Albiglutide Pen for Injection, for Subcutaneous Use

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.

Dosage Forms And Strengths

TANZEUM is supplied as follows:

• For injection: 30-mg lyophilized powder in a single-dose Pen (pen injector) for reconstitution.
• For injection: 50-mg lyophilized powder in a single-dose Pen (pen injector) for reconstitution.

TANZEUM is available in the following strengths and package size:

30-mg single-dose Pen (NDC 0173-0866-01):

carton of 4 (containing four 29-gauge, 5-mm, thinwall needles): NDC 0173-0866-35

50-mg single-dose Pen (NDC 0173-0867-01):

carton of 4 (containing four 29-gauge, 5-mm, thinwall needles): NDC 0173-0867-35

Storage And Handling

• Prior to dispensing: Store Pens in the refrigerator at 36°F to 46°F (2°C to 8°C). Pens may be stored refrigerated until the expiration date.
• Following dispensing: Store Pens in the refrigerator at 36°F to 46°F (2°C to 8°C). Patients may store Pens at room temperature not to exceed 86°F (30°C) for up to 4 weeks prior to use. Store Pens in the original carton until use.
• Do not freeze.
• Do not use past the expiration date.
• Use within 8 hours after reconstitution.

Manufactured by GlaxoSmithKline LLC Wilmington, DE 19808, U.S. Lic. No. 1727 Marketed by GlaxoSmithKline Research Triangle Park, NC 27709.  Revised: Aug 2017

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 (Cmax) 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, Cmax 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 Coadministered Druga	Dose of TANZEUM	Geometric Mean Ratio (Ratio +/- Co-administered Drug) No Effect = 1
			Analyte	AUC (90% CI)b	Cmax (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 contraceptivec	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. aSingle dose unless otherwise noted. bAUCinf for drugs given as a single dose and AUC24h for drugs given as multiple doses. cSubjects received low-dose oral contraceptive for two 28-day treatment cycles (21 days active/7 days placebo).

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 (LOCFa) in a Trial of TANZEUM as Monotherapy

	Placebo	TANZEUM 30 mg Weekly	TANZEUM 50 mg Weekly
ITTa (N)	99	100	97
HbA1c (%)
Baseline (mean)	8.0	8.1	8.2
Change at Week 52b	+0.2	-0.7	-0.9
Difference from placebob (95% CI)		-0.8 (-1.1, -0.6)c	-1.0 (-1.3, -0.8)c
Patients (%) achieving HbA1c <7%	21	49	40
FPG (mg/dL)
Baseline (mean)	163	164	171
Change at Week 52b	+18	-16	-25
Difference from placebob (95% CI)		-34 (-46, -22)c	-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 (LOCFa) 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
ITTa (N)	297	100	300	302
HbA1c (%)
Baseline (mean)	8.1	8.1	8.1	8.1
Change at Week 104b	-0.6	+0.3	-0.3	-0.4
Difference from placebo + metforminb (95% CI)	-0.9 (-1.16, -0.65)c
Difference from sitagliptin + metforminb (95% CI)	-0.4 (-0.53, -0.17)c
Difference from glimepiride + metforminb (95% CI)	-0.3 (-0.45, -0.09)c
Proportion achieving HbA1c <7%	39	16	32	31
FPG (mg/dL)
Baseline (mean)	165	162	165	168
Change at Week 104b	-18	+10	-2	-8
Difference from placebo + metforminb (95% CI)	-28 (-39, -16)c
Difference from sitagliptin + metforminb (95% CI)	-16 (-24, -8)c
Difference from glimepiride + metforminb (95% CI)	-10 (-18, -2)c
Body Weight (kg)
Baseline (mean)	90	92	90	92
Change at Week 104 b	-1.2	-1.0	-0.9	+1.2
Difference from placebo + metforminb (95% CI)	-0.2 (-1.1, 0.7)
Difference from sitagliptin + metforminb (95% CI)	-0.4 (-1.0, 0.3)
Difference from glimepiride + metforminb (95% CI)	-2.4 (-3.0, -1.7)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 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 (LOCFa) 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)
ITTa (N)	150	149
HbA1c (%)
Baseline (mean)	8.1	8.1
Change at Week 52b	-0.8	-0.1
Difference from placebo + pioglitazoneb (95% CI)	-0.8 (-0.95, -0.56)c
Proportion Achieving HbA1c <7%	44	15
FPG (mg/dL)
Baseline (mean)	165	167
Change at Week 52b	-23	+6
Difference from placebo + pioglitazoneb (95% CI)	-30 (-39, -20)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 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 prespecified, 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 (LOCFa) 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
ITTa (N)	269	115	273
HbA1c (%)
Baseline (mean)	8.2	8.3	8.3
Change at Week 52b	-0.6	+0.3	-0.8
Difference from placebo + met + glimb (95% CI)	-0.9 (-1.07, -0.68)c
Difference from pioglitazone + met + glimb (95% CI)	0.25 (0.10, 0.40)d
Proportion achieving HbA1c <7%	30	9	35
FPG (mg/dL)
Baseline (mean)	171	174	177
Change at Week 52b	-12	+12	-31
Difference from placebo + met + glimb (95% CI)	-24 (-34, -14)c
Difference from pioglitazone + met + glimb (95% CI)	19 (11, 27)c
Body Weight (kg)
Baseline (mean)	91	90	91
Change at Week 52b	-0.4	-0.4	+4.4
Difference from placebo + met + glimb (95% CI)	-0.0 (-0.9, 0.8)
Difference from pioglitazone + met + glimb (95% CI)	-4.9 (-5.5, -4.2)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 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, liraglutidecontrolled, 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 (LOCFa)

