CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`208745Orig1s000
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`
`
`
`
`
`

`

`OFFICE OF CLINICAL PHARMACOLOGY REVIEW
`
`NDA
`Relevant IND(s)
`Submission Date (s)
`PDUFA Date:
`Brand Name
`Generic Name
`Submission Type
`Dosage Form, Strength
`Proposed indication
`Sponsor Recommended
`Dosing Regimen
`Sponsor
`OND Division
`OCP Division
`OCP Reviewer
`OCP Team Leader
`
`208-745
`74883
`01/29/2016, 9/22/2016
`01/29/2017
`TRULANCE™
`Plecanatide
`Original, 505(b)(1), NME
`Tablet, 3 mg
`Treatment of chronic idiopathic constipation (CIC) in adults
`
`3 mg Once daily
`
`Synergy Pharmaceuticals Inc
`Division of Gastroenterology and Inborn Errors Products
`Division of Clinical Pharmacology 3
`Dilara Jappar, Ph.D.
`Sue-Chih Lee, Ph.D.
`
`2
`
`Table of Contents
`1.
`Executive Summary .................................................................................................................2
`1.1
`Recommendations ......................................................................................................2
`1.2
`Recommended Post-Marketing Studies .....................................................................2
`1.3
`Clinical Pharmacology Highlights .............................................................................2
`Question-Based Review ...........................................................................................................4
`2.1
`General Attributes of the drug....................................................................................4
`2.2
`General Clinical Pharmacology..................................................................................6
`2.3
`Exposure-Response Evaluation..................................................................................8
`2.5.
`PK characteristics of drug ........................................................................................12
`2.6
`Intrinsic Factors........................................................................................................17
`2.7
`Extrinsic Factors.......................................................................................................17
`2.8
`General Biopharmaceutics .......................................................................................31
`2.9
`Analytical Section ....................................................................................................37
`
`
`
`Reference ID: 3996096
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`

`

`1. Executive Summary
`
`Plecanatide (SP-304) is a synthetic, 16-amino acid peptide with 2 disulfide bonds that is a second-
`in-class guanylate cyclase-C (GC-C) receptor agonist. The proposed indication for plecanatide is
`treatment of chronic idiopathic constipation in adults with 3 mg oral dose once daily. In support
`of this NDA, the sponsor had submitted 7 in-vitro studies to evaluate the potential drug-drug
`interaction, 2 phase I studies to evaluate the food effect and single ascending dose PK in healthy
`subjects, 3 phase II studies, 2 phase III efficacy and safety studies with 3 mg and 6 mg dose and
`one long-term phase III safety study to support the safety and efficacy of plecanatide. In addition,
`the submission contained 4 bioanalytical validation reports. PK samples were also obtained from
`the patient population in the phase 2 and 3 studies.
`
`1.1 Recommendations
`The Office of Clinical Pharmacology has found the submission acceptable from a clinical
`pharmacology standpoint provided a mutual agreement on labeling languages is reached between
`the FDA and the sponsor.
`
`1.2 Recommended Post-Marketing Studies
`None
`
`1.3 Clinical Pharmacology Highlights
`
`Dose-Response for Efficacy:
`Exposure-response relationship other than dose response for efficacy for plecanatide was not
`evaluated since plecanatide did not have measurable systemic exposure.
`Phase 2b study (SP304-20210) had evaluated 0.3, 1.0, and 3.0 mg QD oral doses of plecanatide
`versus placebo in a total of 951 CIC patients over a 12-week treatment period. The 3.0 mg dose
`provided the highest overall responder rate (19.0% vs. 10.7% for placebo) and a statistically
`significant treatment difference compared to placebo (p = 0.009) while 1 mg dose did not result in
`statistically significant difference from the placebo (p = 0.057). Interestingly, 0.3 mg dose level
`also resulted in a statistically significant difference from the placebo (p = 0.016) although the
`sponsor claims that 0.3 mg dose was examined in an exploratory nature.
`Two dose levels, 3 mg and 6 mg, were evaluated in 2 phase III studies in CIC patients with 12
`weeks treatment period. No dose-response was observed between 3 mg and 6 mg doses for
`primary efficacy endpoint while both dose levels have shown statistically significant
`improvement over placebo.
`
`Dose-Response for Safety:
`Exposure-response relationship other than dose-response for safety for plecanatide was not
`evaluated since plecanatide did not have measurable systemic exposure.
