CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`208745Orig1s000
`
`MEDICAL REVIEW(S)
`
`Bausch Health Ireland Exhibit 2012, Page 1 of 5
`Mylan v. Bausch Health Ireland - IPR2022-01104
`
`

`

`CLINICAL OUTCOME ASSESSMENT (COA) CONSULT REVIEW
`
`AT 2016-046
`COA CONSULT TRACKING NUMBER
`NDA 208745
`IND/NDA/BLA NUMBER
`IND 74883
`REFERENCED IND FOR NDA/BLA
`January 29, 2016/SDN 0
`LETTER DATE/SUBMISSION NUMBER
`January 29, 2017
`PDUFA GOAL DATE
`DATE OF CONSULT REQUEST March 1, 2016
`
`REVIEW DIVISION
`
`Division of Gastroenterology and Inborn
`Errors Products (DGIEP)
`Lesley Hanes, M.D./Laurie Muldowney, M.D.
`MEDICAL REVIEWER/TEAM LEADER
`REVIEW DIVISION PM Maureen Dewey
`
`Sarrit M. Kovacs, Ph.D.
`
`Elektra Papadopoulos, M.D., M.P.H.
`
`PRIMARY COA REVIEWER
`COA TEAM LEADER
`ASSOCIATE DIRECTOR, COA STAFF
`(ACTING)
`REVIEW COMPLETION DATE
`ESTABLISHED NAME/TRADE NAME
`APPLICANT
`CLINICAL OUTCOME ASSESSMENT TYPE
`ENDPOINT(S) CONCEPT(S)
`
`December 5, 2016
`Plecanatide/SP-304
`Synergy
`Patient-reported outcome (PRO)
`Stool frequency, stool consistency, and
`straining
`Single PRO sign/symptom items
`Treatment of chronic idiopathic constipation
`(CIC) in adult patients
`Adult patients (18 and 80 years of age,
`inclusive) meeting the Rome III functional
`constipation criteria as modified for this study
`for at least 3 months prior to the Screening
`visit
`PLEASE CHECK ALL THAT APPLY: ☐Rare Disease/Orphan Designation
`☐Pediatric
`
`COA NAME(S)
`INDICATION
`
`INTENDED POPULATION(S)
`
`Reference ID: 4017868
`
`Bausch Health Ireland Exhibit 2012, Page 2 of 5
`Mylan v. Bausch Health Ireland - IPR2022-01104
`
`

`

`Clinical Review
`Lesley S. Hanes, MD MSc
`NDA 208745
`Plecanatide (Trulance)
`
`In animals, plecanatide was rapidly absorbed following oral administration, but it did not persist
`in the plasma since it does not bind to plasma proteins. Plecanatide did not accumulate in plasma
`with repeated oral dosing and there were no clear sex differences in plecanatide exposure.
`Plecanatide and its active metabolite SP-338 did not interact with key transporters or CYP
`metabolic enzymes in the GI tract. Despite systemic exposure in animal studies, results from
`general, reproductive, and developmental toxicity studies with plecanatide demonstrated
`substantial safety margins compared to the MRHD. Plecanatide was not genotoxic in vitro or in
`vivo and was not carcinogenic in rats or mice.
`
`Toxicity studies in juvenile mice suggested that very young mice, less than postnatal day 21,
`exhibit increased sensitivity to plecanatide compared to older juvenile mice, with ages
`corresponding to approximately 2 years of age in humans. Overall, the nonclinical safety data
`support the approval of plecanatide for the treatment of CIC at
` mg/day in adults.
`
`4.5.
`
`
`4.5.1.
`
`
`
`Clinical Pharmacology
`
`Mechanism of Action
`
`Plecanatide is a synthetic analogue of human endogenous peptide uroguanylin and is an
`agonist of the guanylate cyclase- C (GC-C) receptor. GC-C receptors are found in the GI
`tract and are involved in the regulation of fluid and electrolyte transport. Binding of an
`agonist to the GC-C stimulates cyclic guanosine monophosphate (cGMP) synthesis and
`activates the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), a major
`chloride channel in the GI tract. The result is chloride and sodium/potassium ion efflux
`and secretion of fluid into the intestinal lumen. This fluid secretion is expected to
`facilitate bowel movements.
`
`4.5.2.
`
`
`
`Pharmacodynamics
`
`In pharmacodynamic (PD), in vitro screening studies, plecanatide did not exhibit any off-target
`binding or activity at a large number of targets, including G-protein coupled and neurotransmitter
`receptors, ion channels, or cytochrome P450 metabolic enzymes. These data suggest that
`plecanatide is unlikely to produce any potential adverse off-target effects in vivo at clinically
`relevant doses.
`
`
`CDER Clinical Review Template 2015 Edition
`Version date: November 5, 2015 for initial rollout (NME/original BLA reviews)
`
`41
`
`Reference ID: 3997834
`
`(b) (4)
`
`Bausch Health Ireland Exhibit 2012, Page 3 of 5
`Mylan v. Bausch Health Ireland - IPR2022-01104
`
`

