CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`208745Orig1s000
`
`SUMMARY REVIEW
`
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`
`
`
`
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`

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`Division Director Summary Review for Regulatory Action
`
`Date
`
`electronic stam
`
`Donna Griebel, MD
`From
`
`Subject
`Division Director Summary Review
`NDA#
`208745
`
`S er 3 Pharmaceuticals, Inc.
`A .licant
`
`Date of Submission
`1/29/2016
`
`PDUFA Goal Date
`
`1/29/2017
`
`Trulance/plecanatide
`Proprietary Name /
`
`Non-Proprietary Name
`Dosa e Form 5 / Stren th s
`
`Tablet; 3 m
`
`Applicant Proposed
`Indicafion@/Populafion@
`Recommended Action:
`
`Approved/Recommended
`Indication/Population(s) (if
`a t .licable
`
`Treatment of chronic idiopathic constipation
`
`A roval
`
`Treatment of chronic idiopathic constipation
`
`
`
`
`
`Material Reviewed/Consulted
`
`0ND Action Package, including:
`Names of discipline reviewers
`Medical Officer Review
`Lesley Hanes, MD/Lauiie Muldowney, MD
`Statistical Review
`Shahla Farr, MS/ Yeh-Fong Chen, PhD
`
`Pharmacology Toxicology Review
`Yuk-Chow Ng, PhD/David Joseph, PhD
`DB-VI Carcinogenicity Study
`Hepei Chen/Karl Lin, PhD
`Review
`
`0P9 Review
`COA
`Clinical Pharmacology Review
`
`DPMH
`
`See table below
`Sarrit Kovacs, PhD/Elektra Papadopoulos, MD, MPH
`Dilara Jappar, PhD/ Sue Chih Lee, PhD/ Hae Young
`Ahn, PhD
`
`Christos Mastroyannis, MD/Tamar Johnson,
`MD/Carolyn Yancey, MD/Mona Khurana, MD/Lynne
`Yao, MD
`
`OPDP
`Adewale Adeleye, PharmD, 1\/IBA
`
`CDTL Review
`Joette Meyer, PharmD
`OMPT/DMPP
`Karen Dowdy/Marcia Britt Williams
`OSE/DMEPA
`Matt Barlow, PharmD/
`Sherly Abraham, RPh/Mishale Mistry, PharmD, MPH
`Jacqueline Sheppard, PharmD/Robert Pratt,
`PharmD/Jamie Wilkins Parker, PharmD
`
`OSE/DRISK
`
`OSI
`
`ONMflice ofNew Drugs
`OPQ=0flice ofPharmaceutical Quality
`
`Susan Leibenhaut, MD/Susan Thompson, MD/Kassa
`Ayalew, MD, MPH
`
`CDER Division Director Summary Review Template 2015 Edition
`Version date: July 29. 2015. For initial rollout (NMEforiginal BLA reviews)
`
`Reference ID: 4044239
`
`
`
`1
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`

