CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`208745Orig1s000
`
`PHARMACOLOGY REVIEW(S)
`
`
`
`
`
`
`

`

`MEMORANDUM
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`FROM: David B. Joseph
`Lead Pharmacologist
`
`DATE: December 2, 2016
`
`SUBJECT: NDA 208,745 (SD # 1 dated January 29, 2016)
`
`Sponsor: Synergy Pharmaceuticals Inc.
`
`Drug Product: TRULANCE (plecanatide) tablets
`
`Comments:
`
`There are no nonclinical issues which preclude the approval of Trulance. I concur with
`the recommendations related to approvability, stated in the Pharmacology/Toxicology
`review by Dr. Yuk-Chow Ng. The final revisions to nonclinical information in labeling
`subsections 5.1, 8.1, 8.4, 12.1, and 13.1 include minor changes from the recommended
`version in Dr. Ng’s review. The additional labeling revisions were developed through
`collaboration of the nonclinical team with other members of the review team.
`
` __________________________________ ____________
`
`David B. Joseph, PhD Date
` Lead Pharmacologist
`Division of Gastroenterology and Inborn Errors Products
`
`cc:
`NDA 208,745
`DGIEP
`DGIEP/PM
`DGIEP/D. Joseph
`DGIEP/Y-C. Ng
`OND IO/A. Jacobs
`
`Reference ID: 4021862
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`DAVID B JOSEPH
`12/02/2016
`
`Reference ID: 4021862
`
`

`

`
`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
`
`Application number:
`
`208,745
`
`Supporting document/s:
`
`1
`
`Applicant’s letter date:
`
`1/29/2016
`
`CDER stamp date:
`
`1/29/2016
`
`Product:
`
`Trulance (plecanatide) tablets
`
`Indication:
`
`Chronic idiopathic constipation
`
`Applicant:
`
`Synergy Pharmaceuticals, Inc
`
`Review Division:
`
`Gastroenterology and Inborn Errors Products
`
`Reviewer:
`
`Yuk-Chow Ng, PhD
`
`Supervisor/Team Leader:
`
`David B. Joseph, PhD
`
`Division Director:
`
`Donna Griebel, MD
`
`Project Manager:
`
`Maureen D. Dewey
`
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 208,745 are owned by Synergy or are data for which
`Synergy has obtained a written right of reference. Any information or data necessary
`for approval of NDA 208,745 that Synergy 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 208,745.
`
`Reference ID: 4000392
`
`1
`
`

