CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
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`203441Orig1s000
`
`PHARMACOLOGY REVIEW(S)
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`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:
`Applicant:
`Review Division:
`
`Reviewer:
`Supervisor/Team Leader:
`Division Director:
`Project Manager:
`
`203441
`002
`November 30, 2011
`November 30, 2011
`Gattex® (Teduglutide )
`Short Bowel Syndrome (SBS)
`NPS Pharmaceuticals
`Division of Gastroenterology and Inborn Errors
`Products (DGIEP)
`Tamal K. Chakraborti, Ph.D.
`Sushanta K. Chakder, Ph.D.
`Donna Griebel, MD
`Matthew Scherer, MBA
`
`
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 203441 are owned by NPS Pharmaceuticals or are data
`for which NPS Pharmaceuticals has obtained a written right of reference.
`Any information or data necessary for approval of NDA 203441 that NPS
`Pharmaceuticals 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 NDA 203441.
`
`Reference ID: 3169353
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`NDA 203441
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`
`
`
`Tamal K. Chakraborti, Ph.D.
`
`TABLE OF CONTENTS
`
` 1
`
` EXECUTIVE SUMMARY ......................................................................................... 4
`1.1
`INTRODUCTION.................................................................................................... 4
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 4
`1.3 RECOMMENDATIONS............................................................................................ 6
`2 DRUG INFORMATION ............................................................................................ 9
`2.1 DRUG................................................................................................................. 9
`2.2 RELEVANT IND/S, NDA/S, AND DMF/S ............................................................... 10
`2.3 DRUG FORMULATION ......................................................................................... 10
`2.4 COMMENTS ON NOVEL EXCIPIENTS..................................................................... 11
`2.5 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ....................................... 11
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN .................................... 17
`2.7 REGULATORY BACKGROUND .............................................................................. 17
`3 STUDIES SUBMITTED.......................................................................................... 18
`3.1
`STUDIES REVIEWED........................................................................................... 18
`3.2
`STUDIES NOT REVIEWED ................................................................................... 20
`3.3
`PREVIOUS REVIEWS REFERENCED...................................................................... 20
`4 PHARMACOLOGY................................................................................................ 20
`PRIMARY PHARMACOLOGY................................................................................. 20
`4.1
`4.2
`SECONDARY PHARMACOLOGY............................................................................ 42
`4.3
`SAFETY PHARMACOLOGY................................................................................... 43
`5 PHARMACOKINETICS/ADME/TOXICOKINETICS .............................................. 49
`5.1
`PK/ADME........................................................................................................ 49
`TOXICOKINETICS ............................................................................................... 65
`5.2
`6 GENERAL TOXICOLOGY..................................................................................... 65
`SINGLE-DOSE TOXICITY..................................................................................... 65
`6.1
`6.2 REPEAT-DOSE TOXICITY.................................................................................... 66
`7 GENETIC TOXICOLOGY .................................................................................... 169
`7.1
`IN VITRO REVERSE MUTATION ASSAY IN BACTERIAL CELLS (AMES)..................... 169
`IN VITRO ASSAYS IN MAMMALIAN CELLS............................................................ 172
`7.2
`7.3
`IN VIVO CLASTOGENICITY ASSAY IN RODENT (MICRONUCLEUS ASSAY)................ 174
`7.4 OTHER GENETIC TOXICITY STUDIES.................................................................. 179
`8 CARCINOGENICITY ........................................................................................... 179
`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY .............................. 212
`FERTILITY AND EARLY EMBRYONIC DEVELOPMENT............................................. 212
`9.1
`9.2
`EMBRYONIC FETAL DEVELOPMENT ................................................................... 215
`PRENATAL AND POSTNATAL DEVELOPMENT....................................................... 224
`9.3
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`NDA 203441
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`Tamal K. Chakraborti, Ph.D.
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`SPECIAL TOXICOLOGY STUDIES................................................................. 233
`INTEGRATED SUMMARY AND SAFETY EVALUATION............................... 243
`APPENDIX/ATTACHMENTS........................................................................... 246
`
`10
`11
`12
`
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`Reference ID: 3169353
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`
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`Tamal K. Chakraborti, Ph.D.
