduction in fasting plasma glucose occurs after a single dose, consistent with the pharmacokinetic profile of albiglutide. In a Phase II trial in Japanese patients with type 2 diabetes mellitus who received TANZEUM 30 mg, a reduction (22%) in postprandial glucose AUC_{(0-3 h)} was observed at steady state (Week 16) compared with placebo following a mixed meal.

A single dose of TANZEUM 50 mg subcutaneous (SC) did not impair glucagon response to low glucose concentrations.

Gastric Motility

TANZEUM slowed gastric emptying compared with placebo for both solids and liquids when albiglutide 100 mg (2 times the maximum approved dosage) was administered as a single dose in healthy subjects.

Cardiac Electrophysiology

At doses up to the maximum recommended dose (50 mg), TANZEUM does not prolong QTc to any clinically relevant extent.

Pharmacokinetics

Absorption

Following SC administration of a single 30-mg dose to subjects with type 2 diabetes mellitus, maximum concentrations of albiglutide were reached at 3 to 5 days post-dosing. The mean peak concentration (C_max) and mean area under the time-concentration curve (AUC) of albiglutide were 1.74 mcg/mL and 465 mcg.h/mL, respectively, following a single dose of 30 mg albiglutide in type 2 diabetes mellitus subjects. Steady-state exposures are achieved following 4 to 5 weeks of once-weekly administration. Exposures at the 30-mg and 50-mg dose levels were consistent with a dose-proportional increase. Similar exposure is achieved with SC administration of albiglutide in the abdomen, thigh, or upper arm. The absolute bioavailability of albiglutide following SC administration has not been evaluated.

Distribution

The mean estimate of apparent volume of distribution of albiglutide following SC administration is 11 L. As albiglutide is an albumin fusion molecule, plasma protein binding has not been assessed.

Metabolism

Albiglutide is a protein for which the expected metabolic pathway is degradation to small peptides and individual amino acids by ubiquitous proteolytic enzymes. Classical biotransformation studies have not been performed. Because albiglutide is an albumin fusion protein, it likely follows a metabolic pathway similar to native human serum albumin which is catabolized primarily in the vascular endothelium.

Elimination

The mean apparent clearance of albiglutide is 67 mL/h with an elimination half-life of approximately 5 days, making albiglutide suitable for once-weekly administration.

Specific Patient Populations

Age, Gender, Race, and Body Weight: Based on the population pharmacokinetic analysis with data collected from 1,113 subjects, age, gender, race, and body weight had no clinically relevant effect on the pharmacokinetics of albiglutide.

Pediatric: No pharmacokinetic data are available in pediatric patients.

Renal: In a population pharmacokinetic analysis including a Phase III trial in patients with mild, moderate, and severe renal impairment, exposures were increased by approximately 30% to 40% in severe renal impairment compared with those observed in type 2 diabetic patients with normal renal function.

Hepatic: No clinical trials were conducted to examine the effects of mild, moderate, or severe hepatic impairment on the pharmacokinetics of albiglutide. Therapeutic proteins such as albiglutide are catabolized by widely distributed proteolytic enzymes, which are not restricted to hepatic tissue; therefore, changes in hepatic function are unlikely to have any effect on the elimination of albiglutide.

Drug Interactions

In multiple-dose, drug-drug interaction trials no significant change in systemic exposures of the co-administered drugs were observed, except simvastatin (see Table 3). When albiglutide was co-administered with simvastatin, C_max of simvastatin and its active metabolite simvastatin acid was increased by approximately 18% and 98%, respectively. In the same trial, AUC of simvastatin decreased by 40% and AUC of simvastatin acid increased by 36%. Clinical relevance of these changes has not been established (see Table 3).

Additionally, no clinically relevant pharmacodynamic effects on luteinizing hormone, follicle-stimulating hormone, or progesterone were observed when albiglutide and a combination oral contraceptive were co-administered. Albiglutide did not significantly alter the pharmacodynamic effects of warfarin as measured by the international normalized ratio (INR).

