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

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY NDA/BLA REVIEW AND EVALUATION
`
`Application number:
`Supporting document/s:
`
`Applicant’s letter date:
`CDER stamp date:
`Product:
`
`Indication:
`
`206321
`1 / 12.20.13 / new NDA
`29 / 07.15.14 / Response to Information Request
`20 December 2013
`20 December 2013
`Saxenda™ (liraglutide injection for weight
`management)
`An adjunct to a reduced calorie diet and increased
`physical activity for chronic weight management in
`overweight adults with at least 1 weight-related co-
`morbidity or obese adults
`
`Applicant:
`Review Division:
`Reviewer:
`Supervisor/Team Leader:
`Division Director:
`Project Manager:
`
`Novo Nordisk Inc., Plainsboro, NJ 08536
`Endocrinology and Metabolism Products
`Anthony Parola, PhD
`Karen Davis-Bruno, PhD
`Jean-Marc Guettier, MD
`Patricia Madara
`
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and necessary for
`approval of 206321 are owned by Novo Nordisk or are data for which Novo Nordisk has
`obtained a written right of reference.
`Any information or data necessary for approval of 206321 that Novo Nordisk does not own or
`have a written right to reference constitutes one of the following: (1) published literature, or (2) a
`prior FDA finding of safety or effectiveness for a listed drug, as reflected in the drug’s approved
`labeling. Any data or information described or referenced below from reviews or publicly
`available summaries of a previously approved application is for descriptive purposes only and is
`not relied upon for approval of 206321.
`
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`TABLE OF CONTENTS
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`EXECUTIVE SUMMARY.................................................................................................... 4
`1.1
`INTRODUCTION............................................................................................................. 4
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS .............................................................. 4
`1.3
`RECOMMENDATIONS..................................................................................................... 6
`DRUG INFORMATION......................................................................................................10
`2.1
`DRUG .........................................................................................................................10
`2.2
`RELEVANT INDS, NDAS, BLAS AND DMFS...................................................................11
`2.3
`DRUG FORMULATION...................................................................................................11
`2.4
`COMMENTS ON NOVEL EXCIPIENTS ..............................................................................13
`2.5
`COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ................................................13
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN.............................................17
`2.7
`REGULATORY BACKGROUND........................................................................................17
`STUDIES SUBMITTED.....................................................................................................20
`3.1
`STUDIES REVIEWED ....................................................................................................20
`3.2
`STUDIES NOT REVIEWED .............................................................................................22
`3.3
`PREVIOUS REVIEWS REFERENCED ...............................................................................22
`PHARMACOLOGY...........................................................................................................23
`4.1
`PRIMARY PHARMACOLOGY...........................................................................................28
`4.2
`SECONDARY PHARMACOLOGY .....................................................................................75
`4.3
`SAFETY PHARMACOLOGY ............................................................................................75
`PHARMACOKINETICS/ADME/TOXICOKINETICS ..........................................................75
`5.1
`PK/ADME ..................................................................................................................79
`5.2
`TOXICOKINETICS .........................................................................................................81
`GENERAL TOXICOLOGY................................................................................................83
`
`GENETIC TOXICOLOGY..................................................................................................88
`7.3
`IN VIVO CLASTOGENICITY ASSAY IN RODENT (MICRONUCLEUS ASSAY)...........................88
`CARCINOGENICITY.......................................................................................................102
