CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`
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`APPLICATION NUMBER:
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`208745Orig1s000
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`OFFICE DIRECTOR MEMO
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`

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`Office Director Decisional Memorandum
`
`January 19, 2017
`
`Julie Beitz, MD
`Office Director Decisional Memo
`
`NDA #
`208745
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`Applicant Name
`
`Date of Submission
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`PDUFA Goal Date
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`Proprietary Name /
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`Established (USAN) Name
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`Synergy Pharmaceuticals, Inc.
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`January 29, 2016
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`January 29, 2017
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`Trulance (plecanatide)
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`Dosage Forms / Strengths
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`Tablets 3 mg
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`Proposed Indication
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`Indicated in adults for the treatment of chronic
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`Recommended Action:
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`Approval
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`idiopathic constipation (CIC)
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`Materials Reviewed/Consulted
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`Action Package, including reviews from:
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`Discipline Reviewers
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`
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`0ND / DPMH / Pediatric Team
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`Carolyn Yancey, MD / Mona Khurana, MD
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`0ND / DPMH / Maternal Health Team
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`Christos Mastroyannis, MD / Tamara Johnson,
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`MD, MS
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`MPH
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`Scott Komo, DrPH
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`OCP / Division of Clinical Pharmacology I|| Dilara Jappar, PhD / Sue Chih Lee, PhD
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`Haoheng Yan, PhD / Michele Dougherty, PhD /
`
`Fred Mills, PhD/Joslyn Brunelle PhD
`
`DGIEP = Division of Gastroenterology and lnbom Errors Products
`DPMH = Division of Pediatrics and Maternal Health
`08 = Office of Biostatisties
`OCP = Office of Clinical Pharmacology
`0ND = Office of New Drugs
`OSE = Office of Surveillance and Epidemiology
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`Reference ID: 4043837
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`

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`1.  
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`Benefit‐Risk Summary and Assessment 
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` 
`Trulance (plecanatide) is structurally related to human uroguanylin, functions as a guanylate cyclase‐C (GC‐C) agonist, and has been evaluated 
`in adults for the treatment of chronic idiopathic constipation (CIC).  Uroguanylin, a member of the guanylin peptide family that is secreted by 
`enterochromaffin cells in the duodenum and proximal small intestine, regulates the secretion of intestinal fluid.  Idiopathic constipation is a 
`common gastrointestinal disorder, affecting up to approximately 15% of the U.S. population.  Although many treatments for CIC are 
`commercially available, additional treatment options are needed, particularly for patients who do not respond to, or tolerate, existing 
`treatments.   
` 
`Trulance (plecanatide) has been shown to be an efficacious, well‐tolerated treatment option for adults with CIC and would be the second FDA‐
`approved GC‐C agonist for this condition.  I concur with the recommendation of the Division of Gastroenterology and Inborn Errors Products to 
`approve Trulance (plecanatide) for the treatment of CIC in adults.  The recommended dose is 3 mg taken orally once daily.  Although a 6 mg 
`daily dose was also studied, the applicant will not market this dose.1  The safety and effectiveness of Trulance (plecanatide) in patients less than 
`18 years of age have not been established. 
` 
`An FDA Advisory Committee Meeting was not held to discuss this application because the application did not raise significant safety or efficacy 
`issues that were unexpected for a drug in this class. 
` 
`Data submitted in the NDA supported the efficacy and safety of Trulance (plecanatide).  The efficacy of Trulance (plecanatide) was established 
`in two randomized placebo‐controlled clinical trials involving adults with CIC.  The assumption that GC‐C agonism leads to movement of 
`chloride and bicarbonate anions and water into the intestinal lumen and increased intestinal transit has been borne out by the submitted 
`clinical trials of Trulance (plecanatide).  I concur that the observed improvements in stool frequency, stool consistency, and straining on 
`plecanatide treatment were both statistically superior to placebo and clinically meaningful to patients with CIC.   
` 
`The safety profile of Trulance (plecanatide) is similar to that of the approved GC‐C agonist, Linzess (linaclotide), including the risk of serious 
`dehydration in pediatric patients.  In nonclinical studies of young juvenile mice, administration of a single oral dose of plecanatide caused 
`
`
`1 In clinical trials of Trulance (plecanatide), the 3 mg and 6 mg daily dose regimens were similarly effective.  However, patients treated with the higher dose 
`reported a slightly higher incidence of severe diarrhea and discontinuations due to diarrhea.  At the July 14, 2016 Mid‐Cycle Communication meeting, the 
`applicant indicated that it will not market the higher dose regimen.     
`
`
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`Reference ID: 4043837
`
`2
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`