Table 3. Effect of Albiglutide on Systemic Exposure of Co-administered Drugs

Co-administered Drug

Dose of Co-administered Drug^a

Dose of TANZEUM

Geometric Mean Ratio
(Ratio +/- Co-administered Drug)
No Effect = 1

Analyte

AUC (90% CI)^b

C_max (90% CI)

No dose adjustments of co-administered drug required for the following:

Simvastatin

80 mg

50 mg QW for 5 weeks

Simvastatin

0.60 (0.52 – 0.69)

1.18 (1.02 – 1.38)

Simvastatin acid

1.36 (1.19 – 1.55)

1.98 (1.75 – 2.25)

Digoxin

0.5 mg

50 mg QW for 5 weeks

Digoxin

1.09 (1.01 – 1.18)

1.11 (0.98 – 1.26)

Oral contraceptive^c

0.035 mg ethinyl estradiol and 0.5 mg norethindrone

50 mg QW for 4 weeks

Norethindrone

1.00 (0.96 – 1.04)

1.04 (0.98 – 1.10)

Levonorgestrel

1.09 (1.06 – 1.14)

1.20 (1.11 – 1.29)

Warfarin

25 mg

50 mg QW for 5 weeks

R-Warfarin

1.02 (0.98 – 1.07)

0.94 (0.89 – 0.99)

S-Warfarin

0.99 (0.95 – 1.03)

0.93 (0.87 – 0.98)

QW = Once weekly.

^a Single dose unless otherwise noted.

^b AUC_inf for drugs given as a single dose and AUC24h for drugs given as multiple doses.

^c Subjects received low-dose oral contraceptive for two 28-day treatment cycles (21 days active/7 days placebo).

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

As albiglutide is a recombinant protein, no genotoxicity studies have been conducted.

Carcinogenicity studies have not been performed with albiglutide because such studies are not technically feasible due to the rapid development of drug-clearing, anti-drug antibodies in rodents. Thyroid C-cell tumors were observed in 2-year rodent carcinogenicity studies with some GLP-1 receptor agonists. The clinical relevance of rodent thyroid findings observed with GLP-1 receptor agonists is unknown.

In a mouse fertility study, males were treated with SC doses of 5, 15, or 50 mg/kg/day for 7 days prior to cohabitation with females, and continuing through mating. In a separate fertility study, females were treated with SC doses of 1, 5, or 50 mg/kg/day for 7 days prior to cohabitation with males, and continuing through mating. Reductions in estrous cycles were observed at 50 mg/kg/day, a dose associated with maternal toxicity (body weight loss and reduced food consumption). There were no effects on mating or fertility in either sex at doses up to 50 mg/kg/day (up to 39 times clinical exposure based on AUC).

Reproductive and Developmental Toxicity

In order to minimize the impact of the drug-clearing, anti-drug antibody response, reproductive and developmental toxicity assessments in the mouse were partitioned to limit the dosing period to no more than approximately 15 days in each study.

In pregnant mice given SC doses of 1, 5, or 50 mg/kg/day from gestation Day 1 to 6, there were no adverse effects on early embryonic development through implantation at 50 mg/kg/day (39 times clinical exposure based on AUC).

In pregnant mice given SC doses of 1, 5, or 50 mg/kg/day from gestation Day 6 through 15 (organogenesis), embryo-fetal lethality (post-implantation loss) and bent (wavy) ribs were observed at 50 mg/kg/day (39 times clinical exposure based on AUC), a dose associated with maternal toxicity (body weight loss and reduced food consumption).

Pregnant mice were given SC doses of 1, 5, or 50 mg/kg/day from gestation Day 6 to 17. Offspring of pregnant mice given 50 mg/kg/day (39 times clinical exposure based on AUC), a dose associated with maternal toxicity, had reduced body weight pre-weaning, dehydration and coldness, and a delay in balanopreputial separation.