`In the phase 2a study (SP304201-09) with 0.3, 1.0, 3.0, and 9.0 mg QD oral dose levels of
`plecanatide over 14 days of treatment (versus placebo) in a total of 78 CIC patients, there is no
`clear trend in AE over plecanatide dose ranges but the 9.0 mg dose appears to be associated with
`a higher rate of drug-related AEs (33.3%) compared to placebo (10%) or other dose levels (6.4-
`14.3%). As such, the 9 mg dose was not included in the Phase 2b study.
`In Phase 2b dose-ranging study (SP304-20210) with 0.3, 1.0, and 3.0 mg QD oral doses of
`plecanatide over 12 weeks of treatment in a total of 951 CIC patients (including those on
`placebo), there appears to be dose-related increase in diarrhea, abdominal pain, number patients
`
`2
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`with at least one Treatment-Emergent Adverse Events (T'EAE), number of T'EAEs and overall
`drug-related AE.
`In the 2 phase III studies, there does not appear to be a clear dose-response for the majority of
`adverse events between 3 mg and 6 mg doses. However, there were some increase in diarrhea
`and nasopharyngitis with the higher dose of 6 mg compared to 3 mg.
`
`Dose Selection:
`
`The phase 2b study evaluated 0.3. 1.0. and 3.0 mg doses of plecanatide and had shown that the
`3.0 mg dose provided a statistically significant treatment difference compared to placebo (p =
`0.009) while 1 mg dose did not result in a statistically significant efficacy compared to placebo (p
`=0.057). Based on the result of this phase 2b study. the 3 mg dose was selected for phase 3
`studies.
`In addition. a 6 mg dose level was added in phase 3 studies to evaluate whether the
`efficacy could be improved further while maintaining the safety profile within an acceptable
`range.
`
`In the phase 3 studies, both 3 mg and 6 mg doses resulted in statistically significant
`improvements over placebo. However, 6 mg dose was not numerically superior to the 3 mg dose
`on most endpoints although the studies were not sized for a direct comparison of 3 and 6 mg
`doses levels of plecanatide.
`new the sponsor had proposed (m4) 3 mg
`specifying the distinct subpopulation
`
`«no dose levels for CIC indication without
`(m4)(m4)
`
`(no) The M" proposed
`dose of 3 mg is consistent with known dose-response relationship for both efficacy and safety.
`
`Pharrnacokinetics:
`
`The sponsor attempted to measure the plasma concentration of plecanatide and its active
`metabolite SP—338 in healthy subjects and in CIC patient population. However. systemic
`exposures of the parent drug plecanatide or its active metabolite SP—338 were not detectable in
`hmnan plasma up to 9 mg plecanatide dose (3 time the clinical dose of 3 mg) with LC-MS/MS
`bioanalytical method (with LLOQ of 1.0 ng/mL for plecanatide and 0.775 ng/mL for SP-338)
`suggesting insignificant absorption of plecanatide peptide and its metabolite SP-338 following
`oral route of administration.
`
`Food Effect:
`
`When 9 mg plecanatide tablet was administered with or without food in 24 healthy subjects, only
`1 subject had detectable level of plecanatide at 0.5 and 1 hour post-dose under fasted state.
`Plecanatide concentrations were below the limit of quantitation for all other time points and for
`all other subjects. The active metabolite was not detected in any subjects. Food had minimal
`effect on bowel movement frequency. time to first bowel movement. fecal urgency, and fecal
`incontinence. Administration of 9 mg plecanatide with food had noticeable PD effect in Bristol
`Stool Form Scale GBSFS) scores and the incidence of abdominal cramping where food (both HF—
`HC and LF—LC) appear to increase BSFS score resulting in looser stool and increase the
`incidence of moderate and severe abdominal cramping and degree of abdominal cramping
`compared to fasted state. In both of the phase III studies. subjects were instructed to take the
`study drug with or without food at their own choice.
`In the proposed label, the sponsor is
`proposing to take plecanatide with or without food. However, based on the result of this food
`effect study, the agency recommends taking plecanatide with or without food in general but for
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`patients who experience abdominal cramping, plecanatide tablet should be taken under fasting
`condition. This is under further discussion with the medical review team.