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`deaths, likely due to dehydration.
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`In adult patients with CIC, treatment with Trulance (plecanatide) was generally well tolerated. The
`
`treatment-emergent adverse event most commonly reported in clinical trials was diarrhea which was severe in some patients.
`
`The prescribers of Trulance (plecanatide) will likely be general practitioners and gastroenterologists familiar with the attendant risks of
`
`available treatments for CIC, including those associated with Linzess (linaclotide), another GC—C agonist. The safety concerns identified in
`
`nonclinical studies and with use of Trulance (plecanatide) in clinical trials can be adequately communicated in professional labeling that will
`
`include a boxed warning about the risk of serious dehydration in pediatric patients, and contraindicate use in patients less than 6 years of age.
`
`A Medication Guide will be required as part of approved labeling to provide important safety information to patients.
`
`A Risk Evaluation and Mitigation Strategy (REMS) will not be required for Trulance (plecanatide) to ensure that the benefits of the drug
`
`outweigh the risks. Routine pharmacovigilance will be conducted in the postmarketing setting. The results of required postmarketing studies
`
`will further inform product labeling regarding safe and effective use of Trulance (plecanatide) in pediatric patients, presence of the product in
`
`human breast milk, and its immunogenic potential.
`
`m
`
`Evidence, Uncertainties and Conclusions
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`Chronic idiopathic constipation (CIC) is a common functional gastrointestinal motility disorder, with approximately 63 million
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`adults in North America meeting Rome ll criteria. To meet these criteria, symptoms should occur in the absence of a structural
`
`or biochemical explanation, should last for at least 12 weeks, which need not be consecutive, in the preceding 12 months, and
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`include two or more of the following:
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`
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`Straining during at least 25% of defecations;
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`Lumpy or hard stools in at least 25% of defecations;
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`Sensation of incomplete evacuation for at least 25% of defecations;
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`Sensation of anorectal obstruction/blockage for at least 25% of defecations;
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`Manual maneuvers to facilitate at least 25% of defecations (e.g., digital evacuation, support of the pelvic floor); and/or
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`< 3 defecations per week.
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`Rome criteria, however, do not identify all the symptoms that patients define as constipation. It is estimated that an additional
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`50 million in North America report that they have constipation but do not meet Rome ll criteria. That is, they consider
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`

`

`m
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`Evidence, Uncertainties and Conclusions
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`themselves constipated, perhaps because they do not have daily bowel movements, despite the absence of straining, hard
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`stools, or feelings of incomplete evacuation. In either case, individuals who self-report constipation or meet Rome criteria will
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`seek treatment either by use of over-the-counter products or by visiting their physician and requesting a prescription
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`medication. Constipation is more common in women than men and increases with advancing age, particularly after age 70.
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`Data on the incidence of constipation, the natural history of constipation, or quality of life in patients with constipation are
`limited.2
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`Comment. The availability of Trulance (plecanatide) would offer an FDA-approved, safe and effective alternative oral treatment
`
`for adults with symptoms of CIC. Although not life-threatening, symptoms of CIC can be bothersome to many millions of
`individuals in the U5.
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`
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`Treatment for patients with CIC is highly individualized and usually includes increased dietary fiber and supplementation with
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`bulking agents, exercise, and bowel habit training. However, patients often obtain only partial relief, and the majority use non-
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`bulking laxatives on a regular basis without medical supervision. Laxatives available over-the-counter are not intended for
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`chronic use however. Chronic use of non-bulking laxatives may lead to dependency and progressive tolerance, electrolyte
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`imbalance, and, for the anthraquinones, melanosis coli. Chronic use of stimulant laxatives may result in bloating, feelings of
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`fullness, abdominal pain, and incomplete fecal evacuation.
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`Linzess (linaclotide) was the first GC—C agonist to be approved in 2012. Linaclotide, structurally related to the guanylin peptide
`
`family, binds to the GC-C receptor expressed on intestinal epithelial cells thereby stimulating the intracellular production of
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`cyclic guanosine monophosphate (cGMP) and activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion
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`channel. Activation of CFTR and the subsequent enhancement of transepithelial efflux of chloride and bicarbonate anions lead
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`to movement of water into the intestinal lumen. The secretion of water into the lumen, in turn, is believed to facilitate bowel
`movements and accelerate intestinal transit. Linaclotide is indicated in adults for the treatment of CIC and for irritable bowel
`
`syndrome with constipation. Plecanatide is structurally related to human uroguanylin, a member of the guanylin peptide
`
`family. Like linaclotide, plecanatide acts as a GC—C agonist to increase intestinal fluid secretion and accelerate intestinal transit.
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`If approved, Trulance (plecanatide) would be the second orally administered GC—C agonist for the treatment of CIC.
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`

