CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`206321Orig1s000
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`
`
`
`
`

`

`OFFICE OF CLINICAL PHARMACOLOGY REVIEW
`
`NDA: 206321
`
`Brand Name
`
`Generic Name
`
`OCP Division
`
`OND Division
`
`Sponsor
`
`Submission Date: 12/20/2013
`
`Saxenda
`
`Liraglutide
`
`Clinical Pharmacology-2
`
`Metabolism and Endocrinology Products
`
`Novo Nordisk
`
`Submission Type, Code
`
`NDA 505 (b) (1); Standard
`
`Formulation; Strength(s)
`
`Injection
`
`Proposed Indication
`
`Clinical Pharmacology and
`Pharmacometrics Reviewer
`
`For weight management in adult patients with an
`initial body mass index (BMI) of 30 kg/m2 or
`greater or 27 kg/m2 or greater in the presence of
`at least one weight related comorbidity
`
`Jayabharathi Vaidyanathan, Ph.D
`
`Clinical Pharmacology TL
`
`Immo Zadezensky, Ph.D
`
`Pharmacometrics TL
`
`Nitin Mehrotra, Ph.D
`
`TABLE OF CONTENTS
`
`1
`
`2
`
`Executive Summary.....................................................................................................3
`1.1
`Recommendations............................................................................................... 3
`1.2
`Phase IV Commitments ...................................................................................... 3
`1.3
`Summary of Clinical Pharmacology and Biopharmaceutics Findings ............... 4
`Question-Based Review.............................................................................................10
`2.1
`General Attributes of the drug .......................................................................... 10
`2.2
`General Clinical Pharmacology........................................................................ 11
`2.3
`Intrinsic Factors ................................................................................................ 33
`2.4
`Extrinsic Factors ............................................................................................... 36
`2.6
`Analytical Section............................................................................................. 38
`Detailed Labeling Recommendations........................................................................39
`3
`4 Appendices................................................................................................................ 41
`4.2
`Results of Sponsor’s Population PK analysis ................................................... 41
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`Reference ID: 3630781
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`LIST OF FIGURES
`
`Figure 1: Body weight distribution in the T2DM and obesity programs………………….6
`Figure 2: Correlation of liraglutide exposure to body weight in Obesity trials. Data for
`subjects receiving 3.0 mg dose is shown………………………………………………….7
`Figure 3: Distribution of liraglutide exposure obtained from population PK analysis
`following administration of 1.8 mg dose in T2DM program (Pink) and 3.0 mg dose in
`obesity program (Blue)……………………………………………………………………7
`Figure 4: Cmax values obtained from various trials. Data are individual Cmax values with
`medians and 2.5-97.5% percentiles………………………….............................................8
`Figure 5: Mean liraglutide plasma concentrations following 1.8 mg and 3.0 mg dose in
`obese subjects…………………………………………………………………………….15
`Figure 6: Mean visual analog scale (VAS) ratings for overall appetite score…………...16
`Figure 7: Body weight change from baseline (%) by liraglutide dose: Trial 1807………18
`Figure 8: Body weight (%) change from baseline observed mean including LOCF at end
`of trial 1922- full analysis set…………………………………………………………….19
`Figure 9: Body weight (%) mean change from baseline − individual trials and pooled..20
`Figure 10: Body weight change from baseline versus exposure of liraglutide expressed as
`model-derived AUC at steady-state in trials 1807, 1839 and 1922……………………...21
`Figure 11: Observed and predicted proportions of subjects reaching at least 5 % weight
`loss versus liraglutide exposure in trials 1807, 1839 and 1922………………………….22