Pregnant mice were given SC doses of 1, 5, or 50 mg/kg/day from gestation Day 15 to lactation Day 10. Increased mortality and morbidity were seen at all doses (≥1 mg/kg/day) in lactating females in mouse pre- and postnatal development studies. Mortalities have not been observed in previous toxicology studies in non-lactating or non-pregnant mice, nor in pregnant mice. These findings are consistent with lactational ileus syndrome which has been previously reported in mice. Since the relative stress of lactation energy demands is lower in humans than mice and humans have large energy reserves, the mortalities observed in lactating mice are of questionable relevance to humans. The offspring had decreased pre-weaning body weight which reversed post-weaning in males but not females at ≥5 mg/kg/day (2.2 times clinical exposure based on AUC) with no other effects on development. Low levels of albiglutide were detected in plasma of offspring.

Lactating mice were given SC doses of 1, 5, or 50 mg/kg/day from lactation Day 7 to 21 (weaning) under conditions that limit the impact of lactational ileus (increased caloric intake and culling of litters). Doses ≥1 mg/kg/day (exposures below clinical AUC) caused reduced weight gain in the pups during the treatment period.

CLINICAL STUDIES

TANZEUM has been studied as monotherapy and in combination with metformin, metformin and a sulfonylurea, a thiazolidinedione (with and without metformin), and insulin glargine (with or without oral anti-diabetic drugs). The efficacy of TANZEUM was compared with placebo, glimepiride, pioglitazone, liraglutide, sitagliptin, insulin lispro, and insulin glargine.

Trials evaluated the use of TANZEUM 30 mg and 50 mg. Five of the 8 trials allowed optional uptitration of TANZEUM from 30 mg to 50 mg if glycemic response with 30 mg was inadequate.

In patients with type 2 diabetes mellitus, TANZEUM produced clinically relevant reduction from baseline in HbA1c compared with placebo. No overall differences in glycemic effectiveness or body weight were observed across demographic subgroups (age, gender, race/ethnicity, duration of diabetes).

Monotherapy

The efficacy of TANZEUM as monotherapy was evaluated in a 52-week, randomized, double-blind, placebo-controlled, multicenter trial. In this trial, 296 patients with type 2 diabetes inadequately controlled on diet and exercise were randomized (1:1:1) to TANZEUM 30 mg SC once weekly, TANZEUM 30 mg SC once weekly uptitrated to 50 mg once weekly at Week 12, or placebo. The mean age of participants was 53 years, 55% of patients were men, the mean duration of diabetes was 4 years, and the mean baseline eGFR was 84 mL/min/1.73 m². Primary and secondary efficacy results are presented in Table 4. Figure 1 shows the mean adjusted changes in HbA1c from baseline across study visits.

Compared with placebo, treatment with TANZEUM 30 mg or 50 mg resulted in statistically significant reductions in HbA1c from baseline at Week 52 (see Table 4). The adjusted mean change in weight from baseline did not differ significantly between TANZEUM (-0.4 to -0.9 kg) and placebo (-0.7 kg) at Week 52.

Table 4. Results at Week 52 (LOCF^a) in a Trial of TANZEUM as Monotherapy

Placebo

TANZEUM
30 mg Weekly

TANZEUM
50 mg Weekly

ITT^a (N)

99

100

97

HbA1c (%)

Baseline (mean)
Change at Week 52^b
Difference from placebo^b (95% CI)

8.0
+0.2

8.1
-0.7
-0.8 (-1.1, -0.6)^c

8.2
-0.9
-1.0 (-1.3, -0.8)^c

Patients (%) achieving HbA1c <7%

21

49

40

FPG (mg/dL)

Baseline (mean)
Change at Week 52^b
Difference from placebo^b (95% CI)

163
+18

164
-16
-34 (-46, -22)^c

171
-25
-43 (-55, -31)^c

^a Intent-to-treat population. Last observation carried forward (LOCF) was used to impute missing data. Data post-onset of rescue therapy are treated as missing. At Week 52, primary efficacy data was imputed for 63%, 34%, and 41% of individuals randomized to placebo, TANZEUM 30 mg, and TANZEUM 50 mg.