`

`NDA 208,745 Reviewer: Yuk-Chow Ng, PhD
`
`
`TABLE OF CONTENTS
`
` EXECUTIVE SUMMARY ......................................................................................... 4
`
`INTRODUCTION .................................................................................................... 4
`1.1
`1.2 BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 4
`1.3 RECOMMENDATIONS ............................................................................................ 5
`
` 1
`
`2 DRUG INFORMATION .......................................................................................... 11
`
`2.1 DRUG ............................................................................................................... 11
`2.2 RELEVANT INDS, NDAS, BLAS AND DMFS ....................................................... 12
`2.3 DRUG FORMULATION ......................................................................................... 12
`2.4 COMMENTS ON NOVEL EXCIPIENTS ..................................................................... 12
`2.5 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ....................................... 12
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN ................................... 14
`2.7 REGULATORY BACKGROUND ............................................................................. 15
`
`3 STUDIES SUBMITTED .......................................................................................... 15
`
`3.1
`3.2
`3.3
`
`STUDIES REVIEWED ........................................................................................... 15
`STUDIES NOT REVIEWED ................................................................................... 22
`PREVIOUS REVIEWS REFERENCED...................................................................... 22
`
`4 PHARMACOLOGY ................................................................................................ 22
`
`4.1
`4.2
`4.3
`
`PRIMARY PHARMACOLOGY ................................................................................ 22
`SECONDARY PHARMACOLOGY ........................................................................... 37
`SAFETY PHARMACOLOGY .................................................................................. 38
`
`5 PHARMACOKINETICS/ADME/TOXICOKINETICS .............................................. 43
`
`5.1
`5.2
`
`PK/ADME ....................................................................................................... 43
`TOXICOKINETICS ............................................................................................... 60
`
`6 GENERAL TOXICOLOGY ..................................................................................... 60
`
`SINGLE-DOSE TOXICITY ..................................................................................... 60
`6.1
`6.2 REPEAT-DOSE TOXICITY .................................................................................... 71
`
`7 GENETIC TOXICOLOGY .................................................................................... 157
`
`IN VITRO REVERSE MUTATION ASSAY IN BACTERIAL CELLS (AMES) ................... 157
`7.1
`IN VITRO ASSAYS IN MAMMALIAN CELLS ........................................................... 161
`7.2
`IN VIVO CLASTOGENICITY ASSAY IN RODENT (MICRONUCLEUS ASSAY)............... 167
`7.3
`7.4 OTHER GENETIC TOXICITY STUDIES .................................................................. 172
`
`8 CARCINOGENICITY ........................................................................................... 172
`
`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY .............................. 220
`
`9.1
`9.2
`9.3
`
`FERTILITY AND EARLY EMBRYONIC DEVELOPMENT ............................................ 220
`EMBRYONIC FETAL DEVELOPMENT ................................................................... 234
`PRENATAL AND POSTNATAL DEVELOPMENT ...................................................... 255
`
`Reference ID: 4000392
`
`2
`
`

`

`NDA 208,745 Reviewer: Yuk-Chow Ng, PhD
`
`
`SPECIAL TOXICOLOGY STUDIES ................................................................. 308
`
`INTEGRATED SUMMARY AND SAFETY EVALUATION ............................... 308
`
`APPENDIX/ATTACHMENTS ........................................................................... 316
`
`10
`
`11
`
`12
`
`
`
`
`
`Reference ID: 4000392
`
`3
`
`

`

`NDA 208,745 Reviewer: Yuk-Chow Ng, PhD
`
`
`1
`
`Executive Summary
`
`1.1
`
`Introduction
`
`Plecanatide (SP-304) is a synthetic hexadecapeptide that is designed to mimic the
`action of uroguanylin and guanylin, which are endogenous peptide agonists for the
`guanylate cyclase C (GC-C) receptor. These peptides are secreted in the GI tract and
`up-regulate intracellular production of cGMP (cyclic guanosine 3’, 5’-monophosphate) in
`the intestinal epithelium. Elevated cGMP activates the cystic fibrosis transmembrane
`conductance regulator (CFTR), which leads to trans-epithelial efflux of chloride and
`bicarbonate from enterocytes lining the GI tract into the lumen of the gut, and secretion
`of water into the intestinal lumen. Increased secretion of water into the GI tract can
`loosen stools, stimulate bowel movements, and thus relieve constipation. The proposed
`indication for plecanatide is treatment of chronic idiopathic constipation.
`
`
`1.2 Brief Discussion of Nonclinical Findings
`
`Plecanatide is well tolerated in adult mice, rats, and monkeys at oral doses up to 3000-,
`2000-, and 2000-times the recommended human dose (3 mg), respectively, on a mg/kg
`basis for an assumed human weight of 60 kg. It should be noted that plecanatide and
`its active metabolite are not measurable in human plasma following administration of
`the recommended dose, whereas limited systemic exposure to plecanatide was
`achieved in the nonclinical studies. Therefore, the animal to human dose ratios listed
`above are not indicative of relative exposure. Neonatal/juvenile mice have been shown
`to be particularly sensitive to plecanatide toxicity. Lethality of plecanatide was found to
`be highly age-dependent; the minimum lethal doses in PND (postnatal day) 7 and PND
`14 mice were 0.5 and 10 mg/kg/day, respectively, as compared to the recommended
`human dose of 3 mg (0.05 mg/kg/day, based on a 60-kg bodyweight). There were no
`deaths at up to 300 mg/kg/day in juvenile mice administered plecanatide starting on
`PND 21. In the PND 7 and PND 14 mice, deaths occurred within the first or second day
`after dosing. Clinical signs included decreased motor activity and dehydration. No
`gross lesions were noted at necropsy. Treatment-related increases in the weight of
`intestinal contents were observed in juvenile mice following single oral doses of 1, 3,
`and 10 mg/kg/day plecanatide on PND 14, and to a lesser extent on PND 21. The
`increase in intestine weight after plecanatide administration appears to be consistent
`with the pharmacological action of plecanatide. The minimum lethal dose of 0.5
`mg/kg/day at PND 7 is 10 times the recommended human dose (0.05 mg/kg/day) based
`on a 60-kg bodyweight. It is noted that the levels of expression of the receptor for heat-
`stable enterotoxin (i.e. GC-C) in the small and large intestine of children is age
`dependent; a greater number of receptors are present in infants, and the number
`decreases with increasing age. Thus, the data from neonatal/juvenile mice may have
`clinical relevance in infants or young pediatric patients.
`
`
`
`Reference ID: 4000392
`
`4
`
`