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`OPDP=Office of Prescription Drug Promotion
`OSI=Office of Scientific Investigations
`CDTL=Cross-Discipline Team Leader
`COA= Clinical Outcome Assessment Team
`OMPT=Office of Medical Policy Initiatives
`OSE= Office of Surveillance and Epidemiology
`OSI=Office of Scientific Investigations
`DB-VI=Division of Biometrics - VI
`DMPP=Division of Medical Policy Programs
`DMEPA=Division of Medication Error Prevention and Analysis
`DPMH=Division of Pediatric and Maternal Health
`DRISK=Division of Risk Management
`
`DISCIPLINE
`Drug Substance
`
`Drug Product
`
`Process
`Microbiology
`Facility
`Biopharmaceutics
`Regulatory Business
`Process Manager
`Application Technical Lead
`
`Laboratory (OTR)
`ORA Lead
`
`Environmental Analysis
`(EA)
`Immunogenicity
`
`Quality Review Team
`REVIEWER
`Martin Haber
`
`Zhengfang Ge
`
`Bo Jiang
`Bo Jiang
`Juandria Williams
`Kalpana Paudel
`Truong Quach
`
`Hitesh Shroff
`
`N/A
`Paul Perdue Jr.
`
`Raanan Bloom
`
`BRANCH/DIVISION
`CDER/OPQ/ONDP/
`DNDAPI/NDBII
`CDER/OPQ/ONDP/
`DNDPII/NDPBV
`CDER/OPQ/OPF/ DPAI/PABI
`CDER/OPQ/OPF/ DPAI/PABI
`CDER/OPQ/OPF/DIA/IABIII
`CDER/OPQ/ONDP/ DB/BBII
`CDER/OPQ/OPRO/DRBPMI/
`RBPMBI
`CDER/OPQ/ONDP/
`DNDPII/NDPBV
`N/A
`ORA/OO/OMPTO/
`DMPTPO/MDTP
`CDER/OPQ/ONDP
`
`Haoheng Yan, MD,
`PhD/Fred Mills PhD
`
`OPQ/OBP/DPRR IV
`
`CDER Division Director Summary Review Template 2015 Edition
`Version date: July 29, 2015. For initial rollout (NME/original BLA reviews)
`
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`Reference ID: 4044239
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`

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`1. Benefit-Risk Assessment
`
`I concur with the CDTL’s risk benefit assessment. The following Risk-Benefit Summary and
`Assessment table was presented in the CDTL review. I have reproduced it within my review,
`with some limited modifications, as I concur. My modifications are marked with double
`underlining. I have deleted a few sentences, which are not tracked.
`
`CDER Division Director Summary Review Template 2015 Edition
`Version date: July 29, 2015. For initial rollout (NME/original BLA reviews)
`
`3
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`Reference ID: 4044239
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`