^b Least squares mean adjusted for baseline value and stratification factors.

^c P <0.0001 for treatment difference.

Figure 1. Mean HbA1c Change from Baseline (ITT Population-LOCF) in a Trial of TANZEUM as Monotherapy

Combination Therapy

Add-on to Metformin

The efficacy of TANZEUM was evaluated in a 104-week randomized, double-blind, multicenter trial in 999 patients with type 2 diabetes mellitus inadequately controlled on background metformin therapy (≥1,500 mg daily). In this trial, TANZEUM 30 mg SC weekly (with optional uptitration to 50 mg weekly after a minimum of 4 weeks) was compared with placebo, sitagliptin 100 mg daily, or glimepiride 2 mg daily (with optional titration to 4 mg daily). The mean age of participants was 55 years, 48% of patients were men, the mean duration of type 2 diabetes was 6 years, and the mean baseline eGFR was 86 mL/min/1.73 m². Results of the primary and secondary analyses are presented in Table 5. Figure 2 shows the mean adjusted changes in HbA1c across study visits.

Reduction in HbA1c from baseline achieved with TANZEUM was significantly greater than HbA1c reduction achieved with placebo, sitagliptin, and glimepiride at Week 104 (see Table 5). The difference in body weight change from baseline between TANZEUM and glimepiride was significant at Week 104.

Table 5. Results at Week 104 (LOCF^a) in a Trial Comparing TANZEUM with Placebo as Add-on Therapy in Patients Inadequately Controlled on Metformin

TANZEUM + Metformin

Placebo
+ Metformin

Sitagliptin
+ Metformin

Glimepiride
+ Metformin

ITT^a (N)

297

100

300

302

HbA1c (%)

Baseline (mean)
Change at Week 104^b
Difference from placebo + metformin^b (95% CI)
Difference from sitagliptin + metformin^b (95% CI)
Difference from glimepiride + metformin^b (95% CI)

8.1
-0.6
-0.9 (-1.16, -0.65)^c
-0.4 (-0.53, -0.17)^c
-0.3 (-0.45, -0.09)^c

8.1
+0.3

8.1
-0.3

8.1
-0.4

Proportion achieving HbA1c <7%

39

16

32

31

FPG (mg/dL)

Baseline (mean)
Change at Week 104^b
Difference from placebo + metformin^b (95% CI)
Difference from sitagliptin + metformin^b (95% CI)
Difference from glimepiride + metformin^b (95% CI)

165
-18
-28 (-39, -16)^c
-16 (-24, -8)^c
-10 (-18, -2)^c

162
+10

165
-2

168
-8

Body Weight (kg)

Baseline (mean)
Change at Week 104^b
Difference from placebo + metformin^b (95% CI)
Difference from sitagliptin + metformin^b (95% CI)
Difference from glimepiride + metformin^b (95% CI)

90
-1.2
-0.2 (-1.1, 0.7)
-0.4 (-1.0, 0.3)
-2.4 (-3.0, -1.7)^c

92
-1.0

90
-0.9

92
+1.2

^a Intent-to-treat population. Last observation carried forward (LOCF) was used to impute missing data. Data post-onset of rescue therapy are treated as missing. At Week 104, primary efficacy data was imputed for 76%, 46%, 55%, and 51% of individuals randomized to placebo, TANZEUM, sitagliptin, and glimepiride, respectively.

^b Least squares mean adjusted for baseline value and stratification factors.

^c P <0.0137 for treatment difference.

