CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`208745Orig1s000
`
`RISK ASSESSMENT and RISK MITIGATION
`REVIEW(S)
`
`
`
`
`
`
`

`

`
`
`
`Application Type
`Application Number
`PDUFA Goal Date
`OSE RCM #
`
`Reviewer Name(s)
`
`Acting DRISK Team Leader
`
`Acting Deputy Division
`Director
`
`Review Completion Date
`
`Subject
`
`Established Name
`(Proposed) Trade Name
`Applicant
`
`Therapeutic Class
`Formulation(s)
`Dosing Regimen
`
`
`Division of Risk Management (DRISK)
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`Office of Surveillance and Epidemiology (OSE)
`Center for Drug Evaluation and Research (CDER)
`
`NDA
`208745
`January 29, 2017
`2016-286
`
`Jacqueline Sheppard, PharmD
`
`Robert Pratt, PharmD
`
`Jamie Wilkins Parker, PharmD
`
`
`November 9, 2016
`
`Evaluation to determine if a REMS is necessary
`
`Plecanatide
`Trulance
`Synergy Pharmaceuticals, Inc
`
`Guanylate cyclase agonist
`Oral tablet
`3 mg daily
`
`
`
`Reference ID: 4007210
`
`1
`
`

`

`
`
`Table of Contents
`
`EXECUTIVE SUMMARY ......................................................................................................................................................... 3
`1
`Introduction ..................................................................................................................................................................... 3
`2 Background ...................................................................................................................................................................... 3
`2.1
`Product Information ........................................................................................................................................... 3
`2.2
`Regulatory History............................................................................................................................................... 4
`3
`Therapeutic Context and Treatment Options .................................................................................................... 4
`3.1
`Description of the Medical Condition .......................................................................................................... 4
`3.2
`Description of Current Treatment Options ............................................................................................... 5
`4 Benefit Assessment ....................................................................................................................................................... 6
`5 Risk Assessment & Safe-Use Conditions .............................................................................................................. 7
`5.1
`Serious adverse events (SAEs) ....................................................................................................................... 7
`5.1.1
`Severe Diarrhea ........................................................................................................................................... 8
`5.1.2
`Deaths .............................................................................................................................................................. 8
`6
`Expected Postmarket Use ........................................................................................................................................... 8
`7
`Evaluating the Need for a REMS .............................................................................................................................. 8
`8 Risk Management Activities Proposed by the Applicant ............................................................................... 9
`9
`Conclusion & Recommendations ............................................................................................................................. 9
`10
`Appendices .................................................................................................................................................................. 9
`10.1 Materials Reviewed ............................................................................................................................................. 9
`
`
`
`
`
`Reference ID: 4007210
`
`2
`
`

