Saxenda liraglutide 6 mg/mL Injection, Solution — NDC 0169-2800-90 (Billing 00169-2800-90)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Liraglutide is an acylated human GLP-1 receptor agonist with 97% amino acid sequence homology to endogenous human GLP-1(7-37). Like endogenous GLP-1, liraglutide binds to and activates the GLP-1 receptor, a cell-surface receptor coupled to adenylyl cyclase activation through the stimulatory G-protein, Gs. Endogenous GLP-1 has a half-life of 1.5 to 2 minutes due to degradation by the ubiquitous endogenous enzymes, dipeptidyl peptidase 4 (DPP-4) and neutral endopeptidases (NEP).

Unlike native GLP-1, liraglutide is stable against metabolic degradation by both peptidases and has a plasma half-life of 13 hours after subcutaneous administration. The pharmacokinetic profile of liraglutide, which makes it suitable for once-daily administration, is a result of self-association that delays absorption, plasma protein binding, and stability against metabolic degradation by DPP-4 and NEP. GLP-1 is a physiological regulator of appetite and calorie intake, and the GLP-1 receptor is present in several areas of the brain involved in appetite regulation.

In animal studies, peripheral administration of liraglutide resulted in the presence of liraglutide in specific brain regions regulating appetite, including the hypothalamus. Although liraglutide activated neurons in brain regions known to regulate appetite, specific brain regions mediating the effects of liraglutide on appetite were not identified in rats.

12.2Pharmacodynamics Liraglutide lowers body weight through decreased calorie intake. Liraglutide does not increase 24-hour energy expenditure. As with other GLP-1 receptor agonists, liraglutide stimulates insulin secretion and reduces glucagon secretion in a glucose-dependent manner.

These effects can lead to a reduction of blood glucose. Gastric Emptying Liraglutide delays gastric emptying. Cardiac Electrophysiology (QTc) in healthy volunteers The effect of liraglutide on cardiac repolarization was tested in a QTc study.

Liraglutide at steady-state concentrations after daily doses up to 1.8 mg did not produce QTc prolongation. The maximum liraglutide plasma concentration (C max ) in overweight and obese subjects treated with liraglutide 3 mg is similar to the C max observed in the liraglutide QTc study in healthy volunteers.

12.3Pharmacokinetics Absorption - Following subcutaneous administration, maximum concentrations of liraglutide are achieved at 11 hours post dosing. The average liraglutide steady state concentration (AUCτ /24 ) reached approximately 116 ng/mL in obese (BMI 30-40 kg/m 2 ) subjects following administration of SAXENDA. Liraglutide exposure increased proportionally in the dose range of 0.6 mg to 3 mg.

The intra-subject coefficient of variation for liraglutide AUC was 11% following single dose administration. Liraglutide exposures were considered similar among three subcutaneous injection sites (upper arm, abdomen, and thigh). Absolute bioavailability of liraglutide following subcutaneous administration is approximately 55%.

Distribution - The mean apparent volume of distribution after subcutaneous administration of liraglutide 3 mg is 20 to 25L (for a person weighing approximately 100 kg). The mean volume of distribution after intravenous administration of liraglutide is

0.07L/kg. Liraglutide is extensively bound to plasma protein (greater than 98%). Metabolism - During the initial 24 hours following administration of a single [3H]-liraglutide dose to healthy subjects, the major component in plasma was intact liraglutide.

Liraglutide is endogenously metabolized in a similar manner to large proteins without a specific organ as a major route of elimination. Elimination - Following a [3H]-liraglutide dose, intact liraglutide was not detected in urine or feces. Only a minor part of the administered radioactivity was excreted as liraglutide-related metabolites in urine or feces (6% and 5%, respectively).

The majority of urine and feces radioactivity was excreted during the f… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Liraglutide is an acylated human GLP-1 receptor agonist with 97% amino acid sequence homology to endogenous human GLP-1(7-37). Like endogenous GLP-1, liraglutide binds to and activates the GLP-1 receptor, a cell-surface receptor coupled to adenylyl cyclase activation through the stimulatory G-protein, Gs. Endogenous GLP-1 has a half-life of 1.5 to 2 minutes due to degradation by the ubiquitous endogenous enzymes, dipeptidyl peptidase 4 (DPP-4) and neutral endopeptidases (NEP).