`Figure 12: Change from baseline in HbA1c (%) by treatment…………………………..22
`Figure 13: HbA1c change from baseline versus exposure of liraglutide expressed as
`model derived AUC at steady-state in obese subjects with type 2 diabetes (trial 1922)
`(Left panel) and stratified by baseline HbA1c (Right panel)…………………………….23
`Figure 14: Observed proportion of subjects with nausea at any time at any grade versus
`liraglutide exposure in trials 1839, 1922, and 1807…………………………………...…26
`Figure 15: Observed proportion of subjects with moderate to severe nausea at any time
`versus liraglutide exposure in trials 1839, 1922, and 1807………………………………26
`Figure 16: Observed proportion of subjects with vomiting at any time at any grade versus
`liraglutide exposure in trials 1839, 1922, and 1807……………………………………...27
`Figure 17: Observed proportion of subjects with moderate to severe vomiting at any time
`versus liraglutide exposure in trials 1839, 1922, and 1807………………………………27
`Figure 18: Observed proportion of subjects with a documented symptomatic
`hypoglycaemia event (ADA classification) at any time versus liraglutide exposure in trial
`1922……………………………………………………………………………………....28
`Figure 19: Calcitonin change from baseline versus exposure of liraglutide expressed as
`model derived AUC at steady-state in trials 1807, 1839 and 1922……………………...29
`Figure 20: Percent of patients with adverse events over the treatment duration (0-3, 3-6,
`6-9 and 9-12 months): Total adverse events (Top left); GI disorders (Top right); Nausea
`(Bottom left); and Vomiting (Bottom right) …………………………………………….33
`Figure 21: Correlation of liraglutide clearance (L/h) to body weight in Obesity trials….34
`Figure 22: Estimated liraglutide exposure following administration of 3.0 mg dose versus
`body weight stratified by glycemic status………………………………………………35
`Figure 23: Covariate analysis expressed as steady-state dose-normalized exposure
`(AUC0-24h/dose) relative to reference from the Population PK………………………...36
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`Reference ID: 3630781
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`Figure 24: Mean postprandial paracetamol concentration time profiles following
`liraglutide (1.8 mg and 3.0 mg) and placebo…………………………………………….37
`
`LIST OF TABLES
`
`Table 1: Key efficacy endpoints related to body weight by trial………………………...13
`Table 2: Liraglutide PK parameters following 1.8 mg and 3.0 mg dose in obese
`subjects…………………………………………………………………………………...15
`Table 3: Fasting body weight (%) change from baseline until end of trial: Treatment
`effects stratified by gender and baseline body weight (pooled data set 1807, 1922 and
`1839)……………………………………………………………………………………..24
`Table 4: Proportion of patients losing at least 5% baseline body weight stratified by
`gender and baseline body weight (pooled data set 1807, 1922 and 1839)………………24
`Table 5: Exposure data for subjects with severe hypoglycemia…………………………28
`Table 6: Proportion of patients (%) experiencing adverse events following administration
`of liraglutide 3.0 mg stratified by body weight quartiles and gender (pooled data set 1807,
`1922 and 1839)…………………………………………………………………………..30
`Table 7: Proportion of patients (%) experiencing adverse events following administration
`of placebo stratified by body weight quartiles and gender (pooled data set 1807, 1922 and
`1839)……………………………………………………………………………………..30
`Table 8: Percent of patients experiencing adverse events by weight loss groups for
`treatment groups- liraglutide 3.0 mg (Lira) and placebo (PL)…………………………...32
`Table 9: ELISA assay validation parameters……………………………………………38
`Table 10: ELISA assay validation parameters for second curve………………………...39
`
`1 Executive Summary
`
`1.1 Recommendation
`
`The Office of Clinical Pharmacology (DCP-2 and DPM) has reviewed the clinical
`pharmacology data submitted on 12/2013 under NDA 206321 and recommend approval
`from a clinical pharmacology perspective. An optional Inter-Division Level OCP
`briefing was held on September 17, 2014 to discuss this submission. Labeling comments
`are on pages 38-39.
`
`1.2 Phase IV Commitments
`
`None.