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`Benefit-Risk Summary and Assessment
`The currently available treatment armamentarium does not completely meet the needs of patients with chronic idiopathic constipation (CIC).
`The available treatments are not effective in all patients and may have limited by tolerability; therefore, additional treatment options are
`needed.
`
`Plecanatide is a synthetic hexadecapeptide designed to mimic the action of uroguanylin, an endogenous peptide agonist for the guanylate
`cyclase C (GC-C) receptor, which is secreted in the GI tract and up-regulates 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.
`
`Plecanatide is the second in the GC-C agonist class of drugs. The first GC-C agonist was Linzess (linaclotide) which was approved on August
`30, 2012 for CIC.
`
`The efficacy and safety of plecanatide as a treatment for adults with CIC has been adequately assessed. The data from two adequate and well-
`controlled trials have demonstrated the efficacy of plecanatide over placebo, as measured by the proportion of patients with an increase in the
`number of complete spontaneous bowel movements (CSBMs) in at least 9 weeks out of the 12 weeks in the trial and at least 3 of the last 4
`weeks. Other measures of efficacy included an increase in the number of bowel movements per week and an improvement in stool
`consistency and straining compared to placebo. Although the treatment difference between plecanatide and placebo were modest
`(approximately 10%), this drug may offer an alternative option for patients with CIC.
`
`Plecanatide was shown to be safe and well-tolerated in adult patients with CIC. The most common adverse reaction was diarrhea. Severe
`diarrhea was reported and may lead to discontinuation, but can be managed by patient monitoring, withholding the medication and
`rehydration. In the clinical trials, severe diarrhea did not lead to serious outcomes. Additionally, plecanatide may increase hepatic enzymes.
`
`Due to structural similarity between plecanatide and the endogenous peptides uroguanylin and guanylin, there is a theoretical immunogenicity
`risk for deficiency if patients develop cross-reacting anti-plecanatide antibodies. No signals of deficiency-related adverse events (e.g.,
`hypertension, edema, pulmonary edema, hypernatremia, weight gain) were seen in the clinical trials database for plecanatide.
`
`Serious adverse reactions, related to diarrhea, increases in liver biochemical tests, and guanylin/uroguanylin deficiency should be monitored
`
`CDER Division Director Summary Review Template 2015 Edition
`Version date: July 29, 2015. For initial rollout (NME/original BLA reviews)
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`Reference ID: 4044239
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`using routine postmarketing surveillance.
`
`Plecanatide and its active metabolite are negligibly absorbed systemically following oral administration. There are no clinically relevant
`drug interactions.
`
`Use in pregnant women is not expected to result in fetal exposure; however, there is no information on the effects of maternal plecanatide
`exposure in the breastfed infant; therefore, the developmental and health benefits of breastfeeding should be considered along with the
`mother’s clinical need for plecanatide and the potential risk to the nursing infant.
`
`Pediatric patients have not been studied clinically. The nonclinical findings of death in young juvenile mice (human age equivalent of less than
`2 years of age) and risk of severe dehydration, preclude use of plecanatide in pediatric patients of all ages until more information is available.
`The sponsor will be required to conduct a postmarketing study in patients from birth to 6 years of age to assess the ontogeny of the GC-C
`receptor in the gastrointestinal tract to inform whether plecanatide can be safely dosed in pediatric patients 2 years to less than 6 years of age.
`There will be a partial waiver for clinical studies in pediatric patients less than 2 years of age because there is evidence indicating that
`plecanatide would be unsafe in this age group. The juvenile animal data demonstrating lethality, as well as literature regarding GC-C ontogeny,
`indicate plecanatide would not be safe in patients under 2 years of age. The applicant will be required to conduct postmarketing trials to assess
`the safety, pharmacokinetics and efficacy of plecanatide in pediatric patients 2 years to less than 18 years of age. These trials will begin in the
`oldest pediatric age group. Results will be assessed in order to assure safety before progressively lower age cohorts are studied. Until the
`results of the biopsy study, pharmacokinetic and clinical data in pediatric patients 6 years to less than 18 years of age are available,
`pharmacokinetic dose-ranging and confirmatory clinical studies in pediatric patients 2 years to less than 6 years of age are deferred. A lactation
`study is also required to assess the presence of plecanatide in breast milk to determine the safety of plecanatide for breast-fed infants whose
`mothers are receiving therapy. Finally, the applicant will be required to develop anti-drug antibody assays in order to determine the
`immunogenic potential of plecanatide.
`
`A REMS is not necessary for plecanatide to ensure the benefits outweigh the risks. The safety profile of plecanatide is similar to linaclotide,
`the other approved GC-C agonist. Therefore, the safety and risk mitigation approach of plecanatide will follow that of linaclotide, i.e., the
`risks will be communicated via labeling. A Medication Guide is required to inform patients of the risk of serious outcomes if plecanatide is
`
`CDER Division Director Summary Review Template 2015 Edition
`Version date: July 29, 2015. For initial rollout (NME/original BLA reviews)
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`5
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`Reference ID: 4044239
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`(b) (4)
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`