`

`NDA 208,745 Reviewer: Yuk-Chow Ng, PhD
`
`
`1.3 Recommendations
`
`1.3.1 Approvability
`
`From a nonclinical standpoint, there are no approvability issues.
`
`
`1.3.2 Additional Non Clinical Recommendations
`
`Recommendations for labeling changes are shown in the following section.
`
`
`1.3.3 Labeling
`
`Established Pharmacologic Class (HIGHLIGHTS)
`
`The Sponsor’s proposed EPC (established pharmacologic class) text phrase in the
`Highlights of Prescribing Information is “guanylate cyclase-C agonist”. Plecanatide is an
`analog of the endogenous human uroguanylin peptide, and both are guanylate cyclase-
`C agonists. The mechanism of action of plecanatide is identical to that of the approved
`drug LINZESS (linaclotide), an analog of guanylin. The EPC for linaclotide is “guanylate
`cyclase-C agonist”. Therefore, the Sponsor’s proposed EPC text phrase “guanylate
`cyclase-C agonist” for plecanatide is deemed appropriate.
`
`The following subsections in the labeling should be revised as recommended.
`
`Sponsor’s Proposed Version:
`
`5.1
`
` 6 years of age. The safety and
`TRADENAME is contraindicated in
` patients
` 18 years of age have not
`effectiveness of TRADENAME in
` plecanatide
`been established. In young juvenile mice
`increased fluid-secretion into the intestines as a consequence of stimulation of
`guanylate cyclase-C (GC-C)
` mortality in some within the first 24 hours
`apparently due to dehydration
`
`
`
`
`
` years of age.
` patients 6
`Avoid the use of PLECANATIDE in
`, given the deaths in
`Although there were no deaths in older juvenile mice
`younger mice and the lack of clinical safety and efficacy data in pediatric patients, avoid
`the use of TRADENAME in
` patients 6
` years of age [see
`Contraindications (Error! Reference source not found.), Use in Specific Populations
`
`
`
`Evaluation: The following revised version was developed in collaboration with the
`Medical and Pediatric teams.
`
`Recommended Version:
`
`
`Reference ID: 4000392
`
`5
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`APPEARS THIS WAY ON ORIGINAL
`
`