	TANZEUM	Liraglutide
ITTa (N)	402	403
HbA1c (%)
Baseline (mean)	8.2%	8.2%
Change at Week 32b	-0.8	-1.0
Difference from liraglutideb (95% CI)	0.2 (0.08, 0.34)c
Proportion achieving HbA1c <7%	42%	52%
FPG (mg/dL)
Baseline (mean)	169	167
Change at Week 32b	-22	-30
Difference from liraglutideb (95% CI)	8 (3, 14)d
Body Weight (kg)
Baseline (mean)	92	93
Change at Week 32b	-0.6	-2.2
Difference from liraglutideb (95% CI)	1.6 (1.1, 2.1)d
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 (median starting dose of 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. Sixty-nine 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 (LOCFa) 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)
ITTa (N)	496	239
HbA1c (%)
Baseline (mean)	8.3	8.4
Change at Week 52b	-0.7	-0.8
Difference from insulin glargineb (95% CI)	0.1 (-0.04, 0.27)c
Proportion achieving HbA1c <7%	32	33
FPG (mg/dL)
Baseline (mean)	169	175
Change at Week 52b	-16	-37
Difference from insulin glargineb (95% CI)	21 (14, 29)d
Body Weight (kg)
Baseline (mean)	95	95
Change at Week 52b	-1.1	1.6
Difference from insulin glargineb (95% CI)	-2.6 (-3.2, -2.0)e
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 (≥ 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 51% 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 (LOCFa) 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
ITTa (N)	282	281
HbA1c (%)
Baseline (mean)	8.5	8.4
Change at Week 26b	-0.8	-0.7
Difference from insulin lisprob (95% CI)	-0.2 (-0.32, 0.00)c
Proportion achieving HbA1c <7%	30%	25%
FPG (mg/dL)
Baseline (mean)	153	153
Change at Week 26b	-18	-13
Difference from insulin lisprob (95% CI)	-5 (-13, 3)
Body Weight (kg)
Baseline (mean)	93	92
Change at Week 26b	-0.7	+0.8
Difference from insulin lisprob (95% CI)	-1.5 (-2.1, -1.0)d
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 (LOCFa) in a Trial Comparing TANZEUM with Sitagliptin in Patients with Renal Impairment