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`administered to pediatric patients. A Boxed Warning in the Prescribing Information will convey that plecanatide is contraindicated in less
`than 6 years of age due to the risk of serious dehydration and to avoid use in pediatric patients 6 years to less than 18 years of age.
`
`Dimension
`
`Analysis of
`Condition
`
`Current
`Treatment
`Options
`
`Evidence and Uncertainties
`CIC affects an average of 15% of North Americans and is
`manifested by infrequent stools, incomplete bowel movements,
`straining, bloating, and hard, lumpy stool for at least six months.
`Moderate to severe symptoms of abdominal pain and/or straining
`with defecation can be debilitating for patients and if left untreated
`impact negatively on a patient’s general well-being. CIC has a
`higher prevalence in women, those with reduced caloric intake and
`the elderly.
`Linzess (linaclotide) and Amitiza (lubiprostone) are indicated for use in
`adult patients with CIC. The efficacy of these therapies cannot be directly
`compared to plecanatide due to the fact that there are no randomized trials
`that compare these drugs in the same trial. Cross-study comparisons are
`less valid. The available randomized placebo-controlled trials also use
`varying definitions for the primary endpoint.
`
`Amitiza demonstrated efficacy in primary endpoint of the number of
`spontaneous bowel movements (SBMs) compared to placebo during the
`first of four weeks of treatment (a mean increased of about 2 SBMs).
`Symptom scores were significantly improved with lubiprostone compared
`to placebo for stool consistency, straining, and constipation severity. The
`safety profile of lubiprostone is notable for adverse reactions of nausea,
`diarrhea, headache, and acute symptoms of dyspnea (generally occurring
`with 30 to 60 minutes after the first dose).
`
`Conclusions and Reasons
`CIC is a serious condition associated with
`morbidity and symptoms can be debilitating.
`
`The current treatment armamentarium does
`not completely meet the needs of the
`patients with CIC. The available approved
`drugs have a modest treatment benefit over
`placebo. OTC and nondrug therapies are not
`specifically approved for CIC; OTC
`products are approved for occasional
`constipation.
`
`Therefore, additional treatment options are
`needed for patients with CIC.
`
`CDER Division Director Summary Review Template 2015 Edition
`Version date: July 29, 2015. For initial rollout (NME/original BLA reviews)
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`Reference ID: 4044239
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`Conclusions and Reasons
`
`Dimension
`
`Evidence and Uncertainties
`Linzess demonstrated a treatment difference of 10% to 17% over placebo
`in two trials in the primary efficacy endpoint of complete spontaneous
`bowel movements (CSBMs) where patients met the response criteria in at
`least 9 out of 12 weeks of the study. Linzess is in the same pharmacologic
`class as plecanatide (G-CC agonist); therefore the safety profile is similar
`to plecanatide and is notable for the adverse reaction of diarrhea. In post-
`marketing experience, severe diarrhea associated with dizziness, syncope,
`hypotension and electrolyte abnormalities (hypokalemia and hyponatremia)
`requiring hospitalization or intravenous fluid administration have been
`reported. Other adverse reactions in clinical trials included abdominal
`pain. As with plecanatide, there is a risk of serious diarrhea due to
`dehydration in pediatric patients, especially those less than 6 years of age,
`based on mortality in young juvenile mice and a lack of clinical safety and
`efficacy data in pediatric patients.
`
`Zelnorm (tegaserod maleate) was marketed from 2004 to 2007 for patients
`less than 65 years of age with CIC, but was voluntarily withdrawn due to
` the risk of ischemic
`cardiovascular events. It continues to be available through expanded
`access to individual patients who have failed other therapies.
`
`There are a variety of over-the-counter (OTC) therapies, such as
`laxatives, and nondrug interventions available to prevent/treat
`constipation by increasing bowel motility, decreasing GI transit time,
`or facilitating the passage of stool without straining. OTC therapies
`are labeled for occasional, discreet episodes of constipation and not for
`chronic use.
`
`CDER Division Director Summary Review Template 2015 Edition
`Version date: July 29, 2015. For initial rollout (NME/original BLA reviews)
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`7
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`Reference ID: 4044239
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`(b) (4)
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`