Figure 2. Mean HbA1c Over Time (ITT Population-LOCF) in a Trial Comparing TANZEUM with Placebo as Add-on Therapy in Patients Inadequately Controlled on Metformin

Add-on to Pioglitazone

The efficacy of TANZEUM was evaluated in a 52-week randomized, double-blind, multicenter trial in 299 patients with type 2 diabetes mellitus inadequately controlled on pioglitazone ≥30 mg daily (with or without metformin ≥1,500 mg daily). Patients were randomized to receive TANZEUM 30 mg SC weekly or placebo. The mean age of participants was 55 years, 60% of patients were men, the mean duration of type 2 diabetes was 8 years, and the mean baseline eGFR was 83 mL/min/1.73 m². Results of the primary and secondary analyses are presented in Table 6.

Compared with placebo, treatment with TANZEUM resulted in a statistically significant reduction in HbA1c from baseline at Week 52 (see Table 6). The adjusted mean change from baseline in weight did not differ significantly between TANZEUM (+0.3 kg) and placebo (+0.5 kg) at Week 52.

Table 6. Results at Week 52 (LOCF^a) in a Trial Comparing TANZEUM with Placebo as Add-on Therapy in Patients Inadequately Controlled on Pioglitazone (with or without Metformin)

TANZEUM
+ Pioglitazone
(with or without Metformin)

Placebo
+ Pioglitazone
(with or without Metformin)

ITT ^a (N)

150

149

HbA1c (%)

Baseline (mean)
Change at Week 52^b
Difference from placebo + pioglitazone^b (95% CI)

8.1
-0.8
-0.8 (-0.95, -0.56)^c

8.1
-0.1

Proportion Achieving HbA1c <7%

44

15

FPG (mg/dL)

Baseline (mean)
Change at Week 52^b
Difference from placebo + pioglitazone^b (95% CI)

165
-23
-30 (-39, -20)^c

167
+6

^a Intent-to-treat population. Last observation carried forward (LOCF) was used to impute missing data. Data post-onset of rescue therapy are treated as missing. At Week 52, primary efficacy data was imputed for 58% and 32% of individuals randomized to placebo and TANZEUM, respectively.

^b Least squares mean adjusted for baseline value and stratification factors.

^c P <0.0001 for treatment difference.

Add-on to Metformin Plus Sulfonylurea

The efficacy of TANZEUM was evaluated in a 52-week randomized, double-blind, multicenter trial in 657 patients with type 2 diabetes mellitus inadequately controlled on metformin (≥1,500 mg daily) and glimepiride (4 mg daily). Patients were randomized to receive TANZEUM 30 mg SC weekly (with optional uptitration to 50 mg weekly after a minimum of 4 weeks), placebo, or pioglitazone 30 mg daily (with optional titration to 45 mg/day). The mean age of participants was 55 years, 53% of patients were men, the mean duration of type 2 diabetes was 9 years, and the mean baseline eGFR was 84 mL/min/1.73 m². Results of the primary and main secondary analyses are presented in Table 7.

Treatment with TANZEUM resulted in statistically significant reductions in HbA1c from baseline compared with placebo (see Table 7). Treatment with TANZEUM did not meet the pre-specified, non-inferiority margin (0.3%) against pioglitazone. In this trial, TANZEUM provided less HbA1c reduction than pioglitazone and the treatment difference was statistically significant (see Table 7). The change from baseline in body weight for TANZEUM did not differ significantly from placebo but was significantly different compared with pioglitazone (see Table 7).

Table 7. Results at Week 52 (LOCF^a) in a Trial Comparing TANZEUM with Placebo as Add-on Therapy in Patients Inadequately Controlled on Metformin Plus Sulfonylurea

TANZEUM
+ Metformin
+ Glimepiride

Placebo
+ Metformin
+ Glimepiride

Pioglitazone
+ Metformin
+ Glimepiride

ITT ^a (N)

269

115

273

HbA1c (%)

Baseline (mean)
Change at Week 52^b
Difference from placebo + met + glim^b (95% CI)
Difference from pioglitazone + met + glim^b (95% CI)

8.2
-0.6
-0.9 (-1.07, -0.68)^c
0.25 (0.10, 0.40)^d

8.3
+0.3

8.3
-0.8

Proportion achieving HbA1c <7%

30

9

35

FPG (mg/dL)