`

`
`
`EXECUTIVE SUMMARY
`This review by the Division of Risk Management (DRISK) evaluates whether a risk evaluation and
`mitigation strategy (REMS) for the new molecular entity (NME) Trulance (plecanatide) is necessary to
`ensure the benefits of this product outweigh its risks. Synergy Pharmaceuticals Inc. submitted a New
`Drug Application (NDA 208745) for plecanatide with the proposed indication of treatment of chronic
`idiopathic constipation (CIC). The risk associated with the use of plecanatide is severe diarrhea including
`potentially fatal diarrhea in children. The Sponsor did not submit a proposed REMS or risk management
`plan with this application. Of note, plecanatide was studied in both 3 mg and 6 mg doses for the
`treatment of CIC, however during the course of the review the Sponsor elected to seek approval for only
`the 3 mg strength
`
`.
`
`DRISK and the Division of Gastroenterology and Inborn Errors Products (DGIEP) agree that a REMS is not
`needed to ensure the benefits of plecanatide outweigh its risks. Plecanatide was effective in increasing
`the frequency of complete spontaneous bowel movements (CSBM) and complete bowel movements
`(CBM) in patients with CIC and the side effect profile is similar to other GC-C agonists including the risk
`of severe diarrhea. Therefore, based on the available data, a REMS is not necessary for plecanatide to
`ensure the benefits outweigh its risks.
`
`1 Introduction
`This review by the Division of Risk Management (DRISK) evaluates whether a risk evaluation and
`mitigation strategy (REMS) for the new molecular entity (NME) Trulance (plecanatide) is necessary to
`ensure the benefits of this product outweigh its risks. Synergy Pharmaceuticals Inc. submitted a New
`Drug Application NDA 208745 for plecanatide with the proposed indication of treatment of chronic
`idiopathic constipation (CIC). This application is under review in the division of Gastroenterology and
`Inborn Errors Products (DGIEP). The sponsor did not submit a proposed REMS or risk management plan
`with this application.
`
`2 Background
`2.1 PRODUCT INFORMATION
`Plecanatide, a synthetic analogue of the uroguanylin peptide, is a new molecular entity (NME) that
`functions as an agonist of the guanylate cycylase-C (GC-C) receptor. GC- C receptors are involved in the
`regulation of fluid and electrolyte transport and in the maintenance of GI acidity. By the agonism of the
`GC-C receptors, plecanatide affects the sodium/potassium ion efflux and increases the secretion of fluid
`in the intestinal lumen. This mechanism is predicted to increase the frequency of bowel movements
`and improve stool consistency. Plecanatide’s proposed indication is the treatment of chronic idiopathic
`constipation (CIC) in adults.
`
`
`
`
`Reference ID: 4007210
`
`3
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`The proposed dosage form of plecanatide is an oral tablet. Tablets would be available in a 3 mg
`strength. The proposed dosage is 3 mg daily taken with or without food. Plecanatide will most likely be
`administered in an outpatient or long-term care setting. The duration of treatment for CIC is long-term.
`
`Plecanatide is not part of a drug class that has a REMS. However, the other GC-C agonist currently
`marketed in the United States, linaclotide, has a boxed warning for a contraindication in pediatric
`patients due to deaths in juvenile mice. Plecanatide is not currently approved in any jurisdiction.
`
`
`2.2 REGULATORY HISTORY
`The following is a summary of the regulatory history for NDA 208745 relevant to this review:
`
`• 01/29/2016: NDA 208745 submitted for treatment of chronic idiopathic constipation received.
`
`• 04/13/2016: Filing Review communication where the Agency requested the Sponsor submit a
`Medication Guide (MG) for plecanatide using linaclotide as the template.
`
`• 06/08/2016: Sponsor submitted updated labeling including a Medication Guide in response to
`Agency’s April 13, 2016 filing Review communication.
`
`• 07/14/2016: Mid-cycle teleconference
`
`
`
`
`
` It was
`communicated that at a REMS will not be necessary to ensure that benefits of the drug
`outweigh the risks.
`
`3 Therapeutic Context and Treatment Options
`3.1 DESCRIPTION OF THE MEDICAL CONDITION
`Chronic idiopathic constipation is a common disorder that affects 12-19% of North Americans. CIC is
`defined as active constipation symptoms within the last three months with at least two other symptoms
`during 25% of defecations. Associated symptoms include stool frequency of less than 3 per week,
`straining at stool, feelings of incomplete evacuation, need for digital manipulation, or rectal pressure or
`pain. 1 Multiple studies have demonstrated living with chronic constipation reduces patients’ quality of
`life.2
`
`
`
`1 Lacy B, Levenick J and Crowell, M. (2012) Recent advances in the management of difficult constipation. Current
`gastroenterology reports, 14(4), 306-312.
`
`2 Lacy B, Levenick J and Crowell, M. (2012) Recent advances in the management of difficult constipation. Current
`gastroenterology reports, 14(4), 306-312.
`
`4
`
`
`
`Reference ID: 4007210
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
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`3.2 DESCRIPTION OF CURRENT TREATMENT OPTIONS
`First line treatments for CIC include increased dietary fiber consumption, increased exercise, increased
`water consumption, and bowel habit training which typically result in partial relief. Over-the-counter
`(OTC) laxatives are not suitable for long-term use by patients with CIC as they are recommended for
`periodic use only. Frequently, patients with CIC have regular, chronic use of laxatives leading to adverse
`events including dependency, tolerance, electrolyte imbalance, and melanosis coli.
`
`In the United States, lubiprostone and linaclotide are approved to treat CIC. Lubiprostone is a calcium
`channel activator available as an oral capsule taken twice daily with food or water. The agent may cause
`dyspnea within an hour of dosing. Linaclotide is a GC-C agonist available as an oral capsule taken daily
`on an empty stomach. The agent has a boxed warning for pediatric use as it is contraindicated in
`children up to the age of 6 and should be avoided in patients 6-17 years of age due to causing deaths
`due to dehydration in juvenile mice. Both products are contraindicated in patients with known or
`suspected mechanical bowel obstructions.
`
`The Applicant states that plecanatide, a GC-C agonist similar to linaclotide, would broaden the
`treatment landscape and offer an alternative treatment option for patients with CIC.
`
`
`
`Reference ID: 4007210
`
`5
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`