	TANZEUM	Sitagliptin
ITTa (N)	246	240
HbA1c (%)
Baseline (mean)	8.1	8.2
Change at Week 26b	-0.8	-0.5
Difference from sitagliptinb (95% CI)	-0.3 (-0.49, -0.15)c
Proportion achieving HbA1c <7%	43%	31%
FPG (mg/dL)
Baseline (mean)	166	165
Change at Week 26b	-26	-4
Difference from sitagliptinb (95% CI)	-22 (-31, -13)c
Body Weight (kg)
Baseline (mean)	84	83
Change at Week 26b	-0.8	-0.2
Difference from sitagliptinb (95% CI)	-0.6 (-1.1, -0.1)d
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.

The following serious reactions are described below or elsewhere in the prescribing information:

• Risk of Thyroid C-Cell Tumors [see WARNINGS AND PRECAUTIONS]
• Acute Pancreatitis [see WARNINGS AND PRECAUTIONS]
• Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see WARNINGS AND PRECAUTIONS]
• Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]
• Renal Impairment [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Pool Of Placebo-Controlled Trials

The data in Table 1 are derived from 4 placebo-controlled trials. TANZEUM was used as monotherapy in 1 trial and as add-on therapy in 3 trials [see Clinical Studies]. These data reflect exposure of 923 patients to TANZEUM and a mean duration of exposure to TANZEUM of 93 weeks. The mean age of participants was 55 years, 1% of participants were 75 years or older and 53% of participants were male. The population in these studies was 48% white, 13% African/African American, 7% Asian, and 29% Hispanic/Latino. At baseline, the population had type 2 diabetes for an average of 7 years and had a mean HbA1c of 8.1%. At baseline, 17% of the population in these studies reported peripheral neuropathy and 4% reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR >60 mL/min/1.73 m²) in 91% of the study population and moderately impaired (eGFR 30 to 60 mL/min/1.73 m²) in 9%.

Table 1 shows common adverse reactions excluding hypoglycemia associated with the use of TANZEUM in the pool of placebo-controlled trials. These adverse reactions were not present at baseline, occurred more commonly on TANZEUM than on placebo, and occurred in at least 5% of patients treated with TANZEUM.

Table 1: Adverse Reactions in Placebo-Controlled Trials Reported in ≥ 5% of Patients Treated with TANZEUMa

Adverse Reaction	Placebo (N = 468) %	TANZEUM (N = 923) %
Upper respiratory tract infection	13.0	14.2
Diarrhea	10.5	13.1
Nausea	9.6	11.1
Injection site reactionb	2.1	10.5
Cough	6.2	6.9
Back pain	5.8	6.7
Arthralgia	6.4	6.6
Sinusitis	5.8	6.2
Influenza	3.2	5.2
a Adverse reactions reported includes adverse reactions occurring with the use of glycemic rescue medications which included metformin (17% for placebo and 10% for TANZEUM) and insulin (24% for placebo and 14% for TANZEUM). b See below for other events of injection site reactions reported.

Gastrointestinal Adverse Reactions

In the pool of placebo-controlled trials, gastrointestinal complaints occurred more frequently among patients receiving TANZEUM (39%) than patients receiving placebo (33%). In addition to diarrhea and nausea (see Table 1), the following gastrointestinal adverse reactions also occurred more frequently in patients receiving TANZEUM: vomiting (2.6% versus 4.2% for placebo versus TANZEUM), gastroesophageal reflux disease (1.9% versus 3.5% for placebo versus TANZEUM), and dyspepsia (2.8% versus 3.4% for placebo versus TANZEUM). Constipation also contributed to the frequently reported reactions. In the group treated with TANZEUM, investigators graded the severity of GI reactions as “mild” in 56% of cases, “moderate” in 37% of cases, and “severe” in 7% of cases. Discontinuation due to GI adverse reactions occurred in 2% of individuals on TANZEUM or placebo.

