`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`208745Orig1s000
`
`PHARMACOLOGY REVIEW(S)
`
`
`
`
`
`
`MYLAN EXHIBIT - 1069 (Part 1)
`Mylan Pharmaceuticals, Inc. v. Bausch Health Ireland, Ltd.
`IPR2022-00722
`
`
`
`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
`
`208,745
`1
`1/29/2016
`1/29/2016
`Trulance (plecanatide) tablets
`Chronic idiopathic constipation
`Synergy Pharmaceuticals, Inc
`Gastroenterology and Inborn Errors Products
`Yuk-Chow Ng, PhD
`David B. Joseph, PhD
`Donna Griebel, MD
`Maureen D. Dewey
`
`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:
`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
`
` 1
`
` EXECUTIVE SUMMARY ......................................................................................... 4
`1.1
`INTRODUCTION .................................................................................................... 4
`1.2 BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 4
`1.3 RECOMMENDATIONS ............................................................................................ 5
`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
`STUDIES REVIEWED ........................................................................................... 15
`3.2
`STUDIES NOT REVIEWED ................................................................................... 22
`3.3
`PREVIOUS REVIEWS REFERENCED...................................................................... 22
`4 PHARMACOLOGY ................................................................................................ 22
`4.1
`PRIMARY PHARMACOLOGY ................................................................................ 22
`4.2
`SECONDARY PHARMACOLOGY ........................................................................... 37
`4.3
`SAFETY PHARMACOLOGY .................................................................................. 38
`5 PHARMACOKINETICS/ADME/TOXICOKINETICS .............................................. 43
`5.1
`PK/ADME ....................................................................................................... 43
`5.2
`TOXICOKINETICS ............................................................................................... 60
`6 GENERAL TOXICOLOGY ..................................................................................... 60
`6.1
`SINGLE-DOSE TOXICITY ..................................................................................... 60
`6.2 REPEAT-DOSE TOXICITY .................................................................................... 71
`7 GENETIC TOXICOLOGY .................................................................................... 157
`7.1
`IN VITRO REVERSE MUTATION ASSAY IN BACTERIAL CELLS (AMES) ................... 157
`7.2
`IN VITRO ASSAYS IN MAMMALIAN CELLS ........................................................... 161
`7.3
`IN VIVO CLASTOGENICITY ASSAY IN RODENT (MICRONUCLEUS ASSAY)............... 167
`7.4 OTHER GENETIC TOXICITY STUDIES .................................................................. 172
`8 CARCINOGENICITY ........................................................................................... 172
`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY .............................. 220
`9.1
`FERTILITY AND EARLY EMBRYONIC DEVELOPMENT ............................................ 220
`9.2
`EMBRYONIC FETAL DEVELOPMENT ................................................................... 234
`9.3
`PRENATAL AND POSTNATAL DEVELOPMENT ...................................................... 255
`
`Reference ID: 4000392
`
`2
`
`
`
`NDA 208,745 Reviewer: Yuk-Chow Ng, PhD
`
`10
`11
`12
`
`
`
`SPECIAL TOXICOLOGY STUDIES ................................................................. 308
`INTEGRATED SUMMARY AND SAFETY EVALUATION ............................... 308
`APPENDIX/ATTACHMENTS ........................................................................... 316
`
`Reference ID: 4000392
`
`3
`
`
`
`NDA 208,745 Reviewer: Yuk-Chow Ng, PhD
`
`Executive Summary
`1
`Introduction
`1.1
`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
`
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`
`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:
`
`(b) (4)
`5.1
`
` 6 years of age. The safety and
`TRADENAME is contraindicated in
`(b) (4)
` patients
` 18 years of age have not
`effectiveness of TRADENAME in
`(b) (4)
`(b) (4)
` plecanatide
`been established. In young juvenile mice
`(b) (4)
`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
`(b) (4)
`apparently due to dehydration
`(b) (4)
`
`
` years of age.
` patients 6
`Avoid the use of PLECANATIDE in
`(b) (4)
`(b) (4)
`, given the deaths in
`Although there were no deaths in older juvenile mice
`(b) (4)
`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
`(b) (4)
`(b) (4)
`Contraindications (Error! Reference source not found.), Use in Specific Populations
`
`(b) (4)
`APPEARS THIS WAY ON ORIGINAL
`
`
`
`
`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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`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
`(b) (4)
`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
`(b) (4)
`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
`APPEARS THIS WAY ON
`Precautions (5.2), Use in Specific Populations (8.4)].