`

`m
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`Evidence, Uncertainties and Conclusions
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`Comment. Although many treatments for CIC are commercially available in the U.S., additional therapeutic options are
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`needed, particularly for patients who do not respond to, or tolerate, existing treatments. Trulance (plecanatide) would offer an
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`FDA—approved, safe and effective alternative oral treatment for adults with symptoms of CIC.
`
`The efficacy of Trulance (plecanatide) was established in two identical randomized, double-blind, placebo-controlled clinical
`
`trials involving adults with CIC, Trials SPD-304203-00 and SPD—304203-03. Patients were randomized 1:1 to either placebo or
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`plecanatide 3 mg, once daily for 12 weeks without respect to food intake. The mean age of participants was 45.4 years (range
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`18 to 80 years), 80% were female, 72% were white, and 24% were black.
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`Eligible patients were required to meet modified Rome Ill criteria for at least 3 months prior to the screening visit, that is,
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`report less than 3 defecations per week, rarely have a loose stool without the use of laxatives, not use manual maneuvers to
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`facilitate defecations, and not meet criteria for constipation-predominant irritable bowel syndrome.
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`In addition, patients were
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`required to report at least two of the following symptoms:
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`
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`0 Straining during at least 25% of defecations
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`Lumpy or hard stool in at least 25% of defecations
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`Sensation of incomplete evacuation for at least 25% of defecations
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`O o
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`o Sensation of anorectal obstruction/blockage for at least 25% of defecations
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`Efficacy was assessed using information provided by patients on a daily basis in an electronic diary. The primary efficacy
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`endpoint was the proportion of patients who were CSBM responders (i.e., having spontaneous bowel movements associated
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`with a sense of complete evacuation) during the 12-week treatment period. A responder was defined as a patient who had a
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`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
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`12 week treatment period, and at least 3 of the last 4 weeks of the trial.
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`In Trial SPD-304203-00, 21% of plecanatide-treated patients vs. 10% of placebo-treated patients met the responder criteria, for
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`a treatment difference of 11% (95% CI: 6.1%, 15.4%). In Trial SPD—304203-03, data from 30 patients were removed from
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`analysis clue to integrity issues identified at two clinical sites. The efficacy findings in this trial were similar; 21% of plecanatide-
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`m
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`Evidence, Uncertainties and Conclusions
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`treated patients vs. 13% of placebo-treated patients met the responder criteria, for a treatment difference of 8% (95% CI: 2.6%,
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`12.4%). In both trials, the responder rate for plecanatide was statistically superior to the placebo responder rate.
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`In addition, patients who received plecanatide 3 mg in these trials had statistically significant improvements in the secondary
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`efficacy endpoints of change from baseline over the 12-week treatment period in: CSBM frequency, SBM frequency (i.e.,
`
`spontaneous bowel movements occurring in the absence of laxative use), stool consistency score (as measured by the Bristol
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`Stool Form Scale) and straining score relative to placebo. The meaningfulness of these findings was evaluated using cumulative
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`distribution function plots to assess the amount of separation between treatment groups at meaningful responder thresholds
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`derived from Phase 2 data, if available. A modest but consistent separation between treatment groups was observed at the 1.8
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`CSBM, 2.8 SBM and 1.4 stool consistency thresholds. The meaningfulness of the improvement in straining score was also
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`demonstrated, but to a lesser extent as the separation between treatment groups at the -1 point straining threshold was small.
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`
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`Following completion of the drug treatment period, patients continued to record symptom data in the daily diary for 2 weeks
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`post-treatment. During this time, plecanatide-treated patients generally returned to baseline levels of constipation.