`
`REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY ..........................................105
`
`SPECIAL TOXICOLOGY STUDIES............................................................................119
`10
`LOCAL TOXICITY........................................................................................................127
`10.1
`10.2 MECHANISTIC TOXICITY STUDIES, THYROID SAFETY....................................................133
`10.3 PANCREAS SAFETY ...................................................................................................141
`11
`INTEGRATED SUMMARY AND SAFETY EVALUATION ..........................................146
`
`APPENDIX/ATTACHMENTS ......................................................................................157
`12
`APPENDIX 1: ASSESSMENT OF
` AND
` GENETIC TOXICITY FROM
`NOVO NORDISK ....................................................................................................................157
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`APPENDIX 2: ASSESSMENT OF
` GENETIC TOXICITY FROM
` AND
`THE CHEMICAL INFORMATICS GROUP AT FDA’S CENTER FOR DRUG EVALUATION AND RESEARCH
`............................................................................................................................................159
`APPENDIX 3: CONSULT FROM CDER’S PHARMACOLOGY/TOXICOLOGY COORDINATING COMMITTEE
`GENETIC TOXICOLOGY SUBCOMMITTEE REGARDING THE VALIDITY AND OUTCOME OF IN VIVO
` IN MICE. ..........................161
`MICRONUCLEUS ASSAYS OF
` AND
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`NDA 206321
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`Anthony Parola, PhD
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`1
`
`Executive Summary
`
`1.1
`
`Introduction
`Liraglutide, a lipidated glucagon-like peptide-1 (GLP-1) analog, is a GLP-1 receptor
`(GLP-1R) agonist from Novo Nordisk approved in January 2010 as an adjunct to diet and
`exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM) under New
`Drug Application (NDA) 22341 for Victoza. NDA 206321 from Novo Nordisk seeks marketing
`approval of Saxenda, 3.0 mg/day liraglutide as an adjunct to a reduced calorie diet and
`increased physical activity for chronic weight management in overweight adults (initial body
`mass index (BMI) > kg/m2) with at least 1 weight-related comorbidity (hypertension, prediabetes
`or T2DM, dyslipidemia, or obstructive sleep apnea) or obese adults (initial BMI >30 kg/m2).
`Saxenda and Victoza both consist of 3 mL of 6 mg/mL liraglutide solution for subcutaneous
`injection in a laminated rubber disc capped glass cartridge contained in a pen injector, and the
`only difference between the 2 products is the pen injector. The Victoza FlexPen is capable of
`delivering up to 1.8 mg liraglutide (0.3 mL) in a single injection, the maximum recommended
`human dose (MRHD) for the treatment of T2DM, while the Saxenda PDS290 pen injector is
`capable of delivering up to 3 mg/day liraglutide (0.5 mL dose volume) in a single injection, the
`only proposed maintenance dose and the MRHD for weight management.
`
`1.2
`
`Brief Discussion of Nonclinical Findings
`Pivotal nonclinical studies evaluating the safety of liraglutide were previously reviewed
`under Victoza NDA 22341 and cross-referenced by Saxenda NDA 206321. Because systemic
`clearance of subcutaneously injected liraglutide increases with body weight in humans, steady
`state systemic exposure from 3.0 mg/day liraglutide in obese adults (AUC0-24h 854 nM*h) was
`only slightly higher than steady state systemic exposure in healthy adults administered 1.8
`mg/day liraglutide (AUC0-24h 809 nM*h), based on plasma liraglutide AUC comparison.
`Therefore, human exposure multiples based on systemic exposure for findings in nonclinical
`safety studies of liraglutide, including carcinogenicity and reproductive and developmental
`toxicity studies, are similar for 3.0 mg/day liraglutide in obese adults and 1.8 mg/day liraglutide
`in healthy adults.
`Liraglutide (NN2211 or NNC 90-1170) is a lipidated human GLP-1 analog with prolonged
`pharmacologic activity after subcutaneous bolus injection. Biologic effects of liraglutide are
`mediated by the GLP-1R, a G-protein coupled receptor coupled to the stimulatory G-protein, Gs.
`In vitro, liraglutide is a selective GLP-1R agonist pharmacologically active at cloned GLP-1Rs
`from mice, rats, rabbits, pigs, monkeys, and humans. In vivo, liraglutide is active in animal
`models of type 2 diabetes and obesity. While the effects of liraglutide to improve glycemic
`control are mainly due to blood glucose-dependent enhanced insulin secretion, the effects of
`liraglutide to reduce food consumption and body weight gain are centrally mediated. Studies
`evaluating CNS penetration of peripherally administered liraglutide showed liraglutide accesses
`and activates neurons in brain regions regulating food intake in rats.