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`Table 1: Summary of Pharmaceutical Treatment Options for CIC
`
`Established
`
`Year of
`
`Dosing/Administration
`
`Important Safety
`
`Risk
`
`Name (Trade Approval
`
`and Tolerability
`
`Management
`
`Name)
`
`Issues
`
`Approaches]
`Boxed
`
`Warning,
`Medication
`
`Guide
`
`Lubiprostone
`
`(Amitiza)
`
`Chloride
`
`channel
`activator
`
`24 mcg orally twice
`
`-CI in patients with
`
`daily with food and
`water
`
`known or suspected
`mechanical GI
`
`diarrhea
`
`Linaclotide
`
`(Linzess)
`
`GC-C
`
`agonist
`
`obstruction
`
`-may cause
`
`dyspnea
`
`145 mg orally daily
`
`-CI in patients
`
`-Boxed
`
`under age 6, avoid Warning
`
`use In patients 6-17
`years of age
`
`-Medication
`Guide
`
`-CI in patients with
`
`known or suspected
`mechanical GI
`
`obstruction
`
`—may cause severe
`
`4 Benefit Assessment
`
`The efficacy and safety of plecanatide for the treatment of CIC in adults was demonstrated in two phase
`
`three randomized, double-blind, placebo-controlled trials. Both studies evaluated the efficacy and
`
`safety of oral plecanatide 3 mg and 6 mg tablets in patients with CIC. The two studies were conducted
`
`concurrently in the same geographic area, with the same drug, and the same protocol. The primary
`
`endpoint of the pooled study was the durable overall complete spontaneous bowel movement (CSBM)
`
`responder rate. This was defined as a patient who has greater or equal to 3 CSBM in a given week and
`an increase from baseline of at least 1 CSBM in the same week for at least 9 of the 12 treatment weeks.
`
`Secondary endpoints include change from baseline in stool consistency, mean number of spontaneous
`
`bowel movements, and daily reported constipation symptoms including abdominal discomfort, bloating,
`
`and/or pain. An additional phase three, open label safety study (SP 304203-01) was conducted with a
`
`safety population of 1782 patients with up to two weeks of closing.
`6
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`Reference ID: 4007210
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`
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`During review of the NDA, the Office of Scientific Integrity (OSI) determined that data from two specific
`sites (#362 and #402) may pose data integrity issues due to past FDA violations. As a result, a decision
`was made at mid-cycle meeting that data from these sites should be considered unreliable and the data
`was removed from the efficacy and safety analysis. Furthermore, it was noted that there were 164
`duplicate patients that were randomized more than one time in the primary safety pool studies. These
`duplicate patients, except for the 44 patients identified as index patients, were removed from the safety
`analysis. Additionally during the midcycle teleconference, the Sponsor elected to seek approval for only
`the 3 mg strength
`
`
`The two phase 3 efficacy studies (Studies SP304203-00 and SP304203-03) randomized patients 18 to 80
`years old to receive placebo, plecanatide 3 mg, or plecanatide 6 mg daily over a 12-week treatment
`period. In study SP304203-00, which randomized 453 patients to the 3 mg treatment group and 452
`patients to placebo, the proportion of CSBM responders over Weeks 1 – 12 was significantly greater in
`patients receiving plecanatide compared to placebo (21.0% in the 3 mg group, versus 10.2 %, in the
`placebo, p<0.001). Similarly, in Study SP304203-03 , which randomized 443 patients to the 3 mg
`treatment group and 445 patients to placebo, the proportion of CSBM responders over Weeks 1 – 12
`was significantly greater in patients receiving plecanatide compared to placebo (20.5% in the 3 mg
`group, versus 13.0 %, in the placebo, p<0.003). Therefore, for the primary endpoint analysis, the results
`of the pooled analysis are highly statistically significant for the plecanatide treatment arm compared to
`placebo. The 3 mg plecanatide treatment was also clinically meaningful and statistically significantly
`more effective than placebo for the secondary endpoints of weekly CSBM and SBM frequency, and stool
`consistency. The clinical reviewer concluded that the increases in the stool frequency, via the increase