`
`NDA 203441
`
`1
`1.1
`
`Teduglutide is a 33 amino acid peptide that differs from its natural analog, glucagon-like
`peptide-2 (GLP-2) in the substitution of alanine (in native GLP-2) for glycine at the
`second position at the N-terminus. This single amino acid substitution provides
`resistance to in vivo degradation of teduglutide by dipeptidyl protease-IV (DPP-IV)
`resulting in an extended half-life. Teduglutide is manufactured using a recombinant
`strain of Escherichia coli.
`
`Teduglutide has been shown to preserve mucosal integrity by promoting repair and
`normal growth of the intestine. Teduglutide increased villus height and crypt depth of the
`intestinal epithelium resulting in enhanced absorptive capacity of the intestine as
`demonstrated by greater absorption of fluids, electrolytes and nutrients, reduced fecal
`fluid loss, and diminished diarrhea. In addition, teduglutide accelerated intestinal
`adaptation, increased nutrient transporter activity, enhanced barrier function in the small
`intestine and decreased intestinal inflammation. These effects of teduglutide formed the
`rationale for use in patients with short bowel syndrome (SBS). Short bowel syndrome is
`characterized by the inadequate absorption of fluid and nutrients in patients who have
`undergone significant small bowel resection. This NDA was submitted to support the
`marketing approval of teduglutide for the treatment of SBS in adult patients and for the
`improvement of intestinal absorption of fluid and nutrients.
`
`
`1.2 Brief Discussion of Nonclinical Findings
`
`The applicant has conducted adequate nonclinical studies with teduglutide which
`included pharmacology, safety pharmacology, pharmacokinetics, acute toxicology
`studies mice, repeated dose toxicology studies in mice (14 days to 26 weeks duration),
`rats (14 day to 13 weeks duration), Cynomolgus monkeys (14 to 1 year duration),
`toxicology studies in juvenile minipigs (14 days to 90 days duration), genotoxicity
`studies (Ames test, chromosome aberration test in Chinese hamster ovary cells, in vivo
`micronucleus test in mice), reproductive toxicology studies (fertility and early embryonic
`development in rats, embryofetal development in rats and rabbits, and pre and postnatal
`development in rats), and special toxicology studies (antigenicity and local tolerance
`studies). Toxicology studies were conducted using the subcutaneous (SC) route, the
`intended clinical route of administration.
`
`In toxicology studies, teduglutide was administered subcutaneously to mice (26-week
`treatment) up to 50 mg/kg/day (about 1000 times the recommended daily human dose
`of 0.05 mg/kg), rats (13-week treatment) up to 50 mg/kg/day (about 1000 times the
`recommended daily human dose of 0.05 mg/kg), and Cynomolgus monkeys (1-year
`treatment) up to 25 mg/kg/day (about 500 times the recommended daily human dose of
`0.05 mg/kg). The lowest reported AUC (either male or female) values at the highest
`tested doses in mice (AUC0-8h of 58.5 µg.hr/mL at 50 mg/kg/day), rats (AUC0-8h of 36.7
`
`Executive Summary
`Introduction
`
`Reference ID: 3169353
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`NDA 203441
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`
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`
`Tamal K. Chakraborti, Ph.D.
`
`µg.hr/mL at 50 mg/kg/day) and monkeys (AUC0-8h of 64.6 µg.hr/mL at 25 mg/kg/day)
`were about 250, 156 and 275 times, respectively, the human exposure (AUC0- of 0.235
`µg.hr/mL) at the proposed clinical dose of 0.05 mg/kg/day.
`
`In pivotal repeated dose toxicology studies, major treatment-related effects were related
`to the pharmacological activity of teduglutide which were seen in all species. In the 26-
`week study in mice at 2, 10 and 50 mg/kg/day, major treatment-related histopathological
`changes were seen at all doses in the small and large intestine (epithelial and villus
`hypertrophy and hyperplasia), gall bladder (epithelial hypertrophy and hyperplasia
`accompanied by subacute inflammation), sternal bone marrow (myeloid hyperplasia)
`and injection site (inflammation and necrosis). In the 13-week study in rats at 10, 25 and
`50 mg/kg/day, major treatment-related histopathological changes were seen at all doses
`in the small and large intestine (mucosal hypertrophy and hyperplasia) and injection site
`(inflammation and necrosis). In the 1-year study in Cynomolgus monkeys at 1, 5 and 25
`mg/kg/day, major treatment-related histopathological changes were seen at all doses in
`the small and large intestine (mucosal hyperplasia), stomach (mucosal hyperplasia),
`pancreas (hypertrophy/hyperplasia of the pancreatic duct epithelium), liver and gall
`bladder (epithelial hypertrophy and hyperplasia of the bile duct in the liver and mucosal
`hypertrophy/hyperplasia of the gall bladder) and injection site (inflammation and
`necrosis).