`
`Protein binding:
`Plecanatide do not have detectable level of drug in the plasma at the proposed dose. Therefore,
`protein binding of plecanatide is not a concern. Nonetheless, plecanatide did not have significant
`binding to major human plasma proteins human serum albumin (HSA) and human α1-acid
`glycoprotein (AGP) proteins.
`
`Metabolism:
`In the simulated intestinal fluid (SIF), plecanatide is rapidly hydrolyzed at its C-terminus by
`cleavage of the Leu16 resulting in generation of a biologically active metabolite SP-338. SP-338
`is further processed by an internal cleavage at Leu6-Cys7 resulting in a biologically inactive
`Leu6-clipped SP-338. However, potential metabolites of SP-338 were not quantitated. The
`potential metabolism by CYPs enzymes in human intestinal microsomes was not evaluated.
`
`CYP inhibition /induction:
`As the parent drug SP-304 and its metabolite SP-338 have limited systemic exposure, only CYP
`enzymes that are expressed in gastrointestinal tract, CYP2C9 and CYP3A, were evaluated for
`potential inhibition and induction by the parent drug SP-304 and its metabolite SP-338. Based on
`the in-vitro studies, plecanatide and its major metabolite SP-338 are not likely to inhibit CYP2C9
`and CYP3A4 or induce CYP3A4 at the proposed dose.
`
`Transporters:
`As the parent drug SP-304 and its metabolite SP-338 have limited systemic exposure, only
`transporters that are expressed in the gastrointestinal tract, P-gp and BCRP, were evaluated for
`potential interaction with the parent drug SP-304 and its metabolite SP-338. Based on the in-
`vitro study on Caco-2 cells, both parent drug plecanatide SP-304 and its active metabolite
`SP-338 are not substrates or inhibitors of gut transporters P-gp and BCRP.
`
`2 Question-Based Review
`
`2.1 General Attributes of the drug
`
`2.1.1 What are the highlights of the chemistry and physical-chemical properties of the
`drug substance, and the formulation of the drug product as they relate to clinical
`pharmacology review?
`Plecanatide (SP-304) is a synthetic, 16-amino acid peptide with 2 disulfide bonds. The molecular
`formula is C65H104N18O26S4 and the molecular weight is 1682 g/mol.
`
`Figure 1: Structure of Plecanatide (SP-304)
`
`Reference ID: 3996096
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`4
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`Plecanatide is developed as immediate-release oral tablet at 3 mg
`application.
`
` strength in this
`
`2.1.2 What are the proposed mechanism(s) of action and therapeutic indication(s)?
`The proposed indication for plecanatide is treatment of chronic idiopathic constipation in adults.
`
`Plecanatide (SP-304) is a synthetic, hexadecapeptide, guanylate cyclase-C (GC-C) receptor
`agonist. Plecanatide is an analog of the endogenous human uroguanylin peptide (identical with
`the exception of a single amino acid substitution) which is also a member of the GC-C agonist
`class. It is proposed that both plecanatide and its active metabolite SP-338 bind to GC-C and act
`locally on the luminal surface of the intestinal epithelium. Activation of GC-C results in an
`increase in both intracellular and extracellular concentrations of cyclic guanosine monophosphate
`(cGMP). Elevation of intracellular cGMP stimulates secretion of chloride and bicarbonate into
`the intestinal lumen, mainly through activation of the cystic fibrosis transmembrane conductance
`regulator ion channel (CFTR), resulting in increased intestinal fluid and accelerated transit. In
`animal models, plecanatide has been shown to increase fluid secretion into the gastrointestinal
`(GI) tract, accelerate intestinal transit, and cause changes in stool consistency. Similar to
`uroguanylin, the binding of plecanatide to the intestinal GC-C receptors in the lumen of the GI
`tract is regulated by intestinal pH levels; therefore, plecanatide is anticipated to exert the bulk of
`its effect in the acidic environment of the upper GI tract, where it binds more strongly to GC-C
`receptors.
`
`2.1.3 What are the proposed dosage(s) and route(s) of administration?
`The proposed dose of plecanatide tablet is 3 mg once daily by oral route of administration with or
`without food.
`
`2.1.4 What is the regulatory background?
`The first-in-class guanylate cyclase C (GC-C) receptor agonist, Linzess (linaclotide), was
`approved in 2012. Linaclotide was a chemically synthesized 14-amino acid peptide with 3
`disulfide bonds that was also an analog of the endogenous human uroguanylin peptide.