Baseline (mean)
Change at Week 52^b
Difference from placebo + met + glim^b (95% CI)
Difference from pioglitazone + met + glim^b (95% CI)

171
-12
-24 (-34, -14)^c
19 (11, 27)^c

174
+12

177
-31

Body Weight (kg)

Baseline (mean)
Change at Week 52^b
Difference from placebo + met + glim^b (95% CI)
Difference from pioglitazone + met + glim^b (95% CI)

91
-0.4
-0.0 (-0.9, 0.8)
-4.9 (-5.5, -4.2)^c

90
-0.4

91
+4.4

^a Intent-to-treat population. Last observation carried forward (LOCF) was used to impute missing data. Data post-onset of rescue therapy are treated as missing. At Week 52, primary efficacy data was imputed for 70%, 35%, and 34% of individuals randomized to placebo, TANZEUM, and pioglitazone.

^b Least squares mean adjusted for baseline value and stratification factors.

^c P <0.0001 for treatment difference.

^d Did not meet non-inferiority margin of 0.3%.

Combination Therapy: Active-controlled Trial versus Liraglutide

The efficacy of TANZEUM was evaluated in a 32-week, randomized, open-label, liraglutide-controlled, non-inferiority trial in 805 patients with type 2 diabetes mellitus inadequately controlled on monotherapy or combination oral antidiabetic therapy (metformin, thiazolidinedione, sulfonylurea, or a combination of these). Patients were randomized to TANZEUM 30 mg SC weekly (with uptitration to 50 mg weekly at Week 6) or liraglutide 1.8 mg daily (titrated up from 0.6 mg at Week 1, and 1.2 mg at Week 1 to Week 2). The mean age of participants was 56 years, 50% of patients were men, the mean duration of type 2 diabetes was 8 years, and the mean baseline eGFR was 95 mL/min/1.73 m². Results of the primary and main secondary analyses are presented in Table 8.

The between-treatment difference of 0.2% with 95% confidence interval (0.08, 0.34) between TANZEUM and liraglutide did not meet the pre-specified, non-inferiority margin (0.3%). In this trial, TANZEUM provided less HbA1c reduction than liraglutide and the treatment difference was statistically significant (see Table 8).

Table 8. Results of Controlled Trial of TANZEUM versus Liraglutide at Week 32 (LOCF^a)

TANZEUM

Liraglutide

ITT ^a (N)

402

403

HbA1c (%)

Baseline (mean)
Change at Week 32^b
Difference from liraglutide^b (95% CI)

8.2%
-0.8
0.2 (0.08, 0.34)^c

8.2%
-1.0

Proportion achieving HbA1c <7%

42%

52%

FPG (mg/dL)

Baseline (mean)
Change at Week 32^b
Difference from liraglutide^b (95% CI)

169
-22
8 (3, 14)^d

167
-30

Body Weight (kg)

Baseline (mean)
Change at Week 32^b
Difference from liraglutide^b (95% CI)

92
-0.6
1.6 (1.1, 2.1)^d

93
-2.2

^a Intent-to-treat population. Last observation carried forward (LOCF) was used to impute missing data. Data post-onset of rescue therapy are treated as missing. At Week 32, primary efficacy data was imputed for 31% and 24% of individuals randomized to TANZEUM and liraglutide.

^b Least squares mean adjusted for baseline value and stratification factors.

^c Did not meet non-inferiority margin of 0.3%.

^d P <0.005 for treatment difference in favor of liraglutide.