`
`Teduglutide was also tested in juvenile minipigs in 14-day and 90-day toxicology studies
`up to 25 mg/kg/day (about 500 times the recommended daily human dose of 0.05
`mg/kg). In the 14-day study at 5 and 25 mg/kg/day, major treatment-related
`histopathological changes were seen at all doses in the nonglandular stomach (mucosal
`hyperplasia associated with ulceration/erosion), small and large intestinal tract
`(hyperplasia), gall bladder (mucosal hyperplasia), bile duct (mucosal hyperplasia) and
`injection site (inflammation and necrosis). In the 90-day study at 1, 5 and 25 mg/kg/day,
`major treatment-related histopathological changes were observed at all doses in the
`small intestines (minimal/slight villous hypertrophy), gall bladder (cystic mucosal
`hyperplasia at all doses), extrahepatic bile duct (cystic mucosal hyperplasia), and
`injection site (inflammation and necrosis). In the 90-day study, teduglutide increased the
`P wave, PR, QT (mid and high dose) and RR intervals at all doses in males at Week 13
`compared to respective controls. The ECG changes were predominantly seen in males;
`however, the plasma exposure (AUC) to teduglutide was higher in females than that in
`males at Week 13 at all doses. In addition, these changes were seen at only one time
`point (Week 13), in one species and the magnitude of these changes were small and
`these changes were also not dose-related. Moreover, there were no significant
`treatment-related effects on QTc (Fridericia) in either sex. The QTc values were
`comparable across all groups. Overall, these ECG changes are not meaningful and not
`toxicologically significant.
`
`Teduglutide was negative in the Ames test, in vitro chromosomal aberration test in
`Chinese hamster ovary (CHO) cells, and in vivo mouse micronucleus test. In a 2-year
`carcinogenicity study by subcutaneous route in Wistar Han rats at 3, 10 and 35
`mg/kg/day (about 60, 200 and 700 times the recommended daily human dose of 0.05
`
`Reference ID: 3169353
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`NDA 203441
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`
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`Tamal K. Chakraborti, Ph.D.
`
`mg/kg, respectively), teduglutide caused statistically significant increases in the
`incidences of adenomas in the bile duct and jejunum of male rats. There were no drug
`related tumor findings in females. A 2-year mouse carcinogenicity study is ongoing. By
`virtue of its mechanism of action (intestinotrophic activity or growth promoting
`pharmacological effect) and the findings of the carcinogenicity study in rats, teduglutide
`has the potential to cause hyperplastic changes including carcinogenicity in humans.
`
`In the subcutaneous fertility and early embryonic development study in rats at 2, 10 and
`50 mg/kg/day, teduglutide did not show any adverse effects on early embryonic
`development or fertility parameters up to 50 mg/kg/day (about 1000 times the
`recommended daily human dose of 0.05 mg/kg). In the subcutaneous embryofetal
`development study in rats at 2, 10 and 50 mg/kg/day, teduglutide was not teratogenic
`up to 50 mg/kg/day (about 1000 times the recommended daily human dose of 0.05
`mg/kg). In the subcutaneous embryofetal development study in rabbits at 2, 10 and 50
`mg/kg/day, teduglutide was not teratogenic up to 50 mg/kg/day (about 1000 times the
`recommended daily human dose of 0.05 mg/kg). In the subcutaneous pre and postnatal
`development study in rats at 10, 25 and 50 mg/kg/day, teduglutide did not show any
`significant adverse effect on pre and postnatal development up to 50 mg/kg/day (about
`1000 times the recommended daily human dose of 0.05 mg/kg).
`
`Overall, nonclinical safety of teduglutide has been adequately tested in several
`toxicology studies. Nonclinical studies conducted with teduglutide provide adequate
`assurance of safety and support its proposed use at the intended therapeutic dosage
`and in accordance with the proposed product labeling. However, by virtue of its
`mechanism of action (intestinotrophic activity or growth promoting pharmacological
`effect) and the findings of the carcinogenicity study in rats, teduglutide has the potential
`to cause hyperplastic changes including carcinogenicity in humans.