`

`NDA 208,745 Reviewer: Yuk-Chow Ng, PhD
`
`
`5.1 Risk of Serious Dehydration in Pediatric Patients
`
`
`TRADENAME is contraindicated in patients less than 6 years of age. The safety and
`effectiveness of TRADENAME in patients less than 18 years of age have not been
`established. In young juvenile mice
` plecanatide increased fluid
`secretion into the intestines as a consequence of stimulation of guanylate cyclase-C
`(GC-C) resulting in mortality in some mice within the first 24 hours, apparently due to
`dehydration. Due to increased intestinal expression of GC-C, patients less than 6 years
`of age may be more likely than patients 6 years of age and older to develop significant
`diarrhea and its potentially serious consequences.
`
`Avoid the use of TRADENAME in patients 6 years to less than 18 years of age.
`Although there were no deaths in older juvenile mice
` given the
`deaths in younger mice and the lack of clinical safety and efficacy data in pediatric
`patients, avoid the use of TRADENAME in patients 6 years to less than 18 years of age
`[see Contraindications (Error! Reference source not found.), Warnings and
`Precautions (5.2), Use in Specific Populations (8.4)].
`
`
`Sponsor’s Proposed Version:
`
`8.1 Pregnancy
`
`Risk Summary
`
`Data
`
`Animal data
`
`
`
`Reference ID: 4000392
`
`6
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`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`APPEARS THIS WAY ON
`ORIGINAL
`
`

`

`NDA 208,745 Reviewer: Yuk-Chow Ng, PhD
`
`
`Limited systemic exposure to plecanatide was achieved in animals (area under the
` rabbits given 250
`time-concentration curve [AUCt] = 449 ng•h/mL
`mg/kg/day
` Plecanatide and its active metabolite
`are not measurable in human plasma following administration of the recommended
`clinical
` Therefore, animal and human doses should not be compared directly for
`exposure.
`
`
`Evaluation: The following revised version was developed in collaboration with the
`Maternal Health team (Christos Mastroyannis and Tamara Johnson).
`
`Recommended Version:
`
`8.1 Pregnancy
`
`
`Risk Summary
`
`Plecanatide is negligibly absorbed systemically following oral administration [see
`Clinical Pharmacology (12.3)], and is not expected to result in fetal exposure to the
`drug.
`
`The available data on TRADENAME use in pregnant women are not sufficient to inform
`any drug-associated risk for major birth defects and miscarriage. In animal
`developmental studies, no effects on embryo-fetal development were observed with oral
`administration of plecanatide in mice and rabbits during organogenesis at doses much
`higher than the maximum recommended human dosage.
`
`In the United States general population, the estimated background risk of major birth
`defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to
`20%, respectively.
`
`Data
`
`Animal Data
`
`Pregnant mice and rabbits were administered plecanatide during the period of
`organogenesis. There was no evidence of harm to embryo-fetal development at oral
`doses up to 800 mg/kg/day in mice and 250 mg/kg/day in rabbits. Oral administration of
`up to 600 mg/kg/day in mice during organogenesis through lactation produced no
`developmental abnormalities or effects on growth, learning and memory, or fertility in
`the offspring through maturation.
`
`Reference ID: 4000392
`
`7
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`