`Liraglutide was formulated as a solution for subcutaneous injection. Peak and total
`liraglutide exposure generally increased linearly with dose with no appreciable accumulation in
`mice, rats, or monkeys and with some accumulation in humans due to its longer elimination half-
`life (~1.5 fold). Liraglutide was highly plasma protein bound in all species (> 98%). Liraglutide
`did not readily cross the blood brain barrier and only very low levels were found in the CNS, but
`the central nervous system is believed to be the site of action for liraglutide’s effect to reduce
`food consumption and body weight gain. Liraglutide circulates as the intact parent drug without
`forming any major circulating human metabolite. Liraglutide is primarily eliminated by peptidase
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`metabolism (neutral endopeptidase (NEP) and dipeptidyl peptidase IV (DPP-4)) with further
`extensive and rapid catabolism of intermediate metabolites prior to excretion in urine, feces, and
`expired air. Only low levels of liraglutide cross the placenta in rats or rabbits. Intact liraglutide
`was secreted in milk from rats. Levels of liraglutide in rat milk were ~50% of maternal plasma
`levels.
`
`Safety and toxicity of liraglutide were evaluated in safety pharmacology studies, single
`and repeat dose toxicity studies, genetic toxicity studies, 2 year carcinogenicity studies in rats
`and mice, reproductive and developmental toxicity studies, local tolerance studies, and
`mechanistic studies of liraglutide-induced thyroid C-cell tumors in rodents. All pivotal nonclinical
`safety studies were reviewed under Victoza NDA 22341.
`In safety pharmacology studies, liraglutide increased heart rate in isolated rabbit hearts
`and in conscious rats, increased arterial blood pressure and decreased body temperature in
`rats, induced diuresis in rats, weakly inhibited acetylcholine-induced smooth muscle contraction
`of isolated guinea pig ileum, and delayed gastric emptying in minipigs. Liraglutide had no effect
`on the QTc interval in conscious telemetered monkeys.
`Liraglutide was well tolerated in chronic repeat dose toxicity studies. Clinical signs of
`toxicity and reduced food consumption were dose-limiting in rats, while transiently reduced food
`consumption and decreased body weight gain were dose limiting in rabbits and monkeys. A
`dose limiting toxicity was not observed in mice.
`Liraglutide immunogenicity did not affect exposure to pharmacologically active drug in
`mice, rats, or monkeys. Liraglutide was not immunogenic in mice or rats, but anti-liraglutide
`antibodies (anti-drug antibodies, ADAs) occurred in one mid-dose monkey and several high
`dose monkeys in chronic repeat dose studies. Neutralizing effects of ADAs were not
`characterized.
`Liraglutide toxicity occurred in thyroid (mice and rats), at injection sites (mice, pigs, and
`monkeys), and it induced a mild anemia (mice, rats, and monkeys). In thyroid, liraglutide caused
`ultimobranchial cysts and/or C-cell focal hyperplasia, a preneoplastic lesion, in 4 & 13 week
`mouse studies, a low incidence of inflammatory cell infiltrate in mice in the carcinogenicity study,
`and C-cell focal hyperplasia and tumors at clinically relevant exposures in carcinogenicity
`studies in both mice and rats. Injection site reactions were characterized as subacute
`inflammation and fat necrosis in pigs and inflammation, necrosis, and fibrosis with repeat dosing
`in monkeys. Although inflammation didn’t occur at injection sites in mice, fibrosarcomas in the
`dorsal skin and subcutis, the body surface used for injection, occurred in high dose male mice in
`the carcinogenicity study using a liraglutide dosing solution that was 10 times more dilute than
`the clinical formulation. Local toxicity of the marketed product evaluated after subcutaneous
`injection in pigs and intramuscular, intravenous, and intra-arterial injection in rabbits showed
`subcutaneous injection site reactions in pigs attributed to vehicle persisted for 5 days after
`dosing and intramuscular, intravenous, or intra-arterial injection of liraglutide did not result in
`severe local toxicity or clinical signs of severe toxicity in rabbits. Mild anemia occurred at
`clinically relevant exposures in some repeat dose studies in mice, rats, and monkeys. In a 13-
`week repeat dose study, liraglutide did not cause pancreas inflammation in male or female
`Zucker Diabetic Fatty (ZDF) rats, a rodent model of insulin resistant type 2 diabetes mellitus.