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`Reference ID: 3630781
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`1.3
`
`Summary of Important Clinical Pharmacology Findings
`
`Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor analog with 97% amino acid
`sequence homology to human endogenous GLP-1. Liraglutide is approved to treat type 2
`diabetes (T2DM) at doses up to 1.8 mg once a day (NDA 22-341). This current NDA
`application is proposing the use of liraglutide for weight management at doses of 3.0 mg
`once daily.
`
`Refer to details of general clinical pharmacology information of liraglutide in clinical
`pharmacology review under NDA 22-341. This review will focus on the relevant clinical
`pharmacology information for the proposed indication.
`
`According to the current proposed label, the proposed indication for liraglutide 3 mg is as
`an adjunct to a reduced-calorie diet and increased physical activity for chronic weight
`management in adult patients with an initial Body Mass Index (BMI) of
`30 kg/m2 or greater (obese), or
`
`27 kg/m2 or greater (overweight) in the presence of at least one weight related
`
`comorbidity such as dysglycemia (pre-diabetes and type 2 diabetes mellitus),
`hypertension, dyslipidemia, or obstructive sleep apnea.
`
`Similar to what is approved for T2DM population, to improve gastro-intestinal
`tolerability, for all patients, the starting dose is proposed to be 0.6 mg. The starting dose
`is then proposed to be increased to 3 mg with increments of 0.6 mg with at least one
`week intervals (i.e. 0.6, 1.2, 1.8, 2.4 and 3.0 mg). Treatment should be evaluated after a
`minimum of 12 weeks on the 3.0 mg dose to assess the treatment effect.
`
`The clinical development program of liraglutide draws support from a clinical
`pharmacology study that evaluated the PK/PD of liraglutide in obese subjects, 1 Phase 2
`dose ranging trial (1807) and two Phase 3 efficacy and safety trials (1839 and 1922).
`
`Liraglutide pharmacokinetics (PK) and pharmacodynamics (PD) has been characterized
`following subcutaneous administration of 1.8 mg under the T2DM program and
`following 3.0 mg dose in obese subjects. Clinical pharmacology review of the
`information submitted under NDA 206321 revealed the following key findings:
`
`Liraglutide PK:
`
`The proposed drug product formulation of liraglutide (3.0 mg) used in the obesity
`development program is similar to the currently marketed formulation (1.8 mg). A
`population PK analysis was submitted under NDA 22-341 (Victoza) and for the current
`NDA for obesity (NDA 206321). The sponsor is referring to the data provided under the
`T2DM program to bridge clinical pharmacology and safety information (e.g., QT, and
`DDI).
`
`Baseline body weight was the most significant covariate affecting the clearance (CL/F) of
`liraglutide as determined by the population PK analysis conducted for both programs.
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`The data indicates an increase in liraglutide clearance with increasing body weight.
`Hence, subjects with lower body weight are expected to have a higher liraglutide
`exposure (AUC) as compared to those with higher body weight. The PK parameter
`estimates (e.g., clearance, volume of distribution) obtained from the population PK
`analysis using data from the obesity program was consistent with those observed with the
`population PK analysis conducted in T2DM patients.
`
`In the population PK analyses conducted using data from the obesity program, the effect
`of various covariates on the clearance (CL/F) of liraglutide was analyzed using data from
`the Phase 3 trials 1839 and 1922. The covariates analyzed in addition to baseline body
`weight were: age, gender, race, ethnicity, dose and glycemic status at baseline
`(normoglycemia, pre-diabetes, T2DM). Among these, gender was the other significant
`covariate with males having 24% lower liraglutide exposure than females (after
`accounting for body weight differences). About 72% of subjects included in the
`population PK analyses of obesity trials were females. When exposure following
`administration of 3.0 mg liraglutide was compared in obese subjects in Trial 1922 with
`different baseline glycemic status, there appears to be about 16% lower exposure in
`diabetic obese subjects as compared to obese subjects with normal glycemic or
`prediabetic status. None of the other covariates examined were found to have a
`significant effect on liraglutide PK. No dose adjustments are recommended based on
`gender or diabetic status.