`

`NDA 208,745 Reviewer: Yuk-Chow Ng, PhD
`
`
`The maximum recommended human dose is approximately 0.05 mg/kg/day, based on a
`60-kg body weight. Limited systemic exposure to plecanatide was achieved in animals
`([AUCt] = 449 ng•h/mL in rabbits given 250 mg/kg/day during organogenesis).
`Plecanatide and its active metabolite are not measurable in human plasma following
`administration of the recommended clinical dosages. Therefore, animal and human
`doses should not be compared directly for evaluating relative exposure.
`
`
`Sponsor’s Proposed Version:
`
`8.4 Pediatric Use
`
`
`
`TRADENAME is contraindicated in pediatric patients
`
` 6 years of age.
`
`
`Evaluation: The following revised version was developed in collaboration with the
`Pediatric and Labeling Development teams.
`
`Recommended Version:
`
`8.4 Pediatric Use
`
`TRADENAME is contraindicated in patients less than 6 years of age. Avoid use of
`TRADENAME in patients 6 years to less than 18 years of age [see Contraindications
`(4), Warnings and Precautions (5.1)]. The safety and effectiveness of TRADENAME in
`patients less than 18 years of age have not been established.
`
`In nonclinical studies, deaths occurred within 24 hours in young juvenile mice (human
`age equivalent of approximately 1 month to less than 2 years) following administration
`of one or two once daily oral doses of plecanatide, as described below in Juvenile
`Animal Toxicity Data. Because of increased intestinal expression of GC-C, patients less
`than 6 years of age may be more likely than patients 6 years of age and older to
`develop diarrhea and its potentially serious consequences. TRADENAME is
`contraindicated in patients less than 6 years of age.
`
`
`
`
` Given the deaths in young juvenile
`mice and the lack of clinical safety and efficacy data in pediatric patients, avoid the use
`of TRADENAME in patients 6 years to less than 18 years of age.
`
`Juvenile Animal Toxicity Data
`
`Single oral doses of plecanatide at 0.5 mg/kg and 10 mg/kg caused mortality in young
`juvenile mice on postnatal days
` 7 and 14, respectively (human age equivalent
`of approximately 1 month to less than 2 years). Treatment-related increases in the
`weight of intestinal contents were observed in juvenile mice following single doses of
`
`plecanatide on
` 14 (human age equivalent of approximately less than 2 years),
` consistent
`
`
`with increased fluid in the intestinal lumen.
`
` The
`
`
`
`
`
`Reference ID: 4000392
`
`8
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`

`

`NDA 208,745 Reviewer: Yuk-Chow Ng, PhD
`
`
`recommended human dose is approximately 0.05 mg/kg/day, based on a 60-kg body
`weight. Plecanatide and its active metabolite are not measurable in human plasma
` whereas systemic
`, animal
`absorption was demonstrated in the juvenile animal toxicity studies.
`and human doses should not be compared directly for evaluating relative exposure.
`
`
`Sponsor’s Proposed Version:
`
`12.1 Mechanism of Action
`
` Both plecanatide
`and its active metabolite bind to GC-C and act locally on the luminal surface of the
`intestinal epithelium. Activation of GC-C results in an increase in both intracellular and
`extracellular concentrations of cyclic guanosine monophosphate (cGMP). Elevation of
`intracellular cGMP stimulates secretion of chloride and bicarbonate into the intestinal
`lumen, mainly through activation of the cystic fibrosis transmembrane conductance
`regulator ion channel (CFTR), resulting in increased intestinal fluid and accelerated
`transit. In animal models, plecanatide has been shown to increase fluid secretion into
`the gastrointestinal (GI) tract, accelerate intestinal transit, and cause changes in stool
`consistency.
`
`
`
`
`
`Evaluation: The following revised version is recommended.
`
`Recommended Version:
`
`Plecanatide is a guanylate cyclase-C (GC-C) agonist. Both plecanatide and its active
`metabolite bind to GC-C and act locally on the luminal surface of the intestinal
`epithelium. Activation of GC-C results in an increase in both intracellular and
`extracellular concentrations of cyclic guanosine monophosphate (cGMP). Elevation of
`intracellular cGMP stimulates secretion of chloride and bicarbonate into the intestinal
`lumen, mainly through activation of the cystic fibrosis transmembrane conductance
`regulator (CFTR) ion channel, resulting in increased intestinal fluid and accelerated
`transit. In animal models, plecanatide has been shown to increase fluid secretion into
`the gastrointestinal (GI) tract, accelerate intestinal transit, and cause changes in stool
`consistency.
`
`
`
`
`
`Sponsor’s Proposed Version:
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`Carcinogenesis
`
`The carcinogenic potential of plecanatide was assessed in a 2-year carcinogenicity
`study in mice and
` rats.
`
`
`Reference ID: 4000392
`
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`