`
`Reference ID: 3996096
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`(b) (4)
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`

`2.2 General Clinical Pharmacology
`
`2.2.1 What are the design features of the clinical pharmacology and clinical studies used
`to support dosing or claims?
`In support of this NDA, the sponsor had submitted 2 phase I studies, 3 phase II studies and 2
`phase III efficacy and safety studies, one long-term phase III safety study and 7 in-vitro studies.
`In addition, it contained 4 bioanalytical validation reports. Please see table 1 and table 2 for more
`information.
`
`Phase I clinical pharmacology program included one single ascending dose study and a food
`effect study in healthy subjects. In-vitro studies characterized the protein binding, metabolic
`stability in simulated intestinal fluid (SIF) and in human cadaver intestinal fluid, inhibition and
`induction potential of CYP enzymes expressed in the gastrointestinal tract and potential of
`plecanatide and its metabolite being substrate or inhibitor of transporters expressed in the
`gastrointestinal tract. Additionally, four bioanalytical method validation reports along with 5
`additional amendments to analyze the concentrations of plecanatide and its metabolite SP-338 in
`human plasma were submitted.
`
`Table 1: In-Vivo Clinical Pharmacology and Clinical Studies:
`Study #
`Objective(s)
`Study Design
`Test product; Dosage Regimen;
`Route of administration
`
`Subjects
`
`Duration of
`Treatment
`
`1 day
`
`SP304101-08 Safety and
`tolerability;
`identification of
`the MTD; PK,
`and effect of
`a single dose on
`bowel function
`SP304101-09 Effect of food on
`PD, PK, safety,
`& tolerability
`
`SP304201-09 Safety, PK & PD;
`no efficacy
`assessments
`
`SP304-20210 Safety & efficacy
`of plecanatide
`in adults with
`CIC
`
`Phase 1,randomized
`(6:2 withincohort), DB,
`PBO-ctrl, single-dose,
`ascending-dose study
`
`71 healthy subjects:
`Plecanatide oral solution or PBO
`solution (PBS), with 9 Plecanatide
`53 plecanatide
`
`dose cohorts (8 subjects each): 0.1, 18 PBO
`0.3, 0.9, 2.7, 5.4, 8.1, 16.2, 24.3, &
`48.6 mg Single oral dose
`No rescue med
`
`Phase 1, single-blind,
`PBO-ctrl, crossover,
`Randomized (8:2 & to
`Treatment sequence
`and then to active
`drug or PBO), single
`dose study
`Phase 2a randomized
`(15:5 within cohort),
`DB, PBO-ctrl,
`Ascending dose cohort,
`dose-ranging study
`Phase 2b, randomized,
`DB, PBO-ctrl, dose
`ranging study
`
`30 healthy adult
`subjects:
`24 plecanatide
`6 PBO
`
`Plecanatide tab or PBO tab
`Single oral 9 mg dose under 3
`meal conditions:
`fasted
`fed HFHC meal
`fed LFLC meal
`No rescue med
`78 patients:
`Plecanatide cap or PBO cap, with
`58 plecanatide
`4 plecanatide dose cohorts (0.3,
`(14 at 0.3 & 1.0 mg,
`1.0, 3.0, and 9.0 mg)
`15 at 3 & 9 mg)
`Once daily orally (fasted)
`20 PBO
`Rescue med: bisacodyl
`
`Plecanatide 0.3, 1.0, or 3.0 mg cap 948 patients:
`or PBO cap
`712 plecanatide
`Once daily orally
`(567 for 12 wk)
`Rescue med: bisacodyl
`236 PBO
`
`3 days
`
`14 days
`
`12 weeks
`
`SP304203-00 Safety and
`Efficacy
`
`Phase 3, randomized,
`DB, PBO-ctrl, oral,
`dose ranging study
`
`Plecanatide 3 or 6 mg tab or
`PBO tab
`Once daily orally
`Rescue med: Bisacodyl
`
`12 weeks
`
`Total 1389 patients:
` 474 at 3 mg
` 457 at 6 mg
` 458 PBO
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`Reference ID: 3996096
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`(b) (4)
`
`

`

`SP304203-03 Safety and
`Efficacy
`
`Phase 3, randomized,
`DB, PBO-ctrl study
`
`SP304203-01 Long-term safety
`and tolerability
`
`Phase 3, open-label
`
`Plecanatide 3 or 6 mg tab or PBO
`tab
`Once daily orally
`Rescue med: bisacodyl
`
`Total 1402 patients:
` 467 at 3 mg
` 469 at 6 mg;
` 466 PBO
`
`12 weeks
`
`Plecanatide 3 or 6 mg tab
`Once daily orally
`Rescue med: Bisacodyl
`
`1782 plecanatide
`230 at 3 mg
`1552 at 6 mg;
`
`Up to 2
`Years
`
`Table 2: In-Vitro Studies
`Study #