`
`Comparison of exposure (AUC and Cmax) of liraglutide: 1.8 mg dose [T2DM (NDA
`22-341)] versus 3.0 mg dose [obesity (NDA206321)]:
`
`It should be noted that the doses are different in the two programs, with the dose in the
`obesity program being higher (3.0 mg) as compared to the T2DM program (1.8 mg).
`
`AUC comparison: In order to relate the observed exposure of liraglutide in the obesity to
`that of T2DM population, it is important to understand the body weight distribution in the
`two programs as body weight was the important covariate affecting the clearance of
`liraglutide. The body weight range of the subjects in population PK analysis conducted
`for the T2DM and obesity program was 44 – 163 kg and 60 kg – 234 kg, respectively.
`Figure 1 shows the body weight distribution in the two programs. As shown, although
`there was substantial overlap in the subject’s body weight in the two development
`programs, as expected, the proportion of subjects with higher body weight was greater in
`the obesity program as compared to that in T2DM program.
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`Figure 1: Body weight distribution in the T2DM and obesity programs
`
`Figure 2 shows the correlation of body weight to the AUC for patients receiving 3.0 mg
`dose in the obesity trials and Figure 3 shows the distribution of AUC in the T2DM and
`obesity programs. There is considerable variability in the observed exposure of
`liraglutide (Figures 2 and 3). Although overlap in AUCs was observed in the two
`programs, the proportion of subjects in the obesity program having higher AUC at 3.0 mg
`dose appeared to be greater compared to T2DM patients receiving 1.8 mg dose (Figure
`3). About 16% of subjects in the obesity trials receiving the 3.0 mg dose had higher
`exposure than the maximum exposure observed in the T2DM trial (>~4 mg.h/L) with 1.8
`mg dose (Figures 2 and 3). This observation is consistent with the Figure 1, which shows
`a significant overlap of body weights between the two populations. Thus, subjects with
`similar body weight will likely have a higher exposure if the dose is increased from 1.8 to
`3.0 mg.
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`Figure 2: Correlation of liraglutide exposure to body weight in Obesity trials. Data
`for subjects receiving 3.0 mg dose is shown.
`The horizontal line shows the maximum exposure level observed in the T2DM population receiving 1.8 mg
`dose.
`
`Figure 3: Distribution of liraglutide exposure obtained from population PK analysis
`following administration of 1.8 mg dose in T2DM program (Pink) and 3.0 mg dose
`in obesity program (Blue)
`Note: The output from the T2DM and obesity population PK analyses was used for this purpose. All the
`patients in the T2DM population PK analysis were used. For patients on 1.8 mg dose, AUC was calculated
`using the formula, AUC= (1.8/CL). There were 235 patients at 1.2 mg in the T2DM population. For these
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`patients, the clearance (L/h) obtained from the population PK analysis was used to calculate the AUC
`following 1.8 mg dose (AUC=Dose/CL). In case of obesity trials, the AUC was calculated using individual
`clearance values for the patients receiving the 3.0 mg dose.
`
`comparison: The sponsor compared
`Cmax
`liraglutide maximum
`the observed
`concentrations (Cmax) from various trials – cardiac electrophysiology (TQTc) trial
`(NN211-1644, conducted under T2DM NDA program), Cmax sub study in 1839, 1807 and
`trial 3630 (Figure 4). There appears to be substantial overlap in the observed individual
`liraglutide concentrations in these studies conducted following administration of either
`1.8 mg or 3.0 mg dose.