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`Dimension
`
`Evidence and Uncertainties
`The efficacy of plecanatide for the management of symptoms of CIC was
`evaluated in two 12-week, double-blind, placebo-controlled, randomized,
`multicenter clinical studies in adult patients with CIC, as defined by the
`modified Rome III criteria. Patients were randomized to plecanatide 6 mg,
`plecanatide 3 mg, or placebo once daily. Only the results for the 3 mg dose
`will be described here. In the Intention-to-Treat (ITT) population, a total
`of 905 patients (Study 1) and 870 patients (Study 2) were randomized
`between placebo and plecanatide 3 mg.
`
`Conclusions and Reasons
`The efficacy of plecanatide in increasing the
`number of bowel movements in adult
`patients with CIC was demonstrated
`throughout 12-weeks in two adequate and
`well-controlled trials. In addition, patients
`began to respond to treatment within the
`first week and maintained improvement for
`12 weeks.
`
`Although the treatment difference between
`plecanatide and placebo is modest
`(approximately 10%), plecanatide may offer an
`alternative treatment option to patients with
`CIC.
`
`Benefit
`
`The primary efficacy endpoint was the proportion of patients who were
`responders over the 12-week treatment period. The study population was
`patients with less than 3 complete spontaneous bowel movements
`(CSBMs) per week at baseline. A CSBM is a spontaneous bowel
`movement that is associated with a sense of complete evacuation. A
`responder was defined as a patient who had a least 3 (CSBMs) in a given
`week and an increase of at least 1 CSBM from baseline in the same week
`for at least 9 weeks out of the 12 week treatment period and at least 3 of
`the last 4 weeks of the study.
`
`This endpoint was recommended to the sponsor by FDA during drug
`development and is felt to encompass both magnitude of effect and
`durability of response. In patients with CIC and less than 3 CSBMs per
`week at baseline, an increase to at least 3 CSBMs per week (and in at least
`1 CSBM per week) is considered to be clinically meaningful, given that the
`definition of constipation includes having less than 3 bowel movements per
`week. Based upon assessments of CSBMs, patients were assessed for both
`weekly and overall response. Responders demonstrated a response in at
`least 75% of the weeks (i.e., at least 9 out of 12 weeks), including the last
`month of the study (i.e., at least 3 of the last 4 weeks).
`
`CDER Division Director Summary Review Template 2015 Edition
`Version date: July 29, 2015. For initial rollout (NME/original BLA reviews)
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`Reference ID: 4044239
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`

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`Conclusions and Reasons
`
`Dimension
`
`Evidence and Uncertainties
`In one study the responder rates were 21% for plecanatide and 10% for
`placebo, for an 11% treatment difference. In the second study the
`responder rates were 21% for plecanatide and 13% for placebo, for an 8%
`treatment difference. In both studies the treatment difference was
`statistically significant.
`
`In addition, in both studies improvements in the frequency of
`CSBMs/week were seen as early as week 1, with improvement maintained
`through week 12. The difference between plecanatide and placebo in the
`mean change of CSBMs/week frequency from baseline to week 12 was
`approximately 1.1 CSBMs/week.
`
`In both studies, patients in the plecanatide groups had improvements in the
`number of spontaneous bowel movements (SBM) and in stool consistency
`compared to patients in the placebo groups.
`
`In both studies, patients in the plecanatide groups also had improvements
`in the amount of straining with bowel movements, as further defined by the
`amount of time pushing or physical effort to pass stool, in comparison to
`patients in the placebo groups.
`
`There were insufficient numbers of patients to make meaningful
`conclusions about the efficacy in subgroups of age (less than 65 years vs.
`65 years and older).
`
`In female patients, plecanatide was generally significantly more effective
`than placebo, both over the course of the entire treatment period and for
`each weekly assessment. For male patients, less consistent results were
`observed for both doses; the small population size for male patients likely
`impacted these results.
`
`CDER Division Director Summary Review Template 2015 Edition
`Version date: July 29, 2015. For initial rollout (NME/original BLA reviews)
`
`9
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`Reference ID: 4044239
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`