`Liraglutide was not mutagenic or clastogenic in vitro with or without metabolic activation
`in a bacterial reverse mutation assay or a chromosomal aberrations assay in human peripheral
`blood lymphocytes and it was not clastogenic in vivo in erythrocyte micronucleus assays in rats.
`Two-year carcinogenicity studies in mice and rats showed liraglutide is a multi-sex, multi-
`species carcinogen causing thyroid C-cell tumors at clinically relevant exposures in male and
`female mice and rats and fibrosarcomas on the dorsal skin and subcutis of male mice. Human
`relevance of drug-induced C-cell tumors in rodents is unknown and a mode of action for
`liraglutide-induced rodent C-cell tumors has not been established. Mechanistic toxicity studies in
`wild-type and GLP-1R knockout mice showed liraglutide-induced thyroid C-cell hyperplasia and
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`increased plasma calcitonin was GLP-1R-dependent, and in normal and hyperplastic thyroid C-
`cells, liraglutide induced phosphorylation of ribosomal protein S6, but not the REarranged during
`Transfection (RET) proto-oncogene. Liraglutide-induced proliferative lesions in thyroid C-cells
`were not fully reversed in mice treated for 9 weeks followed by a 15 week recovery period or in
`mice treated for 26 weeks followed by a 78 week recovery period.
`Liraglutide did not affect fertility of male rats, but in female rats treated with liraglutide
`from 2 weeks prior to mating through organogenesis, liraglutide increased the number of early
`embryonic deaths at maternal plasma exposures 11 times systemic exposure in obese humans,
`based on AUC comparison. In fetal rats, liraglutide caused fetal abnormalities of displaced
`kidneys, displaced azygous vein, and irregular ossification in the skull and a more complete
`state of ossification at all doses yielding maternal plasma human exposure multiples > 0.8. At
`the highest dose, mottled liver and minimally kinked ribs occurred at 11-times the human
`exposure. Major abnormalities of misshapen oropharynx or narrowed larynx occurred at 0.8-
`times human exposure and umbilical hernia occurred at 0.8 and 3-times human exposure.
`Pregnant rabbits were treated with liraglutide during organogenesis using doses yielding
`maternal plasma exposures < 1-times human exposure. Liraglutide decreased fetal weight and
`increased the incidence of total major fetal abnormalities at all doses, (2.1%, 3.7%, 5.7%, and
`7.6% of fetuses and 18%, 30%, 35%, and 32% of litters affected by major abnormalities at 0,
`0.01, 0.025, and 0.05 mg/kg liraglutide, respectively). Irregular ossification and/or skeletal
`abnormalities occurred in the skull and jaw, vertebrae and ribs, sternum, pelvis, and scapula.
`Visceral abnormalities occurred in blood vessels and gall bladder. In a prenatal and postnatal
`toxicity study of 0, 0.1, 0.25, or 1 mg/kg liraglutide administered to parental F0 rats from
`gestation day 6 through weaning on lactation day 24, liraglutide delayed delivery to day 22 in
`the majority of treated rats and decreased F1 generation pup weight at all doses during the
`lactation period. Bloody scabs and agitated behavior occurred in male rats descended from
`dams treated with 1 mg/kg/day liraglutide. Group mean body weight from birth to postpartum
`day 14 trended lower in F2 generation rats descended from liraglutide-treated rats compared to
`F2 generation rats descended from controls, but differences did not reach statistical significance
`for any group. In a dose range-finding juvenile toxicity study in rats, liraglutide delayed the onset
`and completion of sexual maturation of male rats, an effect attributed to decreased body weight
`gain, and liraglutide delayed the completion of sexual development of female rats and reduced
`the relative weight of ovaries, effects that occurred in the absence of reduced body weight.