`NDA 208,745 Reviewer: Yuk-Chow Ng, PhD
`
`
`Mutagenesis
`
`Plecanatide was not genotoxic in
` in vitro mouse lymphoma
`
`
`
`
`Impairment of Fertility
`
` in vitro bacterial reverse mutation (Ames) assay
` assay
` in vivo mouse bone marrow micronucleus
`
`
`
`
`effect on fertility
`
` Plecanatide had no
` or reproductive function at oral doses of up to 600
`
`Evaluation: The following revised version is recommended.
`
`Recommended Version:
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`Carcinogenesis
`
`The carcinogenic potential of plecanatide was assessed in 2-year carcinogenicity
`studies in mice and rats. Plecanatide was not tumorigenic in mice at oral doses up to
`90 mg/kg/day or in rats at oral does up to 100 mg/kg/day. Limited systemic exposure to
`plecanatide was achieved at the tested dose levels in animals, whereas no detectable
`exposure occurred in humans. Therefore, animal and human doses should not be
`compared directly for evaluating relative exposure.
`
`
`
`Mutagenesis
`
`Plecanatide was not genotoxic in the in vitro bacterial reverse mutation (Ames) assay, in
`vitro mouse lymphoma mutation assay or the in vivo mouse bone marrow micronucleus
`assay.
`
`
`
`Impairment of Fertility
`
`Plecanatide had no effect on fertility or reproductive function in male and female mice at
`oral doses of up to 600 mg/kg/day.
`
`Reference ID: 4000392
`
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`

`NDA 208,745 Reviewer: Yuk-Chow Ng, PhD
`
`
`
`Sponsor’s Proposed Version:
`
`
`
`Evaluation: This subsection should be removed.
`
`
` 2
`
` Drug Information
`
`2.1 Drug
`
`CAS Registry Number – 467426-54-6
`
`Generic Name - Plecanatide
`
`Code Name – SP-304
`
`
`Reference ID: 4000392
`
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`

`NDA 208,745 Reviewer: Yuk-Chow Ng, PhD
`
`
`Chemical Name -
`
`
`Molecular Formula/Molecular Weight: C65H104N18O26S4 /1682
`
`Structure or Biochemical Description
`
`
`
`Pharmacologic Class – guanylate cyclase-C agonist
`
`
`2.2 Relevant INDs, NDAs, BLAs and DMFs
`
`
`
`
`
`IND 74,883 (Plecanatide for the treatment of chronic idiopathic constipation) Synergy
`Pharmaceuticals Inc., New York
`
`
`2.3 Drug Formulation
`
`Plecanatide tablets are an immediate release solid oral dosage form provided as a 3 mg
` dosage strength. The components and composition of plecanatide tablets, 3
`, are shown in the table below, taken from the Sponsor’s submission.
`
`
`
`
`
`
`
`2.4 Comments on Novel Excipients
`
`There are no novel excipients used in the manufacture of plecanatide tablets. The
`excipients to be used in the plecanatide formulation appear to be safe. The FDA
`Inactive Ingredients Database confirms that all the excipients listed in the table above
`are present in approved oral formulations at levels (e.g., mg/tablet) that exceed the
`maximum daily dose (mg) in plecanatide tablets, based on the proposed maximum dose
`of
` plecanatide (
`
`
`
`Reference ID: 4000392
`
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`NDA 208,745 Reviewer: Yuk-Chow Ng, PhD
`
`
`2.5 Comments on Impurities/Degradants of Concern
`
`In a pre-NDA meeting held on October 30, 2014, the CMC and nonclinical teams
`agreed that the reporting, identification, and qualification thresholds for potential
`impurities should be
`%, respectively, as proposed by the
`Sponsor. The Sponsor has reported and identified five drug product impurities, namely
`
`
`
` Based on a drug substance stress study,
`these 5 impurities were also identified as degradation products. All other drug product
`impurities are below the reporting threshold of %.
`
`
`The specifications for
`
`threshold. The specifications for
`%, respectively. These limits exceed the qualification threshold,
`therefore the safety of
` were evaluated.
`
`
` and are therefore compliant with the qualification
` are
`
` by
`The Sponsor qualified the
`demonstrating the presence of substantial levels of these two impurities in the drug
`substance lots
` The table below
`taken from the Sponsor’s submission shows the safety factors of these two impurities
`based on body surface area.
`
`
`
`
`Reference ID: 4000392
`
`13
`
`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`
`
`
`
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`
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`
`
`
`
`
`
`
`
`
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`(b) (4)
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`
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`(b) (4)
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`(b) (4)
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`(b) (4)
`
`