`

`Dimension
`
`Evidence and Uncertainties
`
`Conclusions and Reasons
`
`Plecanatide was similarly effective in white and nonwhite patients.
`
`In both placebo-controlled trials, the overall incidence of adverse events
`and serious adverse events was similar between plecanatide and placebo. A
`total of 1733 patients received 3 mg plecanatide or placebo in the safety
`population.
`
`The most common adverse reactions (defined as adverse events occurring
`at a higher rate in the plecanatide group compared to placebo) in the two
`trials was diarrhea: 5% in the plecanatide 3 mg group and 1% in the
`placebo group.
`
`The majority of cases of diarrhea occurred within 4 weeks of treatment
`initiation. Severe diarrhea was reported in 0.6% of patients treated with 3
`mg plecanatide compared to 0.3% of placebo-treated patients. Severe
`diarrhea occurred within the first 3 days of treatment.
`
`Risk
`
`Of note, the incidence of severe diarrhea was higher in the 6 mg
`plecanatide group in comparison to the 3 mg plecanatide group and
`placebo (1.3% versus 0.3% for 3 mg and placebo, respectively).
`
`Discontinuations due to adverse reactions occurred in 4% of plecanatide-
`treated patients and 2% of placebo-treated patients. The most common
`adverse reaction leading to discontinuation was diarrhea: 2% of
`plecanatide-treated patients and 0.5% of placebo-treated patients withdrew
`due to diarrhea.
`
`Overall, plecanatide is well-tolerated with
`few serious adverse reactions in adult
`patients. The adverse event profile is
`similar to the other approved GC-C agonist,
`linaclotide.
`
`The most common adverse reaction in the
`plecanatide clinical trials was diarrhea.
`Severe diarrhea was reported and may lead
`to discontinuation, but can be managed by
`patient monitoring, withholding the
`medication and rehydration. In the clinical
`trials severe diarrhea did not lead to serious
`outcomes.
`
`Serious adverse reactions, related to
`diarrhea, increases in liver biochemical
`tests, and UPD should be monitored using
`routine postmarketing surveillance.
`
`Plecanatide and its active metabolite are
`negligibly absorbed systemically following
`oral administration. There are no clinically
`relevant drug interactions.
`
`Increases in liver biochemical tests were seen in 5 patients treated with
`
`Due to the structure similarity between
`
`CDER Division Director Summary Review Template 2015 Edition
`Version date: July 29, 2015. For initial rollout (NME/original BLA reviews)
`
`10
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`Reference ID: 4044239
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`

`

`Dimension
`
`Evidence and Uncertainties
`plecanatide 3 mg: 2 patients with alanine aminotransferase (ALT) greater
`than 5 to 15 times the upper limit of normal and 3 patients with aspartate
`aminotransferase (AST) greater than 5 times the upper limit of normal.
`These laboratory abnormalities were not associated with clinical symptoms
`and did not meet the criteria for Hy’s law.
`
`There are no clinically relevant drug interactions. Plecanatide is
`metabolized in the GI tract to an active metabolite by loss of the terminal
`leucine moiety, and there is negligible systemic absorption of either
`plecanatide or its active metabolite.
`
`Due to the structure similarity between plecanatide and endogenous
`peptides, there is a theoretical immunogenicity risk for deficiency of
`uroguanylin and guanylin if patients develop anti-plecanatide antibodies
`that cross react with the endogenous proteins. Potential adverse events
`associated with uroguanylin/guanylin deficiency include hypernatremia,
`pulmonary edema, peripheral edema, sudden weight gain, and
`hypertension. No safety signals were seen in the clinical trials database for
`plecanatide for these adverse reactions.
`
`There were no clinically meaningful differences in the safety profile with
`respect to age (less than 65 years vs. 65 years and older), race or sex.
`Plecanatide has not been studied in pediatric patients less than 18 years of
`age. In young juvenile mice (1- to 2-week-old mice corresponding to human
`age equivalent of approximately 1 month to less than 2 years), 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
`
`Conclusions and Reasons
`plecanatide and endogenous peptides, there
`is a theoretical immunogenicity risk for
`uroguanylin/guanylin deficiency if patients
`develop cross reacting anti-plecanatide
`antibodies. No safety signals of
`uroguanylin/guanylin deficiency were seen
`in the clinical trials database for
`plecanatide.
`
`Deaths were observed in young juvenile
`mice (human age equivalent of less than 2
`years. There were no deaths in older
`juvenile mice. These data, and other
`published findings, suggest an age-
`dependency of the pharmacodynamic
`response and indicate that plecanatide
`would not be safe to administer to children
`under the age of 2 years; however, more
`data are needed to determine whether
`plecanatide can be administered safely to
`children 2 years to less than 6 years.
`Plecanatide has not been studied in any
`pediatric patients less than 18 years of age.
`Therefore, plecanatide will be
`contraindicated in patients less than 6 years
`of age and should be avoided in patients 6
`years to less than 18 years of age until more
`information is known.
`
`Use of plecanatide in pregnant women is
`
`CDER Division Director Summary Review Template 2015 Edition
`Version date: July 29, 2015. For initial rollout (NME/original BLA reviews)
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`Reference ID: 4044239
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`