`
`Figure 4: Cmax values obtained from various trials. Data are individual Cmax values
`with medians and 2.5-97.5% percentiles
`Source: Sponsor report: Summary of Clinical pharmacology, page 45
`
`Exposure/Dose-response relationship for effectiveness:
`
`The dose-response is evident for the proposed 3 mg once daily liraglutide treatment based
`on efficacy data from the Phase 2 and 3 trials. Trial 1807 evaluated liraglutide 1.2 mg, 1.8
`mg, 2.4 mg, and 3.0 mg doses as compared to placebo and orlistat (active comparator), in
`obese subjects while trial 1922 evaluated 1.8 mg and 3.0 mg liraglutide doses as
`compared to placebo in T2DM subjects. Trials 1839 (subjects with or without pre-
`diabetes), 1923 (subjects with dyslipidemia and/or hypertension) and 3970 (subjects with
`obstructive sleep apnea) studied the effect of liraglutide 3.0 mg versus placebo. The 3.0
`mg dose was selected based on the results of the dose-ranging trial (1807) where it
`showed superior weight loss as compared to the other lower liraglutide dose groups as
`well as orlistat. In Phase 3 trials, treatment with liraglutide 3.0 mg led to a mean weight
`loss (change from baseline in body weight) of 5.7−9.2% (6.0-8.8 kg) depending on the
`trial, while placebo treated subjects achieved a weight loss of 0.2−3.1% (0.2-3.0 kg). In
`the pooled analyses of all trials, the change from baseline in body weight was 7.5% (7.8
`kg) with liraglutide 3.0 mg as compared to 2.3% (2.5 kg) with placebo (Sponsor:
`Integrated summary of efficacy).
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`The exposure-response relationship provides supportive evidence for the effectiveness of
`the liraglutide 3.0 mg dose. Consistent with the observed dose-response relationship,
`there was a clear relationship between liraglutide exposure (data from 1807, 1839 and
`1922) and weight loss with increasing exposure leading to greater weight loss. There was
`considerable overlap between exposures achieved at 1.8 mg and 3.0 mg dose groups
`however there was incremental benefit with the 3.0 mg dose. The weight loss appeared to
`reach plateau at the highest exposure. Exposure-response relationship was similar among
`the three trials, 1807, 1839 and 1922. Further, categorical analysis shows that the
`proportion of subjects reaching at least 5% weight loss increased with increasing
`liraglutide exposure. The proportion of subjects achieving a weight loss of 5% or greater
`ranged from 46−78% across trials in the liraglutide 3.0 mg group as compared to 14−30%
`in the placebo group across trials.
`
`Efficacy and safety analysis by baseline body weight:
`
`As body weight is the significant predictor of liraglutide clearance, some obese subjects
`with lower body weight have an increased exposure with liraglutide 3.0 mg. The Agency
`therefore, requested the sponsor to conduct an exposure-response analyses for adverse
`events such as nausea (all grade and moderate-severe), vomiting (all grade and moderate-
`severe) and hypoglycemia. The Agency also requested sponsor to conduct efficacy and
`safety analysis based on baseline body weight. In addition, since patients lose body
`weight over time while on treatment with liraglutide, and clearance is related to body
`weight, there is a possibility that the drug exposure can increase over time based on the
`magnitude of weight loss. This increase in drug exposure with weight loss can potentially
`lead to higher adverse events in patients experiencing higher weight loss. Therefore,
`Agency recommended the sponsor to conduct an analysis of adverse events based on
`magnitude of weight loss and also evaluate if there is any time dependency of occurrence.
`
`Sponsor’s analysis of exposure-response analysis for safety data from the obesity trials
`did not reveal any significant relationship with observed adverse events such as nausea,
`vomiting, and hypoglycemia. The adverse events profile was also not different for
`different baseline body weight quartiles. There also appeared to be no trend in the
`efficacy when analyzed by baseline body weight. Evaluations of adverse event based on
`the weight loss categories also did not reveal any differences between the different
`groups. Further, adverse events over time in patients treated with liraglutide did not show
`an increase with treatment duration. Most of the events occurred within 0-3 months and
`did not increase in frequency over the duration of the trial.