Unlike native GLP-1, liraglutide is stable against metabolic degradation by both peptidases and has a plasma half-life of 13 hours after subcutaneous administration. The pharmacokinetic profile of liraglutide, which makes it suitable for once-daily administration, is a result of self-association that delays absorption, plasma protein binding, and stability against metabolic degradation by DPP-4 and NEP. GLP-1 is a physiological regulator of appetite and calorie intake, and the GLP-1 receptor is present in several areas of the brain involved in appetite regulation.

In animal studies, peripheral administration of liraglutide resulted in the presence of liraglutide in specific brain regions regulating appetite, including the hypothalamus. Although liraglutide activated neurons in brain regions known to regulate appetite, specific brain regions mediating the effects of liraglutide on appetite were not identified in rats.

12.3Pharmacokinetics Absorption - Following subcutaneous administration, maximum concentrations of liraglutide are achieved at 11 hours post dosing. The average liraglutide steady state concentration (AUCτ /24 ) reached approximately 116 ng/mL in obese (BMI 30-40 kg/m 2 ) subjects following administration of SAXENDA. Liraglutide exposure increased proportionally in the dose range of 0.6 mg to 3 mg.

The intra-subject coefficient of variation for liraglutide AUC was 11% following single dose administration. Liraglutide exposures were considered similar among three subcutaneous injection sites (upper arm, abdomen, and thigh). Absolute bioavailability of liraglutide following subcutaneous administration is approximately 55%.

Distribution - The mean apparent volume of distribution after subcutaneous administration of liraglutide 3 mg is 20 to 25L (for a person weighing approximately 100 kg). The mean volume of distribution after intravenous administration of liraglutide is

0.07L/kg. Liraglutide is extensively bound to plasma protein (greater than 98%). Metabolism - During the initial 24 hours following administration of a single [3H]-liraglutide dose to healthy subjects, the major component in plasma was intact liraglutide.

Liraglutide is endogenously metabolized in a similar manner to large proteins without a specific organ as a major route of elimination. Elimination - Following a [3H]-liraglutide dose, intact liraglutide was not detected in urine or feces. Only a minor part of the administered radioactivity was excreted as liraglutide-related metabolites in urine or feces (6% and 5%, respectively).

The majority of urine and feces radioactivity was excreted during the first 6 to 8 days. The mean apparent clearance following subcutaneous administration of a single dose of liraglutide is approximately 0.9 to

1.4L/h with an elimination half-life of approximately 13 hours, making liraglutide suitable for once daily administration. Specific Populations Elderly - Age had no effect on the pharmacokinetics of liraglutide based on a pharmacokinetic study in healthy elderly subjects (65 to 83 years) and population pharmacokinetic analyses of data from overweight and obese patients 18 to 82 years of age [see Use in Specific Populations ( 8.5 )] . Gender - Based on the results of population pharmacokinetic analyses, females have 24% lower weight adjusted clearance of SAXENDA compared to males.

Race and Ethnicity - Race and ethnicity had no effect on the pharmacokinetics of liraglutide based on the results of population pharmacokinetic analyses that included overweight and obese patients of White, Black or African American, Asian and Hispanic/Non-Hispanic Ethnic groups. Body Weight - Body weight significantly affects the pharmacokinetics of liraglutide based on results of population pharmacokinetic analyses conducted in patients with body weight range of 60 to 234 kg. The exposure of liraglutide decreases as baseline body weight increases.

Pediatric - A population pharmacokinetic analysis was conducted for SAXENDA using data from 134 pediatric patients (12 to 17 years of age) with obesity. The liraglutide exposure in the pediatric patients was similar to that in adults with obesity [see Use in Specific Populations ( 8.4 )] . Renal Impairment - The single-dose pharmacokinetics of liraglutide were evaluated in patients with varying degrees of renal impairment.