`
`1.3 Recommendations
`1.3.1 Approvability
`From a nonclinical standpoint, this NDA is recommended for approval.
`1.3.2 Additional Non Clinical Recommendations
`None
`1.3.3 Labeling
`The draft labeling of Gattex conforms to the content and format of labeling for human
`prescription drugs under 21CFR201.57(b)(1). However, the following changes are
`recommended.
`
`8.1 Pregnancy
`
`Applicant’s Version:
`
`8.1 Pregnancy
`
`Reference ID: 3169353
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`NDA 203441
`
`Tamal K. Chakraborti, Ph.D.
`
`two
`Pregnancy Category B-
`there are no adequate and well-controlled studies in pregnant women.
`Because animal reproduction studies are not always predictive of human response, "M"
`should be used during pregnancy only if clearly needed.
`
`Evaluation: The text is not in accordance with 21 CFR 201 .57(c)(9)(i)(A)(2). The
`pregnancy category B is acceptable. However, the text should be modified as
`recommended below to reflect the dose. In addition, the findings of the pre and
`postnatal development study in rats should be incorporated in this section.
`
`Recommended Version:
`
`8.1 Pregnancy
`
`Pregnancy Category B
`
`Reproduction studies with teduglutide have been performed in pregnant rats at
`subcutaneous doses up to 50 mglkglday (about 1000 times the recommended daily
`human dose of 0.05 mglkg) and in rabbits at subcutaneous doses up to 50 mglkglday
`(about 1000 times the recommended daily human dose of 0.05 mglkg). These studies
`did not reveal any evidence of impaired fertility or harm to the fetus due to teduglutide. A
`pre and postnatal development study in rats showed no evidence of any adverse effect
`on pre and postnatal development at subcutaneous doses up to 50 mglkglday (about
`1000 times the recommended daily human dose of 0.05 mglkg). There are, however, no
`adequate and well—controlled studies in pregnant women. Because animal reproduction
`studies are not always predictive of human response, teduglutide should be used during
`pregnancy only if clearly needed.
`
`8.3. Nursing Mothers
`
`Applicant’s Version:
`
`8.3 Nursing Mothers
`
`(b) (4)
`
`It is unknown whether
`concentration in milk was
`SC injection of 25 mg/kg.
`GA TTEX during nursing should be avoided.
`
`is excreted in human milk.
`m" of the plasma concentration following a single
`M" The use of
`
`(5) (4)
`
`Evaluation: The text is in not accordance with 21 CFR 201.57(c)(9)(iii) 8.3. Since
`teduglutide is excreted through breast milk and teduglutide has tumorigenic potential,
`the text should be modified as follows as per the CFR.
`
`Recommended Version:
`
`Reference ID: 31 69353
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`

`NDA 203441
`
`
`
`
`Tamal K. Chakraborti, Ph.D.
`
`8.3 Nursing Mothers
`
`It is unknown whether teduglutide is excreted in human milk. Teduglutide is excreted in
`the milk of lactating rats and the highest concentration in the milk was 2.9% of the
`plasma concentration following a single subcutaneous injection of 25 mg/kg. Because
`many drugs are excreted in human milk and because of the potential for serious
`adverse reactions to nursing infants from teduglutide and because of the potential for
`tumorigenicity shown for teduglutide in rats, a decision should be made whether to
`discontinue nursing or to discontinue the drug, taking into account the importance of the
`drug to the mother.
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`Applicant’s Version:
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`Evaluation: The format is in accordance with 21CFR 201.57(c)(14)(i) 13.1. However,
`the text should be modified as proposed below to reflect the findings of the rat
`carcinogenicity study.
`
`Recommended Version:
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`Reference ID: 3169353
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`(b) (4)
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`NDA 203441
`
`
`
`
`Tamal K. Chakraborti, Ph.D.
`
`In a 2-year carcinogenicity study in Wistar Han rats at subcutaneous doses of 3, 10 and
`35 mg/kg/day (about 60, 200 and 700 times the recommended daily human dose of
`0.05 mg/kg, respectively), teduglutide caused statistically significant increases in the
`incidences of adenomas in the bile duct and jejunum of male rats.