Injection Site Reactions

In the pool of placebo-controlled trials, injection site reactions occurred more frequently on TANZEUM (18%) than on placebo (8%). In addition to the term injection site reaction (see Table 1), the following other types of injection site reactions also occurred more frequently on TANZEUM: injection site hematoma (1.9% versus 2.1% for placebo versus TANZEUM ), injection site erythema (0.4% versus 1.7% for placebo versus TANZEUM), injection site rash (0% versus 1.4% for placebo versus TANZEUM), injection site hypersensitivity (0% versus 0.8% for placebo versus TANZEUM), and injection site hemorrhage (0.6% versus 0.7% for placebo versus TANZEUM). Injection site pruritus also contributed to the frequently reported reactions. The majority of injection site reactions were judged as “mild” by investigators in both groups (73% for TANZEUM versus 94% for placebo). More patients on TANZEUM than on placebo: discontinued due to an injection site reaction (2% versus 0.2%), experienced more than 2 reactions (38% versus 20%), had a reaction judged by investigators to be “moderate” or “severe” (27% versus 6%) and required local or systemic treatment for the reactions (36% versus 11%).

Pool Of Placebo-And Active-Controlled Trials

The occurrence of adverse reactions was also evaluated in a larger pool of patients with type 2 diabetes participating in 7 placebo-and active-controlled trials. These trials evaluated the use of TANZEUM as monotherapy, and as add-on therapy to oral antidiabetic agents, and as add-on therapy to basal insulin [see Clinical Studies]. In this pool, a total of 2,116 patients with type 2 diabetes were treated with TANZEUM for a mean duration of 75 weeks. The mean age of patients treated with TANZEUM was 55 years, 1.5% of the population in these studies was 75 years or older and 51% of participants were male. Forty-eight percent of patients were white, 15% African/African American, 9% Asian, and 26% were Hispanic/Latino. At baseline, the population had diabetes for an average of 8 years and had a mean HbA1c of 8.2%. At baseline, 21% of the population reported peripheral neuropathy and 5% reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR >60 mL/min/1.73 m²) in 92% of the population and moderately impaired (eGFR 30 to 60 mL/min/1.73 m²) in 8% of the population.

In the pool of placebo-and active-controlled trials, the types and frequencies of common adverse reactions excluding hypoglycemia were similar to those listed in Table 1.

Other Adverse Reactions

Hypoglycemia

The proportion of patients experiencing at least one documented symptomatic hypoglycemic episode on TANZEUM and the proportion of patients experiencing at least one severe hypoglycemic episode on TANZEUM in clinical trials [see Clinical Studies] is shown in Table 2. Hypoglycemia was more frequent when TANZEUM was added to sulfonylurea or insulin [see WARNINGS AND PRECAUTIONS].

Table 2: Incidence (%) of Hypoglycemia in Clinical Trials of TANZEUMa

Monotherapyb (52 Weeks)	Placebo N = 101	TANZEUM 30 mg Weekly N = 101
Documented symptomaticc	2%	2%
Severed	-	-
In Combination with Metformin Trial (104 Weeks)e	Placebo N = 101	TANZEUM N = 302
Documented symptomatic	4%	3%
Severe	-	-
In Combination with Pioglitazone ± Metformin (52 Weeks)	Placebo N = 151	TANZEUM N = 150
Documented symptomatic	1%	3%
Severe	-	1%
In Combination with Metformin and Sulfonylurea (52 Weeks)	Placebo N = 115	TANZEUM N = 271
Documented symptomatic	7%	13%
Severe	-	0.4%
In Combination with Insulin Glargine (26 Weeks)	Insulin Lispro N = 281	TANZEUM N = 285
Documented symptomatic	30%	16%
Severe	0.7%	-
In Combination with Metformin ± Sulfonylurea (52 Weeks)	Insulin Glargine N = 241	TANZEUM N = 504
Documented symptomatic	27%	17%
Severe	0.4%	0.4%
In Combination with OADs in Renal Impairment (26 Weeks)	Sitagliptin N = 246	TANZEUM N = 249
Documented symptomatic	6%	10%
Severe	0.8%	-
OAD = Oral antidiabetic agents. a Data presented are to the primary endpoint and include only events occurring on-therapy with randomized medications and excludes events occurring after use of glycemic rescue medications (i.e., primarily metformin or insulin). b In this trial, no documented symptomatic or severe hypoglycemia was reported for TANZEUM 50 mg and these data are omitted from the table. c Plasma glucose concentration ≤ 70 mg/dL and presence of hypoglycemic symptoms. d Event requiring another person to administer a resuscitative action. e Rate of documented symptomatic hypoglycemia for active controls 18% (glimepiride) and 2% (sitagliptin).