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`Comment. The efficacy of Trulance (plecanatide) has been established in two randomized placebo-controlled clinical trials in
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`adults with CIC. The efficacy of plecanatide in pediatric patients less than 18 years of age has not been established. The
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`assumption that GC—C agonism leads to movement of chloride and bicarbonate anions and water into the intestinal lumen and
`
`increased intestinal transit has been borne out by the submitted clinical trials of Trulance (plecanatide).
`
`I concur that the
`
`observed improvements in stool frequency, stool consistency and straining on plecanatide treatment were both statistically
`
`superior to placebo and clinically meaningful to adult patients with CIC.
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`A total of 863 and 870 adult patients with CIC administered plecanatide 3 mg or placebo, respectively, once daily for 12 weeks
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`in two double-blind, placebo-controlled clinical trials are evaluable for safety. The safety of plecanatide in pediatric patients
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`less than 18 years of age has not been established.
`
`General Considerations. Plecanatide is negligibly absorbed systemically following oral administration. Plecanatide does not
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`inhibit CYP2C9 or CYP3A4, and does not induce CYP3A4 in vitro. Plecanatide is neither a substrate or inhibitor of the
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`transporters P-glycoprotein or breast cancer resistance protein in vitro.
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`m
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`Evidence, Uncertainties and Conclusions
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`Although there are no data on plecanatide use in pregnancy to inform any drug-associated risks, use by pregnant women is not
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`expected to result in fetal exposure to the drug. No information is available regarding the presence of plecanatide in human
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`milk, or its effects on milk production or the breastfed infant.
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`Plecanatide is not tumorigenic in 2-year carcinogenicity studies in mice and rats. Plecanatide is not genotoxic in in vitro assays
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`or the in viva mouse bone marrow micronucleus assay, and has no effect on fertility or reproductive function in male or female
`mice.
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`Treatment—Emergent Adverse Events. During the 12-week double-blind, placebo-controlled period of the two randomized
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`clinical trials, the most frequent treatment-emergent adverse event was diarrhea. Diarrhea was reported in 5% and 1% of
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`patients treated with plecanatide 3 mg and placebo, respectively. The majority of cases occurred within 4 weeks of treatment
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`initiation. Severe diarrhea was reported in 0.6% and 0.3% of patients treated with plecanatide 3 mg and placebo, respectively,
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`and occurred within 3 days of treatment. Diarrhea was the most common adverse reaction leading to treatment
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`discontinuation: 2% of patients treated with plecanatide 3 mg and 0.5% of patients treated with placebo withdrew due to
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`diarrhea. Treatment-emergent adverse events were similar across age, gender, race and BMI subgroups.
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`
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`Comment.
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`In adults with CIC, treatment with plecanatide was generally well tolerated. Consistent with the known activity of
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`the drug, the treatment-emergent adverse event most commonly reported in clinical trials of plecanatide was diarrhea which
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`was severe in some cases.
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`I concur with the recommendation to suspend treatment with plecanatide and rehydrate the
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`patient if severe diarrhea develops. Plecanatide shares structural homology with uroguanylin, however, there was no evidence
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`of uroguanylin peptide depletion syndrome in clinical trials (as evidenced by hypernatremia, pulmonary edema, peripheral
`
`edema, sudden weight gain, and/or hypertension).
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`Risk of Serious Dehydration in Pediatric Patients. In young (1- to 2-week-old) juvenile mice (human age equivalent of
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`approximately 1 month to less than 2 years), single oral daily doses of plecanatide at 0.5 mg/kg and 10 mg/kg increased fluid
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`secretion into the intestine as a consequence of stimulation of GC—C. Deaths occurred in some mice within the first 24 hours,
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`apparently due to dehydration. Due to increased intestinal expression of GC—C, patients less than 6 years of age may be more
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`likely than older patients to develop severe diarrhea and its potentially serious complications.
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`