`Type of Study
`RSN00008
`Protein Binding
`
`13SYNRP1A Transporter
`
`13SYNRP6A Transporter
`13SYNRP1B CYP inhibition
`/induction by plecanatide
`13SYNRP6B CYP inhibition
`/induction by metabolite
`Stability
`Stability in SIF
`
`SP-PH-018
`SP-PH-015
`
`Title/Objective(s) of the Study
`Binding of Test Compound SP-304 to HAS and Human AGP
`
`Determining the Substrate and Inhibition Potential of Plecanatide (SP-304) for P-
`gp and BCRP
`Determining the Substrate and Inhibition Potential of SP-338 for P-gp and BCRP
`In Vitro Metabolism Studies of Plecanatide (SP-304)
`
`In Vitro Metabolism Studies of SP-338
`
`Stability of Plecanatide in Human Intestinal Fluid
`Assessment of Plecanatide Stability and Metabolite Identification After Treatment
`with Simulated Intestinal Fluid in the Presence and Absence of Reducing Agents
`
`2.2.2 What is the basis for selecting the response endpoints and how are they measured in
`clinical pharmacology and clinical studies?
`The proposed indication is treatment of chronic idiopathic constipation in adults. Accordingly,
`evaluation of clinical efficacy of plecanatide focused on resolving constipation.
`
`Phase I studies:
`SAD study SP-SP304101-08
`PD: Time to first stool, stool frequency (48-hour period), and stool consistency (48-hour period)
`using the Bristol Stool Form Scale (BSFS)
`
`Food Effect study SP304101-09
`PD: bowel movement frequency, stool consistency, time to first bowel movement, fecal urgency,
`fecal incontinence and soiling, and abdominal cramping.
`
`Phase II studies:
`Phase 2a study SP-SP304201-09:
`PD: Stool frequency was assessed as a combination of Complete Spontaneous Bowel Movement
`(CSBM) and Spontaneous Bowel Movement (SBM); Stool Consistency was assessed with 7-
`point Bristol Stool Form Scale; Ease of Passage (Straining) measured using the 7-point Ease-of-
`Passage Scale; Completeness of Evacuation, The time to first bowel movement
`
`Phase 2b study SP-SP304202-10:
`The primary efficacy endpoint was the proportion of patients who were overall CSBM
`responders.
`The secondary efficacy endpoints included change from baseline in 12-week CSBM frequency
`rate, time to first CSBM, change from baseline in the 12-week SBM frequency rate, time to first
`SBM, stool consistency as measured by the Bristol Stool Form Scale (BSFS), days of rescue
`medication use, and straining.
`
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`Phase III studies (SP304203-00 and SP304203-03):
`The primary efficacy endpoint was the proportion of patients who were durable overall complete
`spontaneous bowel movement (CSBM) responders over the 12-week treatment period. A CSBM
`weekly responder was defined as patient how had ≥3 CSBM in a given week and an increase
`from baseline of ≥ 1 CSBM for that same week. An overall CSBM responder was defined as a
`patient who was a weekly responder for at least 9 of the 12 treatment weeks, and a durable overall
`CSBM responder was also a weekly responder in at least 3 of the last 4 weeks.
`
`Secondary efficacy endpoints included:
` Change from baseline in frequency rate of CSBMs and Spontaneous bowel movements
` Change from baseline in stool consistency based on the Bristol Stool Form Scale
` Change from baseline in Straining Score
` Treatment satisfaction
`Patient reported symptoms associated with constipation in the Daily Symptom Diary
`
`
`2.2.3 Are the active moieties in the plasma and urine appropriately identified and
`measured
`to assess pharmacokinetic parameters and
`exposure-response
`relationships?
`Yes, concentrations of plecanatide and its active metabolite SP-338 in plasma were analyzed by
`appropriately validate LC-MS/MS bioanalytical methods with LLOQ of 1.0 ng/mL for
`plecanatide and LLOQ of 0.775 ng/mL for SP-338. Please see the analytical section 2.9 for more
`details. Plasma levels for both plecanatide and its metabolite SP-338 were undetectable in plasma
`up to 9 mg of oral dose.