`
`Teduglutide was negative in the Ames test, chromosomal aberration test in Chinese
`hamster ovary cells, and in vivo mouse micronucleus assay.
`
`Teduglutide at subcutaneous doses up to 50 mg/kg/day (about 1000 times the
`recommended daily human dose of 0.05 mg/kg) was found to have no adverse effect on
`fertility and reproductive performance of male and female rats.
`
`
`
`
`2 Drug Information
`2.1 Drug
`CAS Registry Number: 197922-42-2
`
`Generic Name: Teduglutide
`
`Code Name: ALX-0600
`
`Chemical Name: L-histidyl-L-glycyl-L-aspartyl-L-glycyl-L-seryl-L-phenylalanyl-L-seryl-L-
`aspartyl-L-glutamyl-L-methionyl-L-asparaginyl-Lthreonyl-L-isoleucyl-L-leucyl-L-aspartyl-
`L-asparaginyl-L-leucyl-L-alanyl-L-alanyl-L-arginyl-L-aspartyl-L-phenylalanyl-Lisoleucyl-
`L-asparaginyl-L-tryptophanyl-L-leucyl-L-isoleucyl-Lglutaminyl-L-threonyl-L-lysyl-L-
`isoleucyl-L-threonyl-L-aspartic acid
`
`Molecular Formula/Molecular Weight: C164H252N44O55S/3752 Daltons
`
`
`Reference ID: 3169353
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`NDA 203441
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`Tamal K. Chakraborti, Ph.D.
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`Structure or Biochemical Description: Teduglutide is an analog of naturally occurring
`human GLP-2, a peptide secreted by L cells of the distal intestine. Like GLP-2,
`teduglutide is 33 amino acids in length with an amino acid substitution of alanine by
`glycine at the second position of the N-terminus of GLP-2. The structure of teduglutide
`is shown below (from page 2 of Section 2.3.S.1 of the electronic submission).
`Teduglutide was manufactured using a recombinant strain of Escherichia coli.
`
`
`
`
`
`
`
`Pharmacologic Class: Glucagon-like-peptide-2 (GLP-2) receptor agonist
`
`2.2 Relevant IND/s, NDA/s, and DMF/s
`1. IND 58,213 (ALX-0600, NPS Pharmaceuticals)
`2.3 Drug Formulation
`Teduglutide for injection is supplied in a sterile, single-use 3-mL, USP Type I glass vial
`containing 5 mg of teduglutide as a white lyophilized powder. The lyophilized powder is
`intended for reconstitution with 0.5 mL of sterile Water for Injection, USP immediately
`before administration by subcutaneous injection. The reconstituted product is a clear,
`colorless to light straw-colored solution (10 mg/mL), which also contains the following
`excipients:
` sodium phosphate,
` L-histidine, and
` mannitol. The
`reconstituted solution has a pH of approximately 7.4. The composition of the drug
`product is shown below (from page 1 of 2.3.P.1).
`
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`Reference ID: 3169353
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`NDA 203441
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`Tamal K. Chakraborti, Ph.D.
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`Table 2.3.P.l—1:
`
`Composition of Teduglutide for Injection
`
`Quantity per Vial
`
`
`Name of Ingredients
`
`
`Teduglutide Drug
`Active Ingredient
`NPS ill-hOlLSe standard
`5 mg
`
`Substance
`~
`-
`.
`.
`.
`L-Hisudnie
`Mannitol
`
`(0(4)
`
`USP
`
`3.88 mg
`
`
`
`
`
`
`Monobasic Sodium
`Phosphate. h/Ionohyth'ate
`
`
`
`Dibasic Sodium
`
`Phosphate. Heptahydrate
`
`Water for Injection
`
`USP
`
`(I!) (4)
`
`
`N'PS = NPS Pharmaceuticals: USP = United States Pharmacooeia: NF = National Formularv
`
`(b)(0
`
`2.4 Comments on Novel Excipients
`
`The excipients used in the manufacture of teduglutide for injection are all compendial.
`The quality standard for each excipient is shown in the table (from page 1 of Section
`2.3.P.4 of the electronic submission) below. No novel excipients were used in the
`manufacture of the drug product.