`in number of CSBMs and SBMs in a week, may have clinical meaningfulness to many patients who suffer
`from CIC.
`
`5 Risk Assessment & Safe-Use Conditions
`The primary safety population included 2627 subjects exposed to either 3 mg, 6 mg, or placebo in the
`pooled analysis of the two phase three studies. Due to the data integrity issues that arose during review
`of this application, select safety analyses were performed excluding duplicate patients that enrolled in
`more than one plecanatide study. Additionally, data from sites #362 and #402 was excluded from
`analysis. The secondary safety pool was comprised of 2370 patients in a long-term, open-label
`extension study and 508 patients in two phase 2 studies. For the purpose of this review, an adverse
`event (AE) was defined as any untoward medical occurrence in subject that might or might not have had
`a causal relationship with plecanatide. The most commonly occurring adverse reactions associated with
`plecanatide include was diarrhea (5 %) and sinusitis (1.4%).
`
`5.1 SERIOUS ADVERSE EVENTS (SAES)
`
`
`7
`
`
`
`Reference ID: 4007210
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`5.1.1 Severe Diarrhea
`Plecanatide use was associated with severe diarrhea in 0.6% of patients in the 3 mg plecanatide group
`compared to 0.3% patients in the placebo group. Sites were instructed to record an AE of diarrhea only
`if the patient reported the effect was bothersome, had a Bristol Stool Chart (BSFS)3 score of 6 or 7, had a
`sense of urgency or required treatment or hospitalization. Events were coded as severe if they were
`medically significant but not immediately life-threatening; disabling; or involved limitations of self-care
`activities of daily living. Severe diarrhea led to discontinuation in 2.1% of the primary safety pool. The
`Applicant’s proposed labeling includes a statement in the Warnings and Precautions section for severe
`diarrhea. This warning is also included in the labeling for linaclotide, another agent in the class.
`
`In six separate non-clinical studies, plecanatide was associated with deaths of juvenile mice. Deaths
`were observed in neonatal mice after a single dose of 1 mg/kg/day at postnatal day 7 and juvenile mice
`after a single dose of 10 mg/kg at postnatal day 14. These ages correspond to human infants and
`children under the age of 2. Therefore, plecanatide will be contraindicated in children under the age of
`six. The Applicant’s proposed labeling includes a boxed warning for contraindication in pediatric
`patients up to 6 years of age due to death from dehydration in juvenile mice and avoidance in pediatric
`patients age 6 to 17 years of age.
`
`5.1.2 Deaths
`One death occurred during the clinical development program for plecanatide. One patient in the 6 mg
`plecanatide long-term safety study died due to myocardial infarction attributed to recent cocaine abuse
`in the setting of underlying coronary disease. The patient, a 47 year old male, with a history of
`substance abuse was hospitalized for acute renal insufficiency and myocardial infarction. He was
`subsequently discharged and suffered another myocardial infarction which was fatal. The clinical
`reviewer agrees with the Sponsor that the death was unrelated to the study drug.
`
`6 Expected Postmarket Use
`The likely prescribers for plecanatide will be general practitioners and gastroenterologists which are the
`same prescribers for the existing approved treatments for CIC, lubiprostone and linaclotide.
`Plecanatide will be prescribed primarily in outpatient and long-term care settings. A Medication Guide
`(MG) will be included in the final labeling.
`
`7 Evaluating the Need for a REMS
`The pivotal trials showed that plecanatide achieved the primary endpoints and was effective in
`increasing the frequency of CSBMs and CBMs in patients with CIC. The most important safety concern
`with plecanatide is severe diarrhea including potentially fatal diarrhea in children. The safety of
`plecanatide is similar to other treatments for CIC including linaclotide. Linaclotide, approved in 2012,
`
`3 Bristol Stool Chart (BSFS) is a validated measure of stool consistency commonly used in clinical trials.
`
`8
`
`
`
`Reference ID: 4007210
`
`