`

`Clinical Review
`Lesley S. Hanes, MD MSc
`NDA 208745
`Plecanatide (Trulance)
`
`The sponsor submitted a Request for a Waiver of TQT Evaluation on May 16, 2014. In an FDA
`Advice Letter dated August 7, 2014, the FDA agreed that there was no need for Synergy to
`conduct a TQT study because at the plecanatide 3 or 6 mg QD doses, the maximum total plasma
`concentration was expected to be too low for the quantification of both plecanatide and the SP-
`338
` metabolite.
`
`In phase 1 study SP304101-08, PD analyses were based on the frequency and consistency of
`BMs. Overall, mean time to first stool post-dose was variable across the dose range.
`Nonetheless, there was a trend toward lower mean time to first stool values with higher doses of
`plecanatide. Mean stool consistency increased on the BSFS (i.e., indicating looser stools)
`following administration of single doses of plecanatide compared to 7 days pre-dose. Patients
`with an increase in BMs post-baseline had looser stools following plecanatide administration
`compared to placebo, which demonstrated a positive PD effect with respect to the potential for
`plecanatide as a treatment for constipation. These results were repeated in the phase 2 and 3
`studies.
`
`4.5.3.
`
`
`
`Pharmacokinetics
`
`The PK program included evaluations of the transmembrane permeability of plecanatide and
`SP-338, plecanatide’ s biologically active metabolite/
` product, across Caco-2 cell
`monolayers and as substrates or inhibitors of the efflux transporters human P-glycoprotein (P-gp)
`and breast cancer resistance protein (BCRP) in these cells . Neither plecanatide nor SP-338 was a
`substrate or a significant inhibitor of P-gp or BCRP under the conditions of these studies.
`
`The clinical PK of plecanatide was evaluated in multiple phase 1 and 2 studies. In Study
`SP304101-08, patients in each dose cohort received a single oral dose (0.1, 0.3, 0.9, 2.7, 5.4, 8.1,
`16.2, 24.3, or 48.6 mg) of plecanatide solution or placebo solution under fasted conditions. No
`measurable concentrations of plecanatide were observed in plasma samples collected during the
`course of this study up to 48 hours post-dose. Likewise, in phase 2a, 2b, and 3 studies
`SP304201-09, SP304-20210, and SP304203-03 no measurable concentrations of plecanatide or
`SP-338 were observed in plasma samples collected during the course.
`
`Plecanatide and SP-338 were also evaluated as inhibitors of CYP2C9 and CYP3A in human liver
`microsomes and as inducers of CYP3A in intact fresh human hepatocytes. The CYP
`
`
`CDER Clinical Review Template 2015 Edition
`Version date: November 5, 2015 for initial rollout (NME/original BLA reviews)
`
`42
`
`Reference ID: 3997834
`
`(b) (4)
`
`Bausch Health Ireland Exhibit 2012, Page 4 of 5
`Mylan v. Bausch Health Ireland - IPR2022-01104
`
`

`

`Clinical Review
`Lesley S. Hanes, MD MSc
`NDA 208745
`Plecanatide (Trulance)
`
`enzymes 2C9 (inhibition experiments) and 3A (inhibition and induction experiments) were
`studied because these CYP enzymes are predominant in the intestine and there is limited
`systemic exposure to plecanatide following oral dosing. Results indicated that neither
`plecanatide nor SP-338 is an inhibitor of CYP3A or CYP2C9, or an inducer of CYP3A in vitro
`
`Please see the Clinical Pharmacology review by Dilara Jappar, PhD for more details.
`
`4.6.
`
`
`
`Devices and Companion Diagnostic Issues
`
`Not applicable
`
`4.7.
`
`
`
`Consumer Study Reviews
`
`Not applicable
`
`
`CDER Clinical Review Template 2015 Edition
`Version date: November 5, 2015 for initial rollout (NME/original BLA reviews)
`
`43
`
`Reference ID: 3997834
`
`Bausch Health Ireland Exhibit 2012, Page 5 of 5
`Mylan v. Bausch Health Ireland - IPR2022-01104
`
`