`
`Table 2.3.P.4—1:
`
`Specifications for Teduglutide for Injection Excipients
`
`‘ Mannitol
`
`Quality Standard
`Excipients
`L-I-Iistidine
`
`Monobasic Sodium Phosphate. Monohydratc Dibasic Sodium Phosphate. Heptahydtate
`
`Water for Inj ection ‘
`
`USP
`
`2.5 Comments on Impurities/Degradants of Concern
`
`The potential process and product-related impurities in the teduglutide drug substance
`(DS) were controlled as per the lntemational Conference on Harmonization (ICH)
`guideline Q6B: Product-related impurities and Process—related impurities. The major
`product-related impurities have a lower biological activity than teduglutide. The
`biological activities of the minor impurities were not determined. Product-related
`impurities could arise by chemical or physical degradation of teduglutide, molecular
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`Reference ID: 31 69353
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`NDA 203441
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`Tamal K. Chakraborti, Ph.D.
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`rearrangement such as truncation, isomerization, incorporation of incorrect amino acids
`during biosynthesis or incomplete post-translational processing.
`
`The release specifications for the OS are shown in the following table (from page 4 of
`Section 3.2.R.3.P of the submission). Impurity A and B are teduglutide-related impurity
`and related in sequence to teduglutide molecule (parent drug) and the specifications are
`acceptable from a nonclinical standpoint. Impurity A
`“m
`, not more than (NMT)
`0"";
`“M", NMT
`(mo NMT
`(m4) lllMT
`00(4)
`
`(hm.
`(m4);
`(5)“).
`
`(hm) and
`
`NMT (m4);
`’
`"M"; unspecified impurity, NMT
`"M; Total impurity, NMT "’""] and B
`t, NMT “M";
`"M Impurity, NMT M") were
`considered qualified based on calculated exposure in toxicology studies.
`
`(m4), NMT
`"M"
`
`Reference ID: 31 69353
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`NDA 203441
`
`Tamal K. Chaklaborti, Ph.D.
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`Table 3.2.R.3.P—2: Teduglutide Drug Substance Release Specification
`'
`Vtsml
`(0 -ANP-GLP-1005)
`QC-ANP-GLP—5006
`
`.-
`colored '
`Themfiontimofmetemghmde
`peakcmeqaondstoflmofflne
`standardpreparafionasob‘ainedin
`the
`
`QC-ANP-GLP—Zl l0
`
`(RP HPLC)
`
`_ANP-GLP—5011
`
`@— ”mam“
`_QC”mm”1°
`
`Reference ID: 3169353
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`NDA 203441
`
`Tamal K. Chakraborti, Ph.D.
`
`Table 3.2.R.3.P-2: Teduglutide Drug Substance Release Specification
`
` mA-mwmmmw-mmimM-mmm
`
`RP=nlfimeP-MC=MMWWW
`‘ Tenedonlylnleue
`‘Coelmmgmmues
`
`The following table (from page 2 of 3.2.8.3.2) shows the potential product-related
`impurities.
`
`Table 3.2.5.3.2-1: Potential Product-Related Impurities for 'l'eduglutlde
`
`
`
`The majority of the product-related impurities have been identified to be truncated forms
`of the peptide. Fifteen principal impurities have been identified in the drug substance.
`Several of these peaks were co-eluted with other impurities and were quantified as a
`group of impurities. Good Laboratory Practice (GLP) compliant toxicology studies
`ranging from 14 days to one year in duration have been conducted in multiple species.
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`Reference ID: 3169353
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`

`NDA 203441
`
`Tamal K. Chakraborti, Ph.D.
`
`The following table (from page 104 of Section 2.6.6 of the submission) shows impurity
`profiles for the drug product used in the majority of these toxicology studies.
`
`Table 27 Levels of Principal Impurities in Drug Product Batches I'sed in Repeat
`Dose Toxicology Studies
`
`Impurity (‘3 3)
`
`(m4)
`
`Species
`
`Dura- NOAEI.
`mm
`(mgikg’
`day)
`
`Mouse
`
`Rat
`
`Rat
`Rat
`
`Monkey
`
`Human‘
`
`26
`weeksI
`14
`
`days"
`14 days
`l 3
`weeks
`
`52
`weeks
`
`P3
`studies
`
`25 ‘60
`
`50
`
`50
`50
`
`5
`
`0.05‘I
`
`' Animals dosed with 15 mg'kg.l“day for 2 weeks and SO mgrkglday for the duration of the study.
`b Study comparing multiple strains of rats.