`
`2.3 Exposure-Response Evaluation
`
`2.3.1 What are the characteristics of the exposure-response relationships for efficacy?
`Exposure-response relationship for efficacy for plecanatide was not evaluated since plecanatide
`did not have measurable systemic exposure.
`
`Phase 2a study (SP304201-09) was a randomized, double-blind, placebo-controlled, dose-ranging
`study that evaluated 0.3, 1.0, 3.0, and 9.0 mg QD oral doses of plecanatide over 14-day days of
`treatment in a total of 78 CIC patients. As the primary objective study was to evaluate safety, the
`study was not powered to demonstrate statistical differences between SP-304 and placebo
`regarding the efficacy. Nonetheless, multiple parameters assessed during the study indicated that
`SP 304 had a greater effect on symptoms of CIC and greater patient satisfaction compared to
`placebo. SP-304 patients reported a greater degree of improvement compared to baseline in
`complete spontaneous bowel movement, spontaneous bowel movement, stool consistency, and
`straining versus placebo patients; however, no clear dose-response relationship was noticeable for
`most efficacy endpoint except that a trend toward shorter mean time to first bowel movement was
`observed with increasing dose of SP-304 (23.7, 19.5, 17.4, and 11.0 hours for the 0.3, 1.0, 3.0,
`and 9.0 mg SP-304 dose levels, respectively).
`
`Phase 2b Study (SP304-20210) was a randomized, double-blind, placebo-controlled, dose-
`ranging study that evaluated 0.3, 1.0, and 3.0 mg QD oral doses of plecanatide versus placebo
`over 12 weeks of treatment in a total of 951 CIC patients. The primary efficacy endpoint was the
`proportion of patients who were durable overall CSBM responders over the 12-week treatment
`period, which was the same primary endpoint included in the two phase 3 studies. On the
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`

`primary endpoint, the 3.0 mg dose provided the highest overall responder rate versus placebo
`(19.0% vs. 10.7%, respectively) and a statistically significant treatment difference compared
`placebo (p = 0.009) while 1 mg dose did not result in statistically significant difference from the
`placebo (p = 0.057). Interestingly, 0.3 mg dose level also resulted in a statistically significant
`difference from the placebo (p = 0.016) although the sponsor claims that 0.3 mg dose was
`examined in an exploratory nature. The 3.0-mg dose of plecanatide also yielded the best
`responses in the secondary efficacy endpoints.
`
`Table 3: Durable Overall CSBM Responder Rates Over 12-Week Treatment Period (Study
`SP304-20210):
`
`Figure 2: Overall Responder Rates Over the 12-Week Treatment Period
`
`The 3.0 mg dose also provided the highest weekly responder rate of any treatment at each
`treatment period week, maintaining a weekly CSBM responder rate between 31.2% and 38.4%
`where the weekly CSBM response rates for placebo patients ranged from 15.8% to 23.9%.
`
`Figure 3: Study SP304-20210 CSBM Weekly Responder Rates
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`

`Phase 3 studies: The sponsor had evaluated the safety and efficacy of two dose levels, 3 mg and 6
`mg, of oral plecanatide tablets in a 2 phase III, multicenter, randomized, double-blind, placebo-
`controlled, parallel-group study in subjects with CIC. A no dose-proportional increase in primary
`efficacy endpoint was observed between 3 mg and 6 mg while both dose levels have shown
`statistically significant improvements over placebo.
`
`Table 4: Durable Overall CSBM Responder Rates in the Two Placebo Controlled Studies: at
`least 9 of 12 weeks and at least 3 of the last 4 weeks (ITT Population)
`Plecanatide
`Treatment
`Plecanatide
`Difference
`3 Mg
`6 Mg
`[P-Value]
`[95% Ci]
`[P-Value]
`Study 1 (SP304203-00)
`10.8%
`21.0%
`[6.1%, 15.4%]
`[<0.001]
`Study 2 (SP304203-03)
`20.1%
`7.3%
`[0.004]
`[2.4%, 12.1%]
`
`Placebo
`
`Durable Overall
`CSBM Responder
`
`10.2%
`
`Durable Overall
`12.8%
`CSBM Responder
`CI = confidence interval
`
`Treatment
`Difference
`[95% CI]
`
`9.3%
`[4.7%, 14.0%]
`
`7.2%
`[2.4%, 12.1%]
`
`19.5%
`[<0.001]
`
`20.0%
`[0.004]
`
`2.3.2 What are the characteristics of the exposure-response relationships for safety?