Combination Therapy: Active-controlled Trial versus Basal Insulin

The efficacy of TANZEUM was evaluated in a 52-week, randomized (2:1), open-label, insulin glargine-controlled, non-inferiority trial in 735 patients with type 2 diabetes mellitus inadequately controlled on metformin ≥1,500 mg daily (with or without sulfonylurea). Patients were randomized to receive TANZEUM 30 mg SC weekly (with optional uptitration to 50 mg weekly) or insulin glargine (started at 10 units and titrated weekly per prescribing information). The primary endpoint was change in HbA1c from baseline compared with insulin glargine. 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. Seventy-seven percent of patients treated with TANZEUM were uptitrated to 50 mg SC weekly. The mean age of participants was 56 years, 56% of patients were men, the mean duration of type 2 diabetes was 9 years, and the mean baseline eGFR was 85 mL/min/1.73 m². Results of the primary and main secondary analyses are presented in Table 9.

The between-treatment difference of 0.1% with 95% confidence interval (-0.04%, 0.27%) for TANZEUM and insulin glargine met the pre-specified, non-inferiority margin (0.3%). A mean decrease in body weight was observed for TANZEUM compared with a mean increase in body weight for insulin glargine, and the difference in weight change was statistically significant (see Table 9).

Table 9. Results at Week 52 (LOCF^a) in a Trial Comparing TANZEUM with Insulin Glargine as Add-on Therapy in Patients Inadequately Controlled on Metformin ± Sulfonylurea

TANZEUM
+ Metformin
(with or without Sulfonylurea)

Insulin Glargine
+ Metformin
(with or without Sulfonylurea)

ITT ^a (N)

496

239

HbA1c (%)

Baseline (mean)
Change at Week 52^b
Difference from insulin glargine^b (95% CI)

8.3
-0.7
0.1(-0.04, 0.27)^c

8.4
-0.8

Proportion achieving HbA1c <7%

32

33

FPG (mg/dL)

Baseline (mean)
Change at Week 52^b
Difference from insulin glargine^b (95% CI)

169
-16
21 (14, 29)^d

175
-37

Body Weight (kg)

Baseline (mean)
Change at Week 52^b
Difference from insulin glargine^b (95% CI)

95
-1.1
-2.6 (-3.2, -2.0)^e

95
1.6

^a Intent-to-treat population. Last observation carried forward (LOCF) was used to impute missing data. Data post-onset of rescue therapy are treated as missing. At Week 52, primary efficacy data was imputed for 41% and 36% of individuals randomized to TANZEUM and insulin glargine.

^b Least squares mean adjusted for baseline value and stratification factors.

^c Met non-inferiority margin of 0.3%.

^d P <0.0001 in favor of insulin glargine.

^e P <0.0001.

Figure 3. Mean HbA1c Change from Baseline (Completers) in a Trial Comparing TANZEUM with Insulin Glargine as Add-on Therapy in Patients Inadequately Controlled on Metformin (with or without a Sulfonylurea)

Combination Therapy: Active-controlled Trial versus Prandial Insulin

The efficacy of TANZEUM was evaluated in a 26-week, randomized, open-label, multicenter, non-inferiority trial in 563 patients with type 2 diabetes mellitus inadequately controlled on insulin glargine (started at 10 units and titrated to ≥20 units per day). Patients were randomized to receive TANZEUM 30 mg SC once weekly (with uptitration to 50 mg if inadequately controlled after Week 8) or insulin lispro (administered daily at meal times, started according to standard of care and titrated to effect). At Week 26, the mean daily dose of insulin glargine was 53 IU for TANZEUM and 51 IU for insulin lispro. The mean daily dose of insulin lispro at Week 26 was 31 IU, and 69% of patients treated with TANZEUM were on 50 mg weekly. The mean age of participants was 56 years, 47% of patients were men, the mean duration of type 2 diabetes was 11 years, and the mean baseline eGFR was 91 mL/min/1.73 m². Results of the primary and main secondary analyses are presented in Table 10. Figure 4 shows the mean adjusted changes in HbA1c from baseline across study visits.

The between-treatment difference of -0.2% with 95% confidence interval (-0.32%, 0.00%) between albiglutide and insulin lispro met the pre-specified non-inferiority margin (0.4%). Treatment with TANZEUM resulted in a mean weight loss for TANZEUM compared with a mean weight gain for insulin lispro, and the difference between treatment groups was statistically significant (see Table 10).