`

`NDA 208,745 Reviewer: Yuk-Chow Ng, PhD
`
`
`
`
`
`The safety factors shown in the Sponsor’s table were calculated based on NOAEL and
`body surface area. However, similar to the parent compound plecanatide,
`
` are likely to have very little systemic exposure.
`Therefore, a dose multiple calculated on a mg/kg basis will be more appropriate. Based
`on a mg/kg comparison, the safety factors would have been greater than those shown
`in the above table.
`
`In addition, considerations were given to address whether
` could be a mutagenic impurity, which would have a
`lower acceptable daily intake. It is noted that
` itself tested negative in the
`Ames assay (European Chemicals Agency registration-dossier), and therefore,
` appears unlikely to be a mutagenic impurity.
`
`
`
`
`
`Taken together, the impurities known as
` are considered qualified at the proposed limits in the drug product.
`
`
`
`2.6 Proposed Clinical Population and Dosing Regimen
`
`Patients with chronic idiopathic constipation: 3
`
`
` orally once daily.
`
`Reference ID: 4000392
`
`14
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
`
`

`

`
`
`NDA 208,745 Reviewer: Yuk-Chow Ng, PhD
`
`
`2.7 Regulatory Background
`
`IND 74,883 was submitted by Synergy Pharmaceuticals Inc. on 4/2/2008 for SP-304
`(plecanatide) for the treatment of chronic constipation.
`
`Studies Submitted
`
` 3
`
`
`
`3.1 Studies Reviewed
`
`THE FOLLOWING PHARMACOLOGY STUDIES WERE REVIEWED (starting on
`page 22)
`
`
`Reference ID: 4000392
`
`15
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`(b) (4)
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`

`NDA 208,745 Reviewer: Yuk-Chow Ng, PhD
`
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`Reference ID: 4000392
`
`16
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`(b) (4)
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`(b) (4)
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`(b) (4)
`
`

`

`NDA 208,745 Reviewer: Yuk-Chow Ng, PhD
`
`
`THE FOLLOWING PHARMACOKINETIC STUDIES WERE REVIEWED (starting on
`page 43)
`
`
`
`
`Reference ID: 4000392
`
`17
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
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`(b) (4)
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`

`

`NDA 208,745 Reviewer: Yuk-Chow Ng, PhD
`
`
`
`
`Reference ID: 4000392
`
`18
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`(b) (4)
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`(b) (4)
`
`

`

`NDA 208,745 Reviewer: Yuk-Chow Ng, PhD
`
`
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`
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`
`
`Reference ID: 4000392
`
`19
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
`
`

`

`NDA 208,745 Reviewer: Yuk-Chow Ng, PhD
`
`
`THE FOLLOWING TOXICOLOGY STUDIES WERE REVIEWED (starting on page 60)
`
`
`
`
`
`
`Reference ID: 4000392
`
`20
`
`(b) (4)
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`(b) (4)
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`

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`NDA 208,745 Reviewer: Yuk-Chow Ng, PhD
`
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`
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`Reference ID: 4000392
`
`21
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`(b) (4)
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`(b) (4)
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`