`‘ The highest value for each individual impurity that was measured in drug product batches used in all of the
`Phase 3 clinical studies.
`d Clinical dose.
`P3 = Phase 3.
`
`As shown in the above table, impurity profiles for drug substance used in the majority of
`these toxicology studies have been determined and margins of exposure (MOE) based
`upon individual impurity exposure (AUC) at the no-observable-adverse—effect level
`(NOAEL) in animals relative to human exposure (AUC) at the therapeutic dose (0.05
`mg/kg/day) of the commercial drug product have been calculated. Based upon the
`calculated MOE, the impurities were considered to be qualified from a nonclinical
`standpoint. Similarly, MOE based upon release specifications for each of the principal
`impurities identified in the drug substance relative to human exposure were determined
`and the calculated ratios support the release specifications from the nonclinical
`perspective. The following tables (from page 105 of Section 2.6.6 of the submission)
`show the release specifications and margins of exposure based on AUC comparisons
`for principal impurities.
`
`Reference ID: 31 69353
`
`1 5
`
`

`

`NDA 203441
`
`Tamal K. Chakraborti, Ph.D.
`
`Table 29 Release Specifications for Principal Impurities in Drug Substance and
`Drug Product
`
`Release Specification (NMT 95)
`
`NMT=NotmoretlIarL
`
`Table 28 Margins of Exposure (Animal to Human Ratio) for Principal Impurities
`in Drug Product Batches
`
`MOE
`
`
`1m
`
`tion
`
`
`
`Mouse
`
`Rat
`
`Rat
`Rat
`
`Mmkey
`
`26
`weeks
`
`l4days'
`
`l4days
`13
`weeks
`
`52
`weeks
`
`'Studycmatingmnlt'plestninsofmts.
`
`Similarly, MOE based upon release specifieafions for each of the principal impurifies
`identified in me drug product (DP) relative to human exposure (AUC) were determined.
`The following table (from page 106 of Section 2.6.6 of the submission) shows the MOE
`(animal to human AUC ratio) for principal impurities based on release specifications for
`drug product.
`
`Reference ID: 3169353
`
`1 6
`
`

`

`NDA 203441
`
`Tamal K. Chakraborti, Ph.D.
`
`Table 30 Margins of Exposure (Animal to Human Ratio) for Principal Impurities
`Based on Release Specifications for Drug Product
`
`Species
`
`Duration
`
`MOE by Impurity
`
`(5)“)
`
`Mouse
`
`26 weeks
`
`Rat
`
`Rat
`
`Rat
`
`14 days3
`
`14 days
`
`13 weeks
`
`Monkey
`
`52 weeks
`
`' Study comparing multiple strains of rats.
`
`From a nonclinical standpoint, these margins of exposure calculated from the toxicology
`studies adequately support the proposed release specifications.
`
`2.6
`
`Proposed Clinical Population and Dosing Regimen
`
`Gattex® is indicated for the following:
`0 Treatment of adult patients with Short Bowel Syndrome (SBS)
`
`0
`
`Improvement of intestinal absorption of fluid and nutrients
`
`The recommended once daily dose is 0.05 mg/kg by subcutaneous injection, alternating
`sites between 1 of the 4 quadrants of the abdomen, or into alternating thighs or
`alternating arms.
`
`2.7 Regulatory Background
`
`The following are the major regulatory milestones.
`
`1. The pre-IND 58,213 meeting dated October 20, 1998 (FDA meeting minutes
`dated October 20, 1998)
`2. End of Phase 2 (EOP2) meeting dated October 6, 2003 (FDA meeting minutes
`dated November 5, 2003)
`3. Telecon to discuss pre-clinical program on December 19, 2003 (FDA meeting
`minutes dated January 16, 2004)
`4. Type C meeting to discuss clinical pharmacokinetics package on June 6, 2006
`(FDA meeting minutes dated July 7, 2006)
`5. Type C meeting to discuss statistical and regulatory issues on January 23, 2007
`(FDA meeting minutes dated February 12, 2007)
`
`Reference ID: 31 69353
`
`1 7
`
`

`

`NDA 203441
`
`
`
`
`Tamal K. Chakraborti, Ph.D.