`
`Effect of liraglutide 3.0 mg on gastric emptying: The absorption of paracetamol (used
`as marked to assess gastric emptying) was similar following administration of liraglutide
`1.8 mg and 3.0 mg dose. Therefore, sponsor’s proposal to bridge drug interaction
`information from T2DM program is acceptable.
`
`Bioanalytical Methodology:
`liraglutide
`trials,
`the clinical pharmacology
`In
`concentration in plasma was determined using a liraglutide specific enzyme-linked
`immunosorbent assay (ELISA) that measured both protein-bound and unbound
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`liraglutide. The assay method is acceptable and was adequately validated for recovery,
`accuracy, precision, sensitivity and specificity.
`
`Overall:
`
`0 The proposed dose of 3.0 mg is acceptable from a clinical pharmacology
`perspective.
`
`0 There is no dosage adjustment needed based on any covariate (body weight, age,
`gender, race and glycemic status).
`0 The sponsor’s proposal
`to bridge clinical pharmacology information [e.g.,
`ADME, specific population PK (renal, hepatic impairment), TQT, and DDI] from
`T2DM program (Vicotza) is acceptable.
`
`0 There is no need to change the dosing regimen if the patient experiences
`significant weight loss during treatment with liraglutide.
`
`2 Question—Based Review (QBR)
`
`2.1 General Attributes of the Drug and Drug Product
`
`Liraglutide is a solution for subcutaneous injection. Liraglutide is proposed as an adjrmct
`to diet and exercise for chronic weight management in adults. It is proposed to be
`administered as once daily 3 mg subcutaneous (SC) injection. The injection can be
`administered at any time of day independent of meals.
`
`2.1.1 What pertinent background or histon; contributes to the current assessment at
`the clinical gharmacolog}; and bioeharmaceutics at this drug?
`
`Liraglutide is approved as Victoza (up to doses of 1.8 mg) to be used in patients with type
`2 diabetes (1'2DM). As stated in the package insert of Victoza, administration of
`liraglutide leads to insulin dependent insulin secretion, lowering of post-prandial glucose
`and lowering of glucagon secretion. In addition, in the clinical trials conducted in T2DM
`patients, body weight
`reduction was observed (Victoza Package Insert). This
`development program was conducted to systematically evaluate the effect of liraglutide
`in obese subjects.
`
`2.1.2 What are the highlights at the chemist_rz and ghzsicochemical grogerties at the
`dru substance and the armulation 0 the dru
`roduct as th
`relate to
`
`clinical pharmacology' and biogharmaceutics review?
`
`The same formulation of liraglutide drug product was used in all the Phase 2 and 3
`clinical trials. It is the same formulation as the approved formulation for the treatment of
`T2DM (under the trade name Victoza) and contains liraglutide (6.0 mg/mL), phosphate 3i
`propylene glycol
`(m4) and phenol
`(m4)
`Liraglutide 6.0 mg/ml is a clear, colorless or ahnost colorless solution dispensed in a 3
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`mL cartridge. Refer to reviews conducted under NDA 22-341 for details of the chemistry
`and formulation of the drug product.
`
`2.1.3 What is the mechanism of action and therapeutic indication?
`
`Liraglutide is a glucagon like peptide-1 (GLP-1) receptor analog. GLP-1 is a peptide
`hormone with several mechanisms of action including: lowering blood glucose, glucose-
`dependent increase in insulin secretion, glucose-dependent glucagonostatic effect and
`decreasing gastric emptying rate. GLP-1 is also proposed to be a physiological regulator
`of satiety, energy intake and body weight. This receptor is present in specific brain
`regions relevant for energy homeostasis.