Pneumonia

In the pool of 7 placebo-and active-controlled trials, the adverse reaction of pneumonia was reported more frequently in patients receiving TANZEUM (1.8%) than in patients in the all-comparators group (0.8%). More cases of pneumonia in the group receiving TANZEUM were serious (0.4% for TANZEUM versus 0.1% for all comparators).

Atrial Fibrillation/Flutter

In the pool of 7 placebo-and active-controlled trials, adverse reactions of atrial fibrillation (1.0%) and atrial flutter (0.2%) were reported more frequently for TANZEUM than for all comparators (0.5% and 0%, respectively). In both groups, patients with events were generally male, older, and had underlying renal impairment or cardiac disease (e.g., history of arrhythmia, palpitations, congestive heart failure, cardiomyopathy, etc.).

Appendicitis

In the pool of placebo-and active-controlled trials, serious events of appendicitis occurred in 0.3% of patients treated with TANZEUM compared with 0% among all comparators.

Immunogenicity

In the pool of 7 placebo-and active-controlled trials, 116 (5.5%) of 2,098 patients exposed to TANZEUM tested positive for anti-albiglutide antibodies at any time during the trials. None of these antibodies were shown to neutralize the activity of albiglutide in an in vitro bioassay. Presence of antibody did not correlate with reduced efficacy as measured by HbA1c and fasting plasma glucose or specific adverse reactions.

Consistent with the high homology of albiglutide with human GLP-1, the majority of patients (approximately 79%) with anti-albiglutide antibodies also tested positive for anti-GLP-1 antibodies; none were neutralizing. A minority of patients (approximately 17%) who tested positive for anti-albiglutide antibodies also transiently tested positive for antibodies to human albumin.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, the incidence of antibodies to albiglutide cannot be directly compared with the incidence of antibodies of other products.

Liver Enzyme Abnormalities

In the pool of placebo-and active-controlled trials, a similar proportion of patients experienced at least one event of alanine aminotransferase (ALT) increase of 3-fold or greater above the upper limit of normal (0.9% and 0.9% for all comparators versus TANZEUM). Three subjects on TANZEUM and one subject in the all-comparator group experienced at least one event of ALT increase of 10-fold or greater above the upper limit of normal. In one of the 3 cases an alternate etiology was identified to explain the rise in liver enzyme (acute viral hepatitis). In one case, insufficient information was obtained to establish or refute a drug-related causality. In the third case, elevation in ALT (10 times the upper limit of normal) was accompanied by an increase in total bilirubin (4 times the upper limit of normal) and occurred 8 days after the first dose of TANZEUM. The etiology of hepatocellular injury was possibly related to TANZEUM but direct attribution to TANZEUM was confounded by the presence of gallstone disease diagnosed on ultrasound 3 weeks after the event.

Gamma Glutamyltransferase (GGT) Increase

In the pool of placebo-controlled trials, the adverse event of increased GGT occurred more frequently in the group treated with TANZEUM (0.9% and 1.5% for placebo versus TANZEUM).

Heart Rate Increase

In the pool of placebo-controlled trials, mean heart rate in patients treated with TANZEUM was higher by an average of 1 to 2 bpm compared with mean heart rate in patients treated with placebo across study visits. The long-term clinical effects of the increase in heart rate have not been established [see WARNINGS AND PRECAUTIONS].

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of TANZEUM. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Angioedema.

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