`Exposure-response relationship for safety for plecanatide was not evaluated since plecanatide did
`not have measurable systemic exposure.
`
`In the phase 2a study (SP304201-09) with 0.3, 1.0, 3.0, and 9.0 mg QD oral doses of plecanatide
`over 14 days of treatment in a total of 78 CIC patients, although there is no clear trend in AE over
`plecanatide dose ranges or in comparison with placebo, 9.0 mg dose appears to be associated with
`a higher rate of drug-related AEs (33.3%) compared to the placebo (10%) or other dose levels
`(6.4-14.3%).
`In the phase 2b dose-ranging study (SP304-20210) with 0.3, 1.0, and 3.0 mg QD oral doses of
`plecanatide over 12 weeks of treatment in total of 951 CIC patients, there appears to be dose-
`related increase in diarrhea, abdominal pain, number patients with at least one Treatment-
`Emergent Adverse Events (TEAE), number of TEAEs and overall drug-related AE.
`
`Table 5: Most Frequent (Overall Incidence ≥ 2%) Treatment-Emergent Adverse Events
`Incidences, by Preferred Term in Phase 2b study
`Placebo
`
`1.0 mg
`
`3.0 mg
`
`0.3 mg
`
`Reference ID: 3996096
`
`10
`
`

`

`
`
`| Diarrhea
`3 (1.3%)
`13 (5.5%)
`20 (8.4%)
`23 (9.7%)
`
`| Abdominal pain
`11 (4.7%)
`6 (2.5%)
`9 (3.8%)
`12 (5.1%)
`
`| Patients with at least one TEAE
`96 (40.7%)
`99 (41.8%)
`103 (43.3%)
`106 (44.7%)
`
`| Number ofTEAEs
`186
`183
`198
`234
`
`| Drug-related ABS
`6 (2.5%)
`12 (5.1%)
`16 (6.7%)
`21 (8.9%)
`
`In 2 phase 1]] studies there does not appear to be a clear dose-response for the majority of
`adverse event categories between 3 mg and 6 mg dose levels. However there were some increase
`in diarrhea and nasopharyngitis with 6 mg dose compared to 3 mg dose.
`
`Table 6: Adverse Events (Preferred Tenns)0cc1m‘ing in 20.5% ofPatients in the Primary Pool
`
`by System Organ Class (HT-S Population)
`
`|
`Placebo
`3 mg
`6 mg
`I Diarrhea
`12 (1.3%)
`43 (4.6%)
`47 (5.1%)
`
`I Nasopharyngitis
`14 (1.5%)
`11 (1.2%)
`20 (2.2%)
`
`
`
`
`
`
`
`2.3.3 Does this drug prolong the QT 01' QTc interval?
`
`Since plecanatide has negligible systemic exposure in human, the sponsor had requested for a
`waiver for requirement to conduct a thorough QT study, and the agency had agreed that there is
`no need for conducting a thorough QT study during IND stage. Please see advice letter dated
`6/18/2014 for IND 74883.
`
`2.3.4
`
`Is the dose and dosing regimen selected by the sponsor consistent with the known
`relationship between dose—eoneentration—response, and are there any unresolved
`dosing or administration issues?
`
`The phase 2b study had evaluated 0.3. 1.0, and 3.0 mg doses of plecanatide and had shown that
`the 3.0 mg dose provided a statistically significant treatment difference compared to placebo (p =
`0.009) while 1 mg dose did not result in a statistically significant efficacy compared to placebo (p
`=0.057). Based on the result of this phase 2b study. the 3 mg dose was selected for phase 3
`studies.
`In addition. a 6 mg dose level was added in phase 3 studies to evaluate whether the
`efficacy could be improved finther while maintaining the safety profile within an acceptable
`range.
`
`In the phase 3 studies, both 3 mg and 6 mg doses resulted in statistically significant
`improvements over placebo. However, 6 mg dose was not numerically superior to the 3 mg dose
`on most endpoints although the studies were not sized for a direct comparison of 3 and 6 mg
`doses of plecanatide.