`
`1.3
`
`Recommendations
`
`1.3.1
`
`Approvability
`Based on prior approval of up to 1.8 mg/day liraglutide for the treatment of type 2
`diabetes mellitus, the approval of other long-acting GLP-1 receptor agonists that are known or
`suspected to induce rodent thyroid C-cell tumors of unknown human relevance, similar steady
`state systemic exposure to liraglutide in obese adults administered 3.0 mg/day liraglutide
`compared to healthy adults administered 1.8 mg/day, and no new safety concerns from
`nonclinical studies for the proposed indication for weight management in obese adults or
`overweight adults with at least weight-related comorbidity, I recommend approval of up to 3.0
`mg/day liraglutide for the proposed weight management indication. The approved label for
`Victoza and the proposed label for Saxenda both include a boxed warning regarding the
`unknown human relevance of liraglutide-induced thyroid C-cell tumors in rodents. Review of
`post-marketing safety information for Victoza by FDA’s Division of Pharmacovigilance 1
`concluded 6/9 cases of medullary thyroid cancer (MTC) reported to the FDA Adverse Event
`Reporting System (FAERS) were possibly related to liraglutide treatment. However, further
`review of Victoza post-marketing case reports of MTC by a thyroid cancer expert in FDA’s
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`Anthony Parola, PhD
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`Division of Metabolism and Endocrinology Products concluded the relation to liraglutide
`treatment was unknown and these post-marketing reports of MTC were not an impediment to
`recommending approval for a large majority of voting members of an 11 September 2014
`meeting of the Endocrinologic and Metabolic Drug Advisory Committee evaluating the benefits
`and risks of 3.0 mg/day liraglutide for the proposed weight management indication.
`
`Additional Non Clinical Recommendations
`
`1.3.2
`None.
`
`Labeling
`1.3.3
`Relevant nonclinical sections in the proposed label are shown below. Recommended deletions
`are shown by strikethrough text and additions are in red font.
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
`WARNING: RISK OF THYROID C-CELL TUMORS
`See full prescribing information for complete boxed warning.
`Liraglutide causes thyroid C-cell tumors at clinically relevant exposures
`is unknown whether
`Saxenda causes thyroid C-cell tumors, including
`medullary thyroid carcinoma (MTC), in humans, as human relevance could not be
`determined by clinical or nonclinical studies (5.1).
` Saxenda is contraindicated in patients with a personal or family history of MTC or in
`patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) (5.1).
`
`. It
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙INDICATIONS AND USAGE∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`Saxenda is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated 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) (1) or
`
`27 kg/m2 or greater (overweight) in the presence of at least one weight related comorbidity
`
`such as hypertension, dysglycemia (prediabetes and type 2 diabetes mellitus), dyslipidemia
`or obstructive sleep apnea (1)
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙WARNINGS AND PRECAUTIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
` Thyroid C-cell tumors in animals: Counsel patients regarding the risk of medullary thyroid
`carcinoma and the symptoms of thyroid tumors (5.1).
`
`FULL PRESCRIBING INFORMATION
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`WARNING: RISK OF THYROID C-CELL TUMORS
`
`Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors
`at clinically relevant exposures in both genders of rats and mice.
`It is unknown whether
`W" Saxenda causes thyroid C—cell tumors, including medullary thyroid carcinoma
`(MTC), in humans, as human relevance could not be ruled out by clinical or nonclinical
`studies. Saxenda is contraindicated in patients with a personal or family history of MTC and
`(mo
`in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
`
`(b) (4)
`
`[see Contraindications (4), Warnings and Precautions (5.1)
`
`Risk of Thyroid C-cell Tumors
`5.1
`Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors
`(adenomas and/or carcinomas) at clinically relevant exposures in both genders of rats and mice
`[see Nonclinical Toxicology (13.1)]. Malignant thyroid C-cell carcinomas were detected in rats
`and mice.