`
`6. Type C meeting to discuss development plan on January 18, 2008 (FDA meeting
`minutes dated January 25, 2008)
`7. Type B Pre-NDA meeting on July 14, 2008 (FDA meeting minutes dated August
`19, 2008)
`8. Pre-NDA Chemistry Manufacturing and Control (CMC) meeting on October 19,
`2010 (FDA meeting minutes dated November 30, 2010)
`9. Type B Pre-NDA meeting to discuss content and format of the NDA on April 25,
`2011 (FDA meeting minutes dated May 23, 2011)
`
`
`
`STUDY/REPORT NO. REVIEW PAGE #
`20
`49
`49
`50
`
`7203-105*
`
`Studies Submitted
`3
`3.1 Studies Reviewed
`The following studies were reviewed as shown in the table below.
`
`STUDY
`PHARMACOLOGY******
`ABSORPTION, DISTRIBUTION, METABOLISM AND EXCRETION
`ABSORPTION
`Bioavailability of teduglutide following IV and SC
`administration to rabbits
`Bioavailability of teduglutide following IV and SC
`administration to Cynomolgus monkeys
`Bioavailability of teduglutide following IV and SC
`administration to mice
`Pharmacokinetic study in juvenile minipigs
`Comparative study in Wistar and SD rats following
`single SC injection
`Pharmacokinetic study after single IV or SC bolus
`dose of teduglutide to male SD rats
`DISTRIBUTION
`Lacteal excretion and placental transfer of
`teduglutide following administration of SC doses to
`lactating rats and pregnant rabbits
`Determination of teduglutide concentration in
`cerebrospinal fluid and plasma following SC bolus
`doses to male SD rats
`TOXICOLOGY
`Acute
`Mice
`Single, SC
`Subacute/Subchronic/Chronic
`Mouse
`14-Day, SC
`1-Month, SC
`90-Day, SC
`26-Week, SC
`Rat
`14-Day, SC
`14-Day, SC, Wistar Han, Fischer-344 and SD rats
`
`7203-106*
`
`7203-107*
`
`51170*
`800759
`
`10101-R******
`
`7203-104*
`
`10102-R******
`
`88614******
`
`88617******
`88730
`0470MN12.001*
`7203-112*
`
`02-2776***
`800869****
`
`Reference ID: 3169353
`
`18
`
`52
`
`51
`
`53
`58
`
`59
`
`61
`61
`
`64
`
`65
`65
`65
`66
`66
`66
`67
`70
`76
`81
`86
`87
`91
`
`

`

`NDA 203441
`
`
`
`
`Tamal K. Chakraborti, Ph.D.
`
`800069***
`
`51153*
`66585
`
`88616
`88619******
`88729******
`7203-100**
`1368-100*
`
`88665******
`88666******
`
`AA65WK.112.BTL*
`
`80070*****
`
`13-Week, SC, with Dietary optimization
`Minipig
`14-Day, SC, Juvenile
`90-Day, SC, Juvenile
`Cynomolgus Monkey
`3-Day, SC
`14-Day, SC
`1-Month, SC
`13-Week, SC
`12-Month, SC
`GENOTOXICITY
`Ames test
`Chromosome aberration test in Chinese hamster
`ovary (CHO) cells
`In vivo micronucleus test in mice, SC
`CARCINOGENICITY
`Rat, 2-Year, SC
`REPRODUCTIVE TOXICITY
`Rat
`Segment I, SC
`Segment II, SC
`Segment III, SC
`Rabbits
`Segment II, SC
`SPECIAL TOXICOLOGY STUDIES
`Acute IV/perivenous/intraarterial tolerance study in
`rabbits
`13-Day, SC
`Hemolytic potential and blood compatibility study
`Induction of delayed hypersensitivity response
`Immunogenicity study in New Zealand white rabbit
`Exploratory mechanistic toxicology study in
`Cynomolgus monkey on potential increase of CRP
`
`*: Reports reviewed under IND 58,213 (pharmacology review dated December 19,
`2006)
`**: Reports reviewed under IND 58,213 (pharmacology review dated April 1, 2004)
`***: Reports reviewed under IND 58,213 (pharmacology review dated December 5,
`2003)
`****: Reports reviewed under IND 58,213 (pharmacology review dated June 16, 2005)
`*****: Report reviewed under IND 58,213 (pharmacology review dated October 14,
`2008)
`******: Reports reviewed under IND 58,213 (pharmacology review dated May 24, 2002)
`
`
`
`99
`1