`

`Dimension
`
`Evidence and Uncertainties
`patients 6 years of age and older to develop severe diarrhea and its potentially
`serious consequences.
`The available data on plecanatide use in pregnant women are not sufficient
`to inform any drug-associated risks 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 recommended human
`dosage.
`There is no information regarding the presence of plecanatide in human
`breast milk, or its effects on milk production or the breastfed infant. No
`lactation studies in animals have been conducted.
`
`Conclusions and Reasons
`not expected to result in fetal exposure.
`However, it is unknown whether the
`negligible systemic absorption of
`plecanatide in adults will result in a
`clinically relevant exposure to breastfed
`infants. Exposure to plecanatide in
`breastfed infants has the potential for
`serious adverse reactions. Therefore, the
`developmental and health benefits of
`breastfeeding should be considered along
`with the mother’s clinical need for
`plecanatide, and the potential risk to the
`infant.
`
`There are no unresolved issues with product quality. Overall, the
`chemistry, manufacturing and controls information provided were found
`satisfactory.
`
`Pediatric patients have not been studied in the plecanatide developmental
`program. There were deaths in young juvenile mice (human age
`equivalent of approximately 1 month to less than 2 years) in nonclinical
`studies, which occurred within 24 hours following oral administration of
`plecanatide and are thought to be due to the increased expression of
`intestinal GC-C in this age group. These data along with data from a
`review of the literature regarding GC-C ontogeny suggest an age-
`dependency of the pharmacodynamic response and indicate that
`plecanatide would not be safe to administer to children under the age of 2
`years; however, more data are needed to determine whether plecanatide
`can be administered safely to children 2 years to less than 6 years. As a
`result, plecanatide will have a Boxed Warning that there is a risk of
`serious dehydration in pediatric patients, and a Contraindication in
`
`Risk
`Management
`
`A REMS is not necessary for plecanatide to
`ensure the benefits outweigh the risks. The
`safety profile is similar to linaclotide, the
`other approved GC-C agonist. Therefore,
`the safety and risk mitigation approach is
`similar to linaclotide; the risks will be
`communicated via labeling including the use
`of a Medication Guide and Boxed Warning
`in the Prescribing Information.
`
`The Indications and Usage section of the
`Prescribing Information states that
`plecanatide is indicated in adults. There is a
`
`CDER Division Director Summary Review Template 2015 Edition
`Version date: July 29, 2015. For initial rollout (NME/original BLA reviews)
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`12
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`Reference ID: 4044239
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`