Patients with mild (estimated creatinine clearance 50-80 mL/min) to severe (estimated creatinine clearance less than 30 mL/min) renal impairment and patients with end-stage renal disease requiring dialysis were included in the trial. Compared to healthy subjects, liraglutide AUC in mild, moderate, and severe renal impairment and in end-stage renal disease was on average 35%, 19%, 29% and 30% lower, respectively [see Use in Specific Populations ( 8.6 )] . Hepatic Impairment - The single-dose pharmacokinetics of liraglutide were evaluated in patients with varying degrees of hepatic impai… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Liraglutide lowers body weight through decreased calorie intake. Liraglutide does not increase 24-hour energy expenditure. As with other GLP-1 receptor agonists, liraglutide stimulates insulin secretion and reduces glucagon secretion in a glucose-dependent manner.

These effects can lead to a reduction of blood glucose. Gastric Emptying Liraglutide delays gastric emptying. Cardiac Electrophysiology (QTc) in healthy volunteers The effect of liraglutide on cardiac repolarization was tested in a QTc study.

Liraglutide at steady-state concentrations after daily doses up to 1.8 mg did not produce QTc prolongation. The maximum liraglutide plasma concentration (C max ) in overweight and obese subjects treated with liraglutide 3 mg is similar to the C max observed in the liraglutide QTc study in healthy volunteers.

14 CLINICAL STUDIES

14.1Weight Management Trials in Adults with Overweight or Obesity The safety and efficacy of SAXENDA for chronic weight management in conjunction with reduced caloric intake and increased physical activity were studied in three 56-week, randomized, double-blind, placebo-controlled trials. In all studies, SAXENDA was titrated to 3 mg daily during a 4-week period. All patients received instruction for a reduced-calorie diet (approximately 500 kcal/day deficit) and physical activity counseling (recommended increase in physical activity of minimum 150 mins/week) that began with the first dose of study medication or placebo and continued throughout the trial.

Study 1 enrolled 3,731 patients with obesity (BMI greater than or equal to 30 kg/m 2 ) or with overweight (BMI 27-29.9 kg/m 2 ) and at least one weight-related comorbid condition such as treated or untreated dyslipidemia or hypertension; patients with type 2 diabetes mellitus were excluded. Patients were randomized in a 2:1 ratio to either SAXENDA or placebo. Patients were stratified based on the presence or absence of abnormal blood glucose measurements at randomization.

All patients were treated for up to 56 weeks. Those patients with abnormal glucose measurements at randomization (2,254 of the 3731 patients) were treated for a total of 160 weeks. At baseline, mean age was 45 years (range 18 to 78), 79% were female, 85% were White, 10% were Black or African American, and 11% were Hispanic/Latino Ethnicity.

Mean baseline body weight was 106.3 kg, and mean BMI was 38.3 kg/m 2 . Study 2 was a 56-week trial that enrolled 635 patients with type 2 diabetes and with either overweight or obesity (as defined above). Patients were to have an HbA 1c of 7% to 10% and be treated with metformin, a sulfonylurea, or a glitazone as single agent or in any combination, or with a reduced-calorie diet and physical activity alone.

Patients were randomized in a 2:1 ratio to receive either SAXENDA or placebo. The mean age was 55 years (range 18 to 82), 50% were female, 83% were White, 12% were Black or African American, and 10% were Hispanic/Latino Ethnicity. Mean baseline body weight was 105.9 kg and mean BMI was 37.1 kg/m 2 .

Study 3 was a 56-week trial that enrolled 422 patients with obesity (BMI greater than or equal to 30 kg/m 2 ) or with overweight (BMI 27-29.9 kg/m 2 ) and at least one weight-related comorbid condition such as treated or untreated dyslipidemia or hypertension; patients with type 2 diabetes mellitus were excluded. All patients were first treated with a low-calorie diet (total energy intake 1,200-1,400 kcal/day) in a run-in period lasting up to 12 weeks. Patients who lost at least 5% of their screening body weight after 4 to 12 weeks during the run-in were then randomized, with equal allocation, to receive either SAXENDA or placebo for 56 weeks.

The mean age was 46 years (range 18 to 73), 81% were female, 84% were White, 13% were Black or African American, and 7% were Hispanic/Latino Ethnicity. Mean baseline body weight was 99.6 kg and mean BMI was 35.6 kg/m 2 . The proportions of patients who discontinued study drug in the 56-week trials were 27% for the SAXENDA-treated group and 35% for the placebo-treated group, and in the 160-week trial the proportions of patients who discontinued were 47% and 55%, respectively.