`"M"
`. It is unknown whether
`
`Saxenda will cause thyroid C—cell tumors, including medullary thyroid carcinoma (MTC), in
`humans, as the human relevance of liraglutide—induced rodent thyroid C-cell tumors
`"M"
`8 determined
`"M"
`
`5.5
`
`Renal lmpairrnent
`
`one)
`
`Pregnancy
`8.1
`Pregnancy Category 3X.
`
`Risk Summary
`There are no adequate and well-controlled studies of Saxenda in pregnant women. Saxenda
`should not be used during pregnancy. If a patient wishes to become pregnant, or pregnancy
`occurs, treatment with Saxenda should be discontinued.
`
`Clinical Considerations
`
`A minimum weight gain, and no weight loss, is recommended for all pregnant women, including
`those who are already overweight or obese, due to the necessary weight gain that occurs in
`maternal tissues during pregnancy.
`
`Animal Data
`Liraglutide has been shown to be teratogenic in rats at or above (”MOB-times
`systemic exposures in obese humans resulting from the maximum recommended human dose
`(MRHD) of 3.0 mg/day based on plasma area under the time-concentration curve (AUC)
`comparison. Liraglutide has been shown to cause reduced growth and increased total major
`abnormalities in rabbits at systemic exposures below
`(”m-exposure in obese humans at the
`MRHD based on plasma AUC comparison.
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`Female rats given subcutaneous doses of 0.1, 0.25 and 1.0 mg/kg/day liraglutide beginning 2
`weeks before mating through gestation day 17 had estimated systemic exposures
`0.8-
`3-
`, and
`11-times the
`exposure in obese humans at the MRHD based on plasma AUC
`comparison. The number of early embryonic deaths in the 1 mg/kg/day group increased slightly.
`Fetal abnormalities and variations in kidneys and blood vessels, irregular ossification of the
`skull, and a more complete state of ossification occurred at all doses. Mottled liver and
`minimally kinked ribs occurred at the highest dose. The incidence of fetal malformations in
`liraglutide-treated groups exceeding concurrent and historical controls were misshapen
`oropharynx and/or narrowed opening into larynx at 0.1 mg/kg/day and umbilical hernia at 0.1
`and 0.25 mg/kg/day.
`
`Pregnant rabbits given subcutaneous doses of 0.01, 0.025 and 0.05 mg/kg/day liraglutide from
`gestation day 6 through day 18 inclusive, had estimated systemic exposures less than
`
` exposure in obese humans at the MRHD of 3.0 mg/day at all doses, based on plasma
`AUC comparison. Liraglutide decreased fetal weight and dose-dependently increased the
`incidence of total major fetal abnormalities at all doses. The incidence of malformations
`exceeded concurrent and historical controls at 0.01 mg/kg/day (kidneys, scapula), ≥ 0.01
`mg/kg/day (eyes, forelimb), 0.025 mg/kg/day (brain, tail and sacral vertebrae, major blood
`vessels and heart, umbilicus), ≥ 0.025 mg/kg/day (sternum) and at 0.05 mg/kg/day (parietal
`bones, major blood vessels). Irregular ossification and/or skeletal abnormalities occurred in the
`skull and jaw, vertebrae and ribs, sternum, pelvis, tail, and scapula; and dose-dependent minor
`skeletal variations were observed. Visceral abnormalities occurred in blood vessels, lung, liver,
`and esophagus. Bilobed or bifurcated gallbladder was seen in all treatment groups, but not in
`the control group.
`
`In pregnant female rats given subcutaneous doses of 0.1, 0.25 and 1.0 mg/kg/day liraglutide
`from gestation day 6 through weaning or termination of nursing on lactation day 24, estimated
`systemic exposures were
`0.8-,
`3-, and
`11-times human exposure in obese humans at
`the MRHD of 3.0 mg/day, based on plasma AUC comparison. A slight delay in parturition was
`observed in the majority of treated rats. Group mean body weight of neonatal rats from
`liraglutide-treated dams was lower than neonatal rats from control group dams. Bloody scabs
`and agitated behavior occurred in male rats descended from dams treated with 1 mg/kg/day
`liraglutide. Group mean body weight from birth to postpartum day 14 trended lower in F2
`generation rats descended from liraglutide-treated rats compared to F2 generation rats
`descended from controls, but differences did not reach statistical significance for any group.