`

`Dimension
`
`Evidence and Uncertainties
`patients less than 6 years of age. A study characterizing GC-C mRNA
`expression in duodenal and colonic mucosal biopsies in pediatric patients
`will be required as a postmarketing study to assess the ontogeny of the
`GC-C receptor in order to determine if pediatric studies may be safe in
`children 2 years to less than 6 years age.
`
`Under the Pediatric Research Equity Act (PREA), clinical trials of the
`safety, pharmacokinetics and efficacy of plecanatide will be required to be
`conducted. There is an unmet need for treatment of pediatric patients with
`CIC. The sponsor has been granted a waiver from studying pediatric
`patients less than 2 years of age, as plecanatide may be unsafe in this age
`group. Clinical trials will be required in pediatric patients 2 years to less
`than 18 years of age. These trials will be conducted in sequential order in
`pediatric patients from oldest to youngest: 12 years to less than 18 years;
`6 years to less than 12 years, and 2 years to less than 6 years. Until the
`results of the GC-C biopsy study are reviewed, pharmacokinetic and
`clinical data in pediatric patients 6 years to less than 18 years of age are
`available, the pharmacokinetic dose-ranging trials and confirmatory
`clinical trial in pediatrics 2 years to less than 6 years of age will not be
`conducted.
`
`There is no information regarding the presence of plecanatide in human
`breast milk, or its effects on milk production or the breastfed infant. The
`likelihood of plecanatide or its metabolite being measureable in breast
`milk is low due to the fact that there is negligible systemic absorption.
`However, given the anticipated use of plecanatide in females of
`reproductive potential, the lack of data on safe use in lactating women,
`and animal data demonstrating serious findings (mortality) in juvenile
`mice, a milk-only lactation study is required postmarketing to assess
`concentrations of plecanatide and its active metabolite in breast-milk in
`
`Conclusions and Reasons
`Boxed Warning, Contraindication, and
`Warning and Precaution stating that
`plecanatide is contraindicated in patients
`less than 6 years of age due to the risk of
`serious dehydration and to avoid use in
`pediatric patients 6 years to less than 18
`years of age.
`
`A Medication Guide is needed to inform
`patients of the risk of serious outcomes if
`plecanatide is administered to pediatric
`patients.
`
`The sponsor will be required to conduct a
`postmarketing study in patients from birth to
`6 years of age to assess the ontogeny of the
`GC-C receptor in the gastrointestinal tract to
`inform whether plecanatide can be safely
`dosed in pediatric patients 2 years to less
`than 6 years of age [a study to assess a
`signal of a serious risk of a significant fluid
`shift into the intestine due to age-dependent
`expression of the target receptor (GC-C),
`leading to severe dehydration and possibly
`death].
`
`Clinical trials in pediatric patients to obtain
`information of the safety, pharmacokinetics
`and efficacy of plecanatide will be required
`to be conducted sequentially, such that
`
`CDER Division Director Summary Review Template 2015 Edition
`Version date: July 29, 2015. For initial rollout (NME/original BLA reviews)
`
`13
`
`Reference ID: 4044239
`
`

`

`Dimension
`
`Evidence and Uncertainties
`order to inform labeling [to identify an unexpected serious risk associated
`with the presence of plecanatide or its active metabolite in human breast
`milk].
`
`Due to the structure similarity between plecanatide and endogenous
`peptides, there is a theoretical immunogenicity risk for
`uroguanylin/guanylin deficiency if patients develop anti-plecanatide
`antibodies which cross react with the endogenous proteins. The
`sponsor developed an anti-drug antibody screening assay during
`clinical development but it was not adequate. Since the
`immunogenicity risk is theoretical, the lack of adequate
`immunogenicity assays and clinical immunogenicity data does not
`preclude approval. The development of immunogenicity assays and
`sample testing will be required to be conducted post-marketing.
`Hypersensitivity reactions are reported in the product label for another
`drug in the class, linaclotide; although no clear signal of clinical
`hypersensitivity reactions, such as manifestations consistent with
`anaphylaxis, were found in the review of the plecanatide safety
`database, the development of immunogenicity assays and sample
`testing will be required to identify an unexpected serious risk of
`immune mediated reactions with use of plecanatide.
`
`Conclusions and Reasons
`younger age groups will not be initiated
`until safety has been demonstrated in older
`age groups and results from the GC-C
`biopsy study have been reviewed. The
`sponsor is not required to conduct studies in
`pediatric patients less than 2 years, as the
`drug may be unsafe.
`
`A milk-only lactation study will be required
`to assess the presence of plecanatide and
`metabolite in breast-milk.
`
`The sponsor will also be required to develop
`immunogenicity assays to assess for the
`development of anti-plecanatide drug
`antibodies, assays to evaluate the cross-
`reactivity of the potential anti-drug antibodies
`to endogenous