In the 56-week trials, approximately 10% of patients treated with SAXENDA and 4% of patients treated with placebo discontinued treatment due to an adverse reaction [see Adverse Reactions ( 6.1 )] . The majority of patients who discontinued SAXENDA due to adverse reactions did so during the first few months of treatment. In the 160-week trial the proportions of patients who discontinued due to an adverse reaction was 13% and 6% for SAXENDA- and placebo-treated patients, respectively.

Effect of SAXENDA on Body Weight in 56-week Trials For Study 1 and Study 2, the primary efficacy parameters were mean percent change in body weight and the percenta… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week carcinogenicity study was conducted in male and female CD-1 mice at doses of 0.03, 0.2, 1, and 3 mg/kg/day liraglutide administered by bolus subcutaneous injection yielding systemic exposures 0.2-, 2-, 10- and 43-times the exposure in obese humans, respectively, at the maximum recommended human dose (MRHD) of 3 mg/day based on plasma AUC comparison. A dose-related increase in benign thyroid C-cell adenomas was seen in the 1 and the 3 mg/kg/day groups with incidences of 13% and 19% in males and 6% and 20% in females, respectively.

C-cell adenomas did not occur in control groups or 0.03 and 0.2 mg/kg/day groups. Treatment-related malignant C-cell carcinomas occurred in 3% of females in the 3 mg/kg/day group. Thyroid C-cell tumors are rare findings during carcinogenicity testing in mice.

A treatment-related increase in fibrosarcomas was seen on the dorsal skin and subcutis, the body surface used for drug injection, in males in the 3 mg/kg/day group. These fibrosarcomas were attributed to the high local concentration of drug near the injection site. The liraglutide concentration in the clinical formulation (6 mg/mL) is 10-times higher than the concentration in the formulation used to administer 3 mg/kg/day liraglutide to mice in the carcinogenicity study (0.6 mg/mL).

A 104-week carcinogenicity study was conducted in male and female Sprague Dawley rats at doses of 0.075, 0.25 and 0.75 mg/kg/day liraglutide administered by bolus subcutaneous injection with exposures 0.5-, 2- and 7-times the exposure in obese humans, respectively, resulting from the MRHD based on plasma AUC comparison. A treatment-related increase in benign thyroid C-cell adenomas was seen in males in 0.25 and 0.75 mg/kg/day liraglutide groups with incidences of 12%, 16%, 42%, and 46% and in all female liraglutide-treated groups with incidences of 10%, 27%, 33%, and 56% in 0 (control), 0.075, 0.25, and 0.75 mg/kg/day groups, respectively.

A treatment-related increase in malignant thyroid C-cell carcinomas was observed in all male liraglutide-treated groups with incidences of 2%, 8%, 6%, and 14% and in females at 0.25 and 0.75 mg/kg/day with incidences of 0%, 0%, 4%, and 6% in 0 (control), 0.075, 0.25, and 0.75 mg/kg/day groups, respectively. Thyroid C-cell carcinomas are rare findings during carcinogenicity testing in rats. Studies in mice demonstrated that liraglutide-induced C-cell proliferation was dependent on the GLP-1 receptor and that liraglutide did not cause activation of the REarranged during Transfection (RET) proto-oncogene in thyroid C-cells.

Human relevance of thyroid C-cell tumors in mice and rats is unknown and has not been determined by clinical studies or nonclinical studies [see Boxed Warning, Warnings and Precautions ( 5.1 )] . Liraglutide was negative with and without metabolic activation in the Ames test for mutagenicity and in a human peripheral blood lymphocyte chromosome aberration test for clastogenicity. Liraglutide was negative in repeat-dose in vivo micronucleus tests in rats.

In rat fertility studies using subcutaneous doses of 0.1, 0.25 and 1 mg/kg/day liraglutide, males were treated for 4 weeks prior to and throughout mating and females were treated 2 weeks prior to and throughout mating until gestation day 17. No direct adverse effects on male fertility was observed at doses up to 1 mg/kg/day, a high dose yielding an estimated systemic exposure 11-times the exposure in obese humans at the MRHD, based on plasma AUC comparison. In female rats, an increase in early embryonic deaths occurred at 1 mg/kg/day.

Reduced body weight gain and food consumption were observed in females at the 1 mg/kg/day dose.