Table 10. Results at Week 26 (LOCF^a) in a Trial Comparing TANZEUM with Insulin Lispro as Add-On Therapy in Patients Inadequately Controlled on Insulin Glargine

TANZEUM
+ Insulin Glargine

Insulin Lispro
+ Insulin Glargine

ITT ^a (N)

282

281

HbA_1c (%)

Baseline (mean)
Change at Week 26^b
Difference from insulin lispro^b (95% CI)

8.5
-0.8
-0.2(-0.32, 0.00)^c

8.4
-0.7

Proportion achieving HbA_1c <7%

30%

25%

FPG (mg/dL)

Baseline (mean)
Change at Week 26^b
Difference from insulin lispro^b (95% CI)

153
-18
-5 (-13, 3)

153
-13

Body Weight (kg)

Baseline (mean)
Change at Week 26^b
Difference from insulin lispro^b (95% CI)

93
-0.7
-1.5 (-2.1, -1.0)^d

92
+0.8

^a Intent-to-treat population. Last observation carried forward (LOCF) was used to impute missing data. Data post-onset of rescue therapy are treated as missing. At Week 26, primary efficacy data was imputed for 29% and 29% of individuals randomized to TANZEUM and insulin lispro.

^b Least squares mean adjusted for baseline value and stratification factors.

^c Rules out a non-inferiority margin of 0.4%.

^d P <0.0001 for treatment difference.

Figure 4. Mean HbA1c Change from Baseline (ITT-LOCF population) in a Trial Comparing TANZEUM with Insulin Lispro as Add-On Therapy in Patients Inadequately Controlled on Insulin Glargine

Type 2 Diabetes Mellitus Patients with Renal Impairment

The efficacy of TANZEUM was evaluated in a 26-week, randomized, double-blind, active-controlled trial in 486 patients with mild (n = 250), moderate (n = 200), and severe renal impairment (n = 36) inadequately controlled on a current regimen of diet and exercise or other antidiabetic therapy. Patients were randomized to receive TANZEUM 30 mg SC weekly (with uptitration to 50 mg weekly if needed as early as Week 4) or sitagliptin. Sitagliptin was dosed according to renal function (100 mg, 50 mg, and 25 mg daily in mild, moderate, and severe renal impairment, respectively). The mean age of participants was 63 years, 54% of patients were men, the mean duration of type 2 diabetes was 11 years, and the mean baseline eGFR was 60 mL/min/1.73 m².

Results of the primary and main secondary analyses are presented in Table 11. Treatment with TANZEUM resulted in statistically significant reductions in HbA1c from baseline at Week 26 compared with sitagliptin (see Table 11).

Table 11. Results at Week 26 (LOCF^a) in a Trial Comparing TANZEUM with Sitagliptin in Patients with Renal Impairment

TANZEUM

Sitagliptin

ITT ^a (N)

246

240

HbA1c (%)

Baseline (mean)
Change at Week 26^b
Difference from sitagliptin^b (95% CI)

8.1
-0.8
-0.3 (-0.49, -0.15)^c

8.2
-0.5

Proportion achieving HbA1c <7%

43%

31%

FPG (mg/dL)

Baseline (mean)
Change at Week 26^b
Difference from sitagliptin^b (95% CI)

166
-26
-22 (-31, -13)^c

165
-4

Body Weight (kg)

Baseline (mean)
Change at Week 26^b
Difference from sitagliptin^b (95% CI)

84
-0.8
-0.6 (-1.1, -0.1)^d

83
-0.2

^a Intent-to-treat population. Last observation carried forward (LOCF) was used to impute missing data. Data post-onset of rescue therapy are treated as missing. At Week 26 primary efficacy data was imputed for 17% and 25% of individuals randomized to TANZEUM and sitagliptin.

^b Least squares mean adjusted for baseline value and stratification factors.

^c P <0.0003 for treatment difference.

^d P = 0.0281 for treatment difference.

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