`
`M“) the sponsor had proposed «9(4) 3 mg
`specifying a subpopulation
`“M"
`
`om) dose levels for CIC indication without
`00(4)“)
`u"
`
`"M" proposed 3 mg dose is consistent with the
`M" The
`known dose-response relationship for both efficacy and safety.
`
`Reference ID: 3996096
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`

` PK characteristics of drug
`Plecanatide is not orally bioavailable in humans with essentially no measurable plasma
`concentration of plecanatide and its major metabolite SP-338 in both healthy subjects and CIC
`patients.
`
`2.5.1 What are the single dose and multiple dose PK parameters of the parent drug and
`its relevant metabolites in healthy subjects?
`The sponsor attempted to measure plecanatide and its active metabolites SP-338 concentration in
`plasma in healthy subjects in two phase I studies (SAD study and food effect study). However,
`systemic exposures of the parent plecanatide or its active metabolite SP-338 were not detectable
`in human plasma up to 9 mg plecanatide dose (3 time the clinical dose of 3 mg) with LC-MS/MS
`bioanalytical method (with LLOQ of 1.0 ng/mL for plecanatide and 0.775 ng/mL for SP-338)
`suggesting insignificant absorption of plecanatide peptide and its metabolite SP-338 following the
`oral route of administration in healthy subjects.
`
`SAD Study SP-SP304101-08 :
`This was a phase 1, first-in-human, single-site, randomized, double-blind, placebo-controlled,
`single-ascending-dose study to evaluate the safety, tolerability, PK, and PD of SP-304 oral
`solution in healthy subjects following single dose administration. A total of 9 cohorts were
`evaluated in this study at dose levels of 0.1, 0.3, 0.9, 2.7, 5.4, 8.1, 16.2, 24.3, and 48.6 mg SP-
`304. Each cohort consisted of up to 8 subjects randomly assigned in a 3:1 allocation to receive a
`single dose of either SP-304 (N=6) or placebo (N=2) under fasted conditions. PK samples were
`collected at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours post-dose for
`determination of SP-304 plasma concentration. None of the plasma samples assayed in this study
`had a detectable plasma level of SP-304 (LLOQ of 10.0 ng/mL).
`
`Food effect Study SP304101-09:
`This was a phase 1, single-center, single-blind, randomized, crossover, 3 sequence, single-dose
`study of the effect of food on the PD, PK, safety, and tolerability of 9 mg plecanatide tablets and
`placebo administered orally to 30 healthy adult subjects. This study consisted of 3 treatment
`periods and 3 treatment conditions (fasted, fed with high fat-high calories meal, and low fat-low
`calories meal). For each treatment period, PK blood samples were collected at pre-dose and at
`0.5, 1, 2, 4, 8, 12, 24, and 48 hours post-dose to determine the plasma concentration of
`plecanatide and SP-338. Twenty-three of the 24 plecanatide-treated subjects had plecanatide
`(LLOQ of 1.0 ng/mL) plasma concentrations that were BLOQ for all time-points during all 3
`treatment periods. Only one subject had measurable concentrations following treatment of
`plecanatide at 0.5 hour and 1 hour post-dose in the fasted state only (1.99 ng/mL at 0.5 hr and
`2.18 ng/mL at 1.0 hr post dose). Plasma concentrations of metabolite SP-338 (LLOQ of 0.775
`ng/mL) were BLOQ for all subjects at all time-points. Therefore, no PK parameters were
`estimated.
`
`How does the PK of the drug and its major active metabolites in healthy volunteers
`compare to that in patients?
`The sponsor attempted to measure plecanatide and its active metabolites SP-338 concentration in
`the plasma in CIC
` patient population in 3 phase II studies and in one Phase III study
`(SP304203-03). However, systemic exposures of parent drug plecanatide or its active metabolite
`SP-338 were not detectable up to 9 mg dose with LC-MS/MS bioanalytical method (with LLOQ
`of 1.0 ng/mL for plecanatide and 0.775 ng/mL for SP-338) suggesting an insignificant absorption
`of plecanatide peptide and its metabolite SP-338 following the oral route of administration in CIC
`patients.
`
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`(b) (6)
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`

`

`CIC patients:
`
`Phase IIa study SP-SP304201-09:
`This was a phase 2a, randomized, double-blind, placebo-controlled, dose ranging study with 0.3
`mg, 1.0 mg, 3.0 mg and 9.0 mg