`
`8.3 Nursing Mothers
`It is not known whether liraglutide is excreted in human milk. Because many drugs are excreted
`in human milk and because of the potential for tumorigenicity shown for liraglutide in animal
`studies, a decision should be made whether to discontinue nursing or to discontinue Saxenda,
`taking into account the importance of the drug to the mother. In lactating rats, liraglutide was
`excreted unchanged in milk at concentrations approximately 50% of maternal plasma
`concentrations.
`
`13.1 Carcinogenesis, 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, 1.0, and 3.0 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 3.0 mg/day
`based on plasma AUC comparison. A dose-related increase in benign thyroid C-cell adenomas
`was seen in the 1.0 and the 3.0 mg/kg/day groups with incidences of 13% and 19% in males
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b)
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`NDA 206321
`
`Anthony Parola, PhD
`
`and 6% and 20% in females, respectively. C-cell adenomas did not occur in control groups or
`0.03 and 0.2 mglkg/day groups. Treatment-related malignant C-cell carcinomas occurred in 3%
`of females in the 3.0 mglkg/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 mglkg/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 mglkg/day liraglutide administered by bolus subcutaneous
`injection with exposures "’""0.5—, ““92- and (”m-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 mglkg/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 mglkglday groups, respectively. Thyroid C-cell carcinomas are
`rare findings during carcinogenicity testing in rats.
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`(In) (4)
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`Studies in mice demonstrated that “’wliraglutide-induced C-cell proliferation was dependent on
`the GLP—1 receptor
`“m-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 could not be
`determined by clinical studies or nonclinical studies [see Boxed Warning and 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 1.0 mglkg/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 1.0 mglkg/day, a high dose yielding an estimated systemic
`exposure {31 1-times the
`(”m-exposure in obese humans at the MRHD, based on plasma
`AUC comparison. In female rats, an increase in early embryonic deaths occurred at 1.0
`mglkg/day. Reduced body weight gain and food consumption were observed in females at the
`1.0 mg/kglday dose.
`
`2
`
`Drug Information
`
`2.1
`
`Drug
`
`CAS Registry Number. 0204656—20—2
`Generic Name: liraglutide
`
`Reference ID: 3627306
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`NDA 206321
`
`Anthony Parola, PhD
`
`Code Name: NNC 90-1170, NNC 0090-0000—1170, NN2211, glipacyl
`Chemical Name: ArguLysze-(N-a-(y-Glu-(N-a-hexadecanoyl)))-GLP-1[7-37]
`Molecular Formula/Molecular Weight C172H265N43051 / 3751.2 Daltons
`Structure or Biochemical Description:
`- 37
`30
`o
`H
`20
`7
`In
`My%906@fiflfififlfl§§flfia§gjamVJ%§BO&@O@@@EE%{WH
`
`f Us.
`YNH
`
`Glu-spncer
`
`0 _.
`T0
`HO
`NH
`x
` 0
`Palmitic acid
`
`C H
`
`3
`
`Figure l
`
`)Iolecular structure of Iiraglutide
`One-letter ammo and codes an: used 1.1: £1115 figure.
`
`[SD1 Module 2.6 Nonclinical Written and Tabulated Summaries Introduction P6]
`
`Phannacologic Class: glucagon-Iike peptide 1 (GLP-1) receptor agonist
`
`2.2
`
`Relevant INDs, NDAs, BLAs and DMFs
`
`IND 61040: Iiraglutide for the treatment of type 2 diabetes mellitus (opened in October 2000,
`sponsored by Novo Nordisk)
`IND 73206: Iiraglutide for the treatment of obesity (opened September 2008, sponsored by
`Novo Nordisk)
`NDA 22341: Victoza® (Iiraglutide for injection), up to 1.8 mglday Iiraglutide for the treatm