`

`m
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`Evidence, Uncertainties and Conclusions
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`Comment. Given the deaths observed in young juvenile mice in nonclinical studies and the lack of clinical safety and efficacy
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`data in pediatric patients less than 18 years of age, I concur with the recommendation to contraindicate use of Trulance
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`(plecanatide) in pediatric patients less than 6 years of age.
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`Labeling. The prescribers of Trulance (plecanatide) will likely be general practitioners and gastroenterologists familiar with
`
`treatments for CIC, including Linzess (linaclotide). Product labeling will address the serious safety concerns identified in
`
`nonclinical studies in young juvenile mice and with use in clinical trials, namely:
`
`0 Risk of serious dehydration in pediatric patients
`0 Severe diarrhea
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`In addition, a Medication Guide will be required as part of approved labeling to provide important safety information to
`
`patients; routine pharmacovigilance will be conducted in the postmarket setting.
`
`Risk Mitigation. A Risk Evaluation and Mitigation Strategy (REMS) will not be required for Trulance (plecanatide). It is likely
`
`that practitioners who will prescribe Trulance (plecanatide) for CIC will be aware of the attendant risks of treatment with GC—C
`
`agonists, given the previous marketing experience with the FDA-approved Linzess (linaclotide) product.
`
`
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`Postmarketing Required Studies.
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`Pediatric Research Equity Act (PREA)
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`The Agency is waiving the pediatric study requirement for ages birth to less than 2 years because there is evidence strongly
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`suggesting that Trulance (plecanatide) would be unsafe in this pediatric group. The applicant will be required to 1) assess the
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`pharmacokinetic profile of Trulance (plecanatide) in pediatric patients with CIC ages 12 to less than 18 years, then in patients
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`ages 6 to less than 12 years, and finally, in ages 2 to less than 6 years; 2) confirm the product’s efficacy and safety in pediatric
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`

`

`m
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`Evidence, Uncertainties and Conclusions
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`pediatric patients with CIC ages 2 to less than 18 years.
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`Food and Drug Administration Amendments Act (FDAAA)
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`The applicant will be required to:
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`(plecanatide) in pediatric patients, presence of the product in human breast milk, and its immunogenic potential.
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`o Characterize GC—C mRNA expression in duodenal and colonic mucosal biopsies in pediatric patients undergoing
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`diagnostic gastrointestinal endoscopies as part of their medical care. An analogous requirement was imposed on Forest
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`Laboratories, Inc., the applicant for the Linzess (linaclotide) NDA (202811). The Trulance applicant is encouraged to
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`collaborate with Forest Laboratories to complete this study.
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`Perform a milk-only lactation trial in lactating women receiving plecanatide therapeutically to assess concentrations of
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`plecanatide and its active metabolite in breast milk to inform product labeling. Because young juvenile mice
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`demonstrated increased sensitivity to plecanatide, it is important to determine how much drug is present in human
`breast milk.
`
`Develop and validate a sensitive assay for the detection of anti-plecanatide antibodies, including lgM, lgG, and lgA that
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`may be present in patient serum samples, and evaluate individual patient titers and the relationship between antibody
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`status and drug efficacy and safety;
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`Develop and validate assays to evaluate the cross-reactivity of anti-plecanatide antibodies to guanylin and uroguanylin,
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`and evaluate the relationship between cross-reactivity status and drug efficacy and safety; and
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`Develop and validate an assay to evaluate the neutralizing capacity of anti-plecanatide antibodies detected in patient
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`samples, and evaluate the relationship between neutralizing antibody status and drug efficacy and safety.
`
`Comment. The safety concerns identified in nonclinical studies and with use of Trulance (plecanatide) in clinical trials can be
`
`adequately managed by professional labeling, a Medication Guide, that will be required as part of approved labeling to
`
`communicate important safety information to patients, and routine pharmacovigilance in the postmarketing setting. The
`
`results of required postmarketing studies will further inform product labeling regarding the safe and effective use of Trulance
`
`

`

`
`
`
` 
` 
` 
`
`
`
`Reference ID: 4043837
`
`10
`
`APPEARS THIS WAY ON ORIGINAL
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`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JULIE G BEITZ
`01/19/2017
`
`Reference ID: 4043837
`
`