`ORIGINAL
`
`Sponsor’s Proposed Version:
`
`8.1 Pregnancy
`Risk Summary
`
`(b) (4)
`
`Data
`Animal data
`
`(b) (4)
`
`
`
`Reference ID: 4000392
`
`6
`
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`
`NDA 208,745 Reviewer: Yuk-Chow Ng, PhD
`
`
`(b) (4)
`
`Limited systemic exposure to plecanatide was achieved in animals (area under the
` rabbits given 250
`time-concentration curve [AUCt] = 449 ng•h/mL
`(b) (4)
`mg/kg/day
` Plecanatide and its active metabolite
`(b) (4)
`are not measurable in human plasma following administration of the recommended
`clinical
` Therefore, animal and human doses should not be compared directly for
`(b) (4)
`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
`
`
`(b) (4)
` 6 years of age.
`
`(b) (4)
`
`TRADENAME is contraindicated in pediatric patients
`
`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.
`
`(b) (4)
`
`
`
`
` 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
`(b) (4)
`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
`
` 14 (human age equivalent of approximately less than 2 years),
`plecanatide on
`(b) (4)
`(b) (4)
`=
` consistent
`
`(b) (4)
`
`
`with increased fluid in the intestinal lumen.
`
` The
`
`(b) (4)
`
`
`
`Reference ID: 4000392
`
`8
`
`
`
`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
`(b) (4)
`, animal
`absorption was demonstrated in the juvenile animal toxicity studies.
`(b) (4)
`and human doses should not be compared directly for evaluating relative exposure.
`
`Sponsor’s Proposed Version:
`12.1 Mechanism of Action
`
`(b) (4)
` 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.
`
`(b) (4)
`
`
`
`(b) (4)
`
`
`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.
`
`(b) (4)
`
`
`
`
`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.
`
`(b) (4)
`(b) (4)
`
`Reference ID: 4000392
`
`9
`
`
`
`NDA 208,745 Reviewer: Yuk-Chow Ng, PhD
`
`
`(b) (4)
`
`Mutagenesis
`Plecanatide was not genotoxic in
` in vitro mouse lymphoma
`(b) (4)
`
`(b) (4)
`
`
`
`
`Impairment of Fertility
`
`(b) (4)
`
`
` in vitro bacterial reverse mutation (Ames) assay
`(b)
`(4)
`
` assay
`(b) (4)
`(b) (4)
` in vivo mouse bone marrow micronucleus
`
`(b) (4)
`
`(b) (4)
`
`effect on fertility
`
`(b) (4)
` Plecanatide had no
` or reproductive function at oral doses of up to 600
`(b) (4)
`
`(b) (4)
`
`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
`
`10
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`
`NDA 208,745 Reviewer: Yuk-Chow Ng, PhD
`
`
`Sponsor’s Proposed Version:
`
`
`(b) (4)
`
`
`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
`
`11
`
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`
`NDA 208,745 Reviewer: Yuk-Chow Ng, PhD
`
`Chemical Name -
`L-Leucine, L-asparaginyl-L-a-aspartyl-L-a-glutamyl-L-cysteinyl-L-a-glutamyl-L-leucyl-L-
`cysteinyl-L-yalyl-L-asparaginyl-L-yalyl-L-alanyl-L-cysteinyl-L-threonylglycyl-L-cysteinyl-,
`cyclic (4—>12),(7—>15)-bis(disulfide)
`
`Molecular Formula/Molecular Weight: C65H104N18O26S4 /1682
`
`Structure or Biochemical Description
`
`
`
`
`S S
`
`H-Asni-Asp2-G1u3-Cys4-Glu5-Leu6-Cys7-Va18-Asn9-Vall°-Alall-Cyl siz_Thri3_Giyitcysis_Leuio_oH
`I
`
`S
`S
`
`
`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
`(b) (4)
`, are shown in the table below, taken from the Sponsor’s submission.