`
`The proposed indication for liraglutide 3 mg is “as an adjunct to a reduced-calorie diet
`and increased physical activity for chronic weight management in adult patients with an
`initial Body Mass Index (BMI) of 30 kg/m2 or greater (obese), or 27 kg/m2 or greater
`(overweight) in the presence of at least one weight related comorbidity such as
`dysglycemia (pre-diabetes and type 2 diabetes mellitus), hypertension, dyslipidemia, or
`obstructive sleep apnea.”
`
`2.2 General Clinical Pharmacology
`
`2.2.1 What are the design features of the clinical pharmacology and clinical studies
`used to support dosing or claims?
`
`The clinical pharmacology information for liraglutide for the proposed indication was
`obtained from the following trials:
` Trial NN8022-3630 (clinical pharmacology trial)
` Trial NN8022-1807 (Phase 2 trial) for exposure-response analyses
` Trial NN8802-1839 (Phase 3 trial) for population pharmacokinetic analyses and
`exposure-response analyses
` Trial NN8802-1922 (Phase 3 trial) for population pharmacokinetic analyses and
`exposure-response analyses.
`
`Trial 3630: This was a randomized, placebo-controlled, double-blind, incomplete
`crossover trial designed to evaluate the effects of liraglutide on gastric emptying,
`appetite, energy intake and energy expenditure, and to evaluate the pharmacokinetic
`properties of liraglutide in obese, but otherwise healthy subjects. Liraglutide doses of 1.8
`mg and 3.0 mg was studied in this trial. Since it was an incomplete crossover design, no
`subject received all three treatments (placebo, 1.8 mg and 3.0 mg).
`
`Trial 1807: This was a 20-week (with 84-week extension and interim analysis at 52
`weeks), randomized, double-blind, placebo controlled, six armed parallel group, multi-
`center, multinational trial with an open label orlistat comparator group investigating the
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`effect of liraglutide 1.2, 1.8, 2.4 and 3.0 mg and placebo on body weight in obese subjects
`without diabetes. Samples for PK analysis were obtained at 20 weeks.
`
`Trial 1839: This was a 56 weeks randomized, double-blind, placebo-controlled, parallel
`group, multi-center, multinational trial investigating the efficacy of 3.0 mg liraglutide
`versus placebo in inducing and maintaining weight loss in non-diabetic obese subjects
`and overweight subjects with comorbidities (dyslipidemia and/or hypertension). Blood
`samples for plasma liraglutide concentration measurements were drawn at 2, 12 and 28
`weeks after first dosing for the population pharmacokinetic and exposure-response
`analyses.
`
`Trail 1922: This was also a 56-week randomized, double-blind, placebo-controlled, three
`arm parallel group, trial with a 12-week follow up period investigating the effect of
`liraglutide on body weight in overweight or obese subjects with type 2 diabetes. Blood
`samples for plasma liraglutide concentration measurements were drawn at 2, 12 and 28
`weeks after first dosing for the population pharmacokinetic and exposure-response
`analyses.
`
`2.2.2 What is the basis for selecting the response endpoints and how are they
`measured in clinical pharmacology studies?
`
`The Guidance for Industry “Developing products for weight management” has the
`following as efficacy endpoints:
`
`a. Primary efficacy endpoint
`
`The efficacy of a weight-management product should be assessed by analyses of both
`mean and categorical changes in body weight.
` Mean: The difference in mean percent loss of baseline body weight in the active-
`product versus placebo-treated group.
` Categorical: The proportion of subjects who lose at least 5 percent of baseline
`body weight in the active-product versus placebo-treated group.