`

`
`
`has a boxed warning for severe diarrhea and is contraindicated in children under the age of 6 due to
`deaths in juvenile rats. The risk of severe diarrhea including potentially fatal diarrhea in the pediatric
`population associated with plecanatide will be addressed through a boxed warning, and in the Warnings
`and Precautions and Contraindications section of the prescribing information. Additionally, plecanatide
`will have a MG. Therefore, based on the available data the risks of plecanatide a REMS is not necessary
`to ensure its benefits outweigh the risks.
`
`8 Risk Management Activities Proposed by the Applicant
`The Applicant did not propose any risk management activities for plecanatide beyond routine
`pharmacovigilance and labeling.
`
`9 Conclusion & Recommendations
`Based on the available data, a REMS is not necessary for plecanatide to ensure the benefits outweigh
`the risks. Plecanatide was effective in increasing the frequency of CSBMs and CBMs in patients with CIC.
`Additionally, the side effect profile is similar to other GC-C agonists including the risk of severe diarrhea.
`Therefore, based on available data, the safety and risk mitigation approach of plecanatide is similar to
`other drugs in the class, the risks will be communicated via labeling including the use of a Medication
`Guide and boxed warning.
`
`Should DGIEP have any concerns or questions, or if new safety information becomes available, please
`send a consult to DRISK.
`
`10 Appendices
`10.1 MATERIALS REVIEWED
`The following is a list of materials informing this review:
`
`1. Synergy Pharmaceuticals, Inc. Proposed Prescribing Information for plecanatide, dated January
`29, 2016.
`
`2. Synergy Pharmaceuticals, Inc. Clinical Overview for plecanatide, dated January 29, 2016.
`
`3. Synergy Pharmaceuticals, Inc. Summary of Clinical Safety for plecanatide, dated January 29,
`2016.
`
`4.
`
` Hayes, L. DGIEP. Clinical Review for plecanatide [NDA 208745], dated October 12, 2016.
`
`5. Synergy Pharmaceuticals, Inc. Draft Medication Guide for plecanatide, dated June 8, 2016.
`
`
`
`
`
`Reference ID: 4007210
`
`9
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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/
`----------------------------------------------------
`
`JACQUELINE E SHEPPARD
`11/09/2016
`
`JAMIE C WILKINS PARKER
`11/10/2016
`
`Reference ID: 4007210
`
`