`

`NDA 208,745 Reviewer: Yuk-Chow Ng, PhD
`
`
`
`
`3.2 Studies Not Reviewed
`
`None
`
`
`3.3 Previous Reviews Referenced
`
`
`
`Pharmacology/Toxicology Reviews of IND 74,883 by David B. Joseph, PhD dated
`7/2/2008, and by Yuk-Chow Ng, PhD dated 2/2/2010, 5/27/2010, 7/25/2013, 8/2/2013,
`and 6/11/2014 are referenced.
`
`Pharmacology
`
` 4
`
`
`
`4.1 Primary Pharmacology
`
`
`SP-304 (Plecanatide): Stimulation of Intracellular cGMP Synthesis in T84 Cells (Study No. SP-PH-
`001)
`
`Materials and Methods
`The ability of plecanatide to stimulate cGMP production
`was studied in T84 human colon carcinoma cells in vitro.
`Plecanatide (N-terminal amino acid sequence NDE),
`uroguanylin (UG, NDD), and 2 related peptides, SP-302
`(NEE) and SP-303 (NED), were tested at concentrations
`ranging from 10-9 M to 10-5 M. Cell lysates derived from
`cells exposed for 30 minutes to the peptides were
`assayed for cGMP levels using a commercial enzyme-
`linked immunosorbent assay (ELISA).
`
`Results and Conclusion
`All 4 peptides increased cGMP production in
`a concentration-dependent manner. At a
`concentration of 10-6 M, cGMP levels were
`54% higher in plecanatide-treated cells
`compared with UG-treated cells.
`Plecanatide stimulated cGMP production in
`T84 colon carcinoma cells with a half-
`maximal effective concentration (EC50) of 1.1
`x 10-7 M. Plecanatide was 2 to 3 fold
`more potent than UG and the other related
`test peptides in this bioassay, and induced
`
`Reference ID: 4000392
`
`22
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`

`

`NDA 208,745 Reviewer: Yuk-Chow Ng, PhD
`
`
`
`Studies on SP-304 (Plecanatide) Thermostability, pH Dependency, and Topoisomeric Stability
`(Study No. SP-PH-004)
`
`higher cGMP levels (>50% greater)
`compared with the other peptides.
`
`Materials and Methods
`Thermostability of plecanatide was examined after it was
`incubated at 95°C for up to 90 minutes, and the ability of
`plecanatide to stimulate cGMP synthesis was measured
`after 30-minute incubations with T84 cells at different pH.
`The conformational makeup (topoisomeric composition) of
`plecanatide and UG was analyzed by high-performance
`liquid chromatography (HPLC) following a 16-hour
`incubation at pH 3.0 and 37°C.
`
`
`
`
`
`Results and Conclusion
`Plecanatide retained 100% activity after 90
`minutes at 95°C, as assessed by the cGMP
`T84 cell assay. In contrast, UG lost about
`15% of its activity after 90 minutes. The
`ability of plecanatide to stimulate cGMP
`synthesis in cells incubated at pH ranging
`from 6.0 to 6.5 was greater than that of UG
`and 2 related peptides, SP-302 and SP-303,
`used in the study. Maximum plecanatide
`activity was observed at pH 6.0.
`
`After a 16-hour incubation at 37°C and pH
`3.0, UG showed 2 major peaks and 2 minor
`peaks. This result is consistent with the
`interconversion of UG between 2 solution
`conformers, one biologically active and the
`other biologically inactive. In contrast,
`plecanatide showed only
`a single peak. The preparation of
`plecanatide used for the study was found to
`be fully active using the cGMP T84 cell
`assay, indicating that the single peak shown
`in the HPLC represents the fully active
`conformer of plecanatide.
`
`
`Stimulation of Intracellular cGMP Synthesis in T84 Cells: SP-304 (Plecanatide) & SP-338, A
`Comparative Study (Study No. SP-PH-008)
`
`Materials and Methods
`The efficacy of plecanatide and its metabolite SP-338 was
`compared in a cGMP production assay in T84 human
`colo