`(b) (4)
`
`
`
`Component
`
`Plecanatidea
`
`Microcrystalline cellulose
`
`Magnesium stearate
`(b) (4)
`
`Total (mg)
`
`Quality Standard
`
`Function
`
`In-house standard
`
`Dru substance
`(b) (4)
`
`USP-NF
`
`USP-NF
`
`USP-NF
`
`Dosage Strength (mg/tablet)
`(b) (4)
`
`3
`
`3.0
`
`(b) (4)
`
`
`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 (
`
`(b) (4)
`(b) (4)
`
`
`
`
`Reference ID: 4000392
`
`12
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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
`(b) (4)
`Sponsor. The Sponsor has reported and identified five drug product impurities, namely
`(b) (4)
`
`
`(b) (4)
`(b) (4)
` 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 %.
`(b) (4)
`•
`
`
`The specifications for
`
`(b) (4)
`
`(b) (4)
` and are therefore compliant with the qualification
` are
`threshold. The specifications for
`(b) (4)
`(b) (4)
`%, respectively. These limits exceed the qualification threshold,
`therefore the safety of
` were evaluated.
`(b) (4)
`
`(b) (4)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` by
`The Sponsor qualified the
`(b) (4)
`demonstrating the presence of substantial levels of these two impurities in the drug
`substance lots
` The table below
`(b) (4)
`taken from the Sponsor’s submission shows the safety factors of these two impurities
`based on body surface area.
`
`
`
`
`Reference ID: 4000392
`
`13
`
`
`
`NDA 208,745 Reviewer: Yuk-Chow Ng, PhD
`
`
`Table 45:
`
`Drug Product Impurity Specifications and Qualification Assessment
`
`Specified
`Impurity
`
`Specification
`
`Maximum Total
`Daily Exposure
`for 6 mg Tablet
`(b) (4)
`_
`I
`_
`
`Specification
`above
`Qualification
`Threshold
`
`Qualification
`Lever / DS Lot
`No.
`
`Study Description/
`Study No. / Duration of
`Use
`
`Safety Factor
`(6 mg tablet)
`
`No
`
`No
`
`Yes
`
`Yes
`
`NA
`
`NA
`
`(b) (4)
`
`NA
`
`NA
`
`(b) (4)
`
`NA
`
`NA
`
`26-week mouse /
`1896-008 / Weeks 1-23
`13-week rat /
`1896-013 / Weeks 1-5
`13-week rat /
`1896-013 /Weeks 6-13
`39-week monkey /
`1896-009 / Weeks 1-24
`39-week monkey
`1896-009 / Weeks 25-39
`26-week mouse /
`1896-008 / Weeks 1-23
`13-week rat /
`1896-013 / Weeks 1-5
`13-week rat /
`1896-013 /Weeks 6-13
`39-week monkey /
`1896-009 / Weeks 25-39
`
`No
`
`NA
`
`NA
`
`NA
`
`DS = drug substance; NA = not applicable; NOAEL = no observed adverse effect level
`a Qualification levels were calculated according to the following method: [(% area specified impurity / 100)*NOAEL dose (mg/kg/day)] / body surface area
`conversion factor (12.3 mouse, 6.2 rat or 3.1 monkey) * 60 kg human body weight.
`b Safety margin = qualification level / maximum total daily exposure of impurity.
`
`
`
`
`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,
`
`(b) (4)
` 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
`(b) (4)
`lower acceptable daily intake. It is noted that
` itself tested negative in the
`(b) (4)
`Ames assay (European Chemicals Agency registration-dossier), and therefore,
` appears unlikely to be a mutagenic impurity.
`(b) (4)
`
`(b) (4)
`
`
`
`
`
`Taken together, the impurities known as
`(b) (4)
` 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.