`
`b. Secondary efficacy endpoints
`Secondary efficacy endpoints should include, but are not limited to, changes in the
`following metabolic parameters:
` Blood pressure and pulse
` Lipoprotein lipids
` Fasting glucose and insulin
` HbA1c (in type 2 diabetics)
` Waist circumference
`
`The efficacy benchmark as recommended in the guidance is as follows:
`In general, a product can be considered effective for weight management if after 1 year of
`treatment either of the following occurs:
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` The difference in mean weight loss between the active-product and placebo-
`treated groups is at least 5 percent and the difference is statistically significant
` The proportion of subjects who lose greater than or equal to 5 percent of baseline
`body weight in the active-product group is at least 35 percent, is approximately
`double the proportion in the placebo-treated group, and the difference between
`groups is statistically significant
`
`The primary endpoints of liraglutide clinical trials were related to body weight, and
`included both mean and categorical changes in body weight. The key efficacy endpoints
`in all the clinical trials conducted is summarized in Table 1 below:
`
`Table 1: Key efficacy endpoints related to body weight by trial
`
`Source: Sponsor summary of clinical efficacy; Table1-2, page 23
`
`Body weight was measured with an empty bladder, without shoes and only wearing light
`clothing. The primary analyses were based exclusively on fasting measurements.
`
`The sponsor also included the secondary endpoints as indicated in the guidance.
`Glycemic control parameters (including change from baseline in HbA1c, fasting plasma
`glucose, homeostasis model assessment (HOMA-B, HOMA-IR), parameters in OGTT),
`cardio-metabolic parameters (vital signs, fasting lipids, CV biomarkers), patient reported
`outcomes and concomitant medications (change from baseline) were also included as
`secondary endpoints. Refer to clinical review for the discussion of the secondary
`endpoints.
`
`2.2.3 What are the ADME characteristics of liraglutide after SC administration?
`
`The following is based on previous review of liraglutide in T2DM program (Victoza
`package insert) and is applicable to the current application.
`
`Absorption: Following subcutaneous administration, maximum concentrations of
`liraglutide are achieved at 8-12 hours post dosing. After subcutaneous single dose
`
`Reference ID: 3630781
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`13
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`administrations, Cmax and AUC of liraglutide increased proportionally over the
`therapeutic dose range of 0.6 mg to 1.8 mg.
`
`Distribution: The mean apparent volume of distribution after subcutaneous
`administration of Victoza 0.6 mg is approximately 13 L. The mean volume of distribution
`after intravenous administration of Victoza is 0.07 L/kg. Liraglutide is extensively bound
`to plasma protein (>98%).
`
`Metabolism and Excretion: 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. 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 6-8 days. The mean apparent clearance following subcutaneous
`administration of a single dose of liraglutide is approximately 1.2 L/h with an elimination
`half-life of approximately 13 hours.
`
`2.2.4 What are the pharmacokinetic and pharmacodynamic characteristics of
`liraglutide in obese subjects?
`
`Trial NN8022-3630 was conducted to assess the effect of liraglutide on gastric emptying,
`energy expenditure, appetite and evaluate the pharmacokinetics in non-diabetic obese
`subjects (BMI ≥30 kg/m2 and <40 kg/m2). Subjects were dose escalated to the
`maintenance dose in weekly increments of 0.6 mg (a starting dose of 0.6 mg which was
`then increased once to 1.2 mg, and then1.8 mg or further increased to 2.4 mg and finally
`to 3.0 mg). Subjects were on the final dose for at least 7 days (for 3.0 mg) before the
`PK/PD assessments at Visits 4 and 9 (21 days in the 1.8 mg dose).
`
`PK: Liraglutide steady-state was reached with both 1.8 mg and 3.0 mg dose during the
`PK assessment time point (7-21 days). This is consistent with previous finding that steady
`state is attained after 3-5 days treatment. There appears to be a dose-dependent increase
`in the liraglutide trough values (12930-15275 pmol/L and 21220-22680 pmol/L for
`liraglutide 1.8 mg and 3.0 mg, respectively). The PK profile of the two liraglutide doses
`is shown in Figure 5. Liraglutide 3.0 mg resulted in a higher mean plasma concentration
`than liraglutide 1.8 mg. The Tmax, terminal half-life, apparent plasma clearance, apparent
`volume of distribution were similar between the two dose gr