`(b) (4)
`
`
`Reference ID: 4000392
`
`14
`
`
`
`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
`
`3.1 Studies Reviewed
`THE FOLLOWING PHARMACOLOGY STUDIES WERE REVIEWED (starting on
`page 22)
`
`
`Overview
`
`Type of Study
`
`Test System
`
`Method of
`Administration
`
`Test Articles: Plecanatide (SP-304); SP-338
`(metabolite)
`
`Testing Facility
`
`Study Number
`
` 3
`
`Primary Pharmacodynamics
`
`SP-304: Stimulation of Intracellular cGMP Synthesis in
`T84 Cells
`
`Human Colon
`Carcinoma T84 Cells
`
`Studies on SP-304 Thermostability, pH Dependency
`and Topoisomeric Stability
`
`Human Colon
`Carcinoma T84 Cells
`
`Stimulation of Intracellular cGMP Synthesis in T84
`Cells: SP-304 & SP-338, a Comparative Study
`
`Human Colon
`Carcinoma T84 Cells
`
`Biological Activity of Potential Plecanatide Metabolites Human Colon
`Carcinoma T84 Cells
`
`SP-304: Binding Affinity to the Guanylate Cyclase C
`Receptor
`
`Human Colon
`Carcinoma T84 Cells
`
`In Vitro
`
`In VAro
`
`Synergy Pharma
`
`SP-PH-001
`
`In VAro
`
`Synergy Pharma
`
`SP-PH-004
`
`In Vitro
`
`Synergy Pharma
`
`SP-PH-008
`
`In Vitro
`
`Synergy Pharma
`
`SP-PH-011
`
`(b) (4)
`
`SP-PH-003
`
`SP-304:Synergistic Effects with Phosphodiesterase
`Inhibitors on cGMP Stimulation and Caspase-3 Activity
`in T84 Human Colon Carcinoma Cells
`
`Human Colon
`Carcinoma T84 Cells
`
`In VAT')
`
`Synergy Pharma
`
`SP-PH-002
`
`Effect of pH on Plecanatide and Uroguanylin Mediated
`Activation of Guanylate Cyclase-C
`
`Human Colon
`Carcinoma T84 Cells
`Mice Proximal
`Intestine and Colon
`Epithelial Cells and
`Tissues
`
`In Vitro
`
`Synergy Pharma
`
`SP-PH-020
`
`In Vitro / Ex Vivo
`
`
`
`Reference ID: 4000392
`
`15
`
`
`
`NDA 208,745 Reviewer: Yuk-Chow Ng, PhD
`
`
`Overview
`
`Type of Study
`
`Test System
`
`Evaluation of the Bioactivity of Peptides that Target
`Receptor Guanylyl Cyclase C
`
`Influence of Plecanatide (SP-304) and Its Biological
`Active Metabolite SP-338 on Intestinal Transit and
`Fluid Secretion in Ligated Duodenal Loops of Rats.
`
`Human Colon
`Carcinoma T84 Cells;
`HEK Cell Membranes;
`Wistar Rat Ileal Loop
`in Situ
`
`Female CD Rats
`
`Influence of Plecanatide (SP-304) on Inflammation
`(TNBS) and Stress-induced Colorectal Hypersensitivity
`in Rats
`
`TNBS-treated and
`Partially Restrained
`Male Wistar Rats
`
`Test Articles: Plecanatide (SP-304); SP-338
`(metabolite)
`
`Testing Facility
`
`Study Number
`
`(b) (4)
`
`SP-PH-010
`
`Synergy Phanna,
`MB Research
`Laboratories
`Spinnerstown, PA
`
`SP-PH-016
`
`(b) (4)
`
`SP-PH-019
`
`Method of
`Administration
`
`In Vitro
`
`Injection into
`Loop
`
`Oral gavage
`(intestinal transit)
`Injection into
`Duodenal Loop In
`Situ (fluid
`secretion)
`
`Oral gavage
`
`Assessment of SP-304 in DSS and TNBS Murine IBD
`Models
`
`TNBS and DSS-treated
`BDF1 and BALB/c
`Male Mice
`
`Oral gavage
`
`Efficacy Analysis of SP-304 in a TNBS IBD Mouse
`Model
`
`TNBS-treated BDF1
`Male Mice
`
`Oral gavage
`
`06-119
`
`06-169
`
`Anti-inflammatory Activity of SP-304 in an Animal
`Model of Experimental Colitis in BALB/c Mice
`
`Secondary Pharmacodynamics
`
`Female BALB/c Mice Oral gavage
`
`SP-PH-005
`
`Effect of Plecanatide on Off-target Receptor and
`CYP450 Binding in Vitro
`
`Ion Channel, Receptor
`and CYP Panel
`
`In Vitro
`
`AB20754
`
`Overview
`
`Type of Study
`
`Test System
`
`Effect of Plecanatide on Serotonin (5-HT) Receptor
`Binding and Phannacody