A Randomized Phase III Clinical Trial of Plecanatide, a Uroguanylin Analog, in Patients With Chronic Idiopathic Constipation

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1 ORIGINAL CONTRIBUTIONS 3 see relted editoril on pge x A Rndomized Phse III Clinicl Tril of Plecntide, Urogunylin Anlog, in Ptients With Chronic Idiopthic Constiption Philip B. Miner Jr, MD, Willim D. Koltun, MD 2, Gregory J. Wiener, MD 3, Mrinel De L Portill, MD 4, Bls Prieto, MD 5, Kunwr Shilubhi, PhD, Mry Beth Lyton, BA, MT(ASCP), MBA, Lur Brrow, PhrmD, Leslie Mgnus, MD nd Ptrick H. Griffi n, MD OBJECTIVES: METHODS: This study ssessed the efficcy nd sfety of plecntide, gunylte cyclse-c (GC-C) gonist nd the first urogunylin nlog pproved for the tretment of chronic idiopthic constiption (CIC). This phse III, multicenter, double-blind, plcebo-controlled study rndomized,394 ptients with CIC. Ptients received either plecntide (3 or mg) or plcebo, orlly, once dily, for 2 weeks. The primry efficcy endpoint ws the percentge of ptients who were durble overll complete spontneous bowel movement (CSBM) responders over the 2-week tretment period. Ptients were instructed to record their dily bowel movements, stool consistency scores, nd bdominl symptoms in n electronic diry. Tretment-emergent dverse events (AEs) were collected. RESULTS: Ech dose of plecntide resulted in significntly greter percentge of durble overll CSBM responders (2.%, 3 mg; 9.5%, mg) s compred with plcebo (.2%; P <. for both). Plecntide (3 nd mg) lso significntly incresed men weekly CSBM frequency from bseline (increse of 2.5 nd 2.2/week, respectively) vs. plcebo (.2/week; P <. for both) nd men weekly spontneous bowel movement frequency (increse of 3.2 nd 3./week, respectively) vs. plcebo (.3/week; P <., for both) over the 2-week tretment period. Both plecntide doses significntly improved ll secondry nd dditionl efficcy endpoints. The most common AE, dirrhe, occurred in.3% (plcebo), 5.9% (3 mg) nd 5.7% ( mg) of ptients. CONCLUSIONS: Plecntide significntly improved constiption nd its relted symptoms with low rte of dverse events. These results suggest tht plecntide will be useful tretment option in the mngement of CIC. CliniclTrils.gov: NCT SUPPLEMENTARY MATERIAL is linked to the online version of the pper t Am J Gstroenterol 27; 2:3 2; doi:.38/jg.2.; published online 7 Februry 27 INTRODUCTION Chronic idiopthic constiption (CIC) is one of the most common functionl gstrointestinl (GI) disorders, with prevlence rtes rnging from 2 to 27%, nd n overll verge prevlence of 4.8% (,2 ). For severl yers, CIC hd been defined by single symptom, the frequency of bowel movements (BMs). Over time, however, tht definition hs expnded to include the dditionl symptoms of strining, lumpy or hrd stools, the senstion of incomplete BMs, nd bdominl symptoms such s bloting nd bdominl discomfort. Individul symptoms cn be severe, dversely ffecting ptients qulity of life nd elevting helth cre costs ( 3 ). Ptients with CIC often report disstisfction with trditionl tretment options, such s dietry fiber with supplementl bulking gents, exercise, bowel hbit trining, nd Oklhom Foundtion for Digestive Reserch, Oklhom City, Oklhom, USA ; 2 Medicl Center for Clinicl Reserch, Sn Diego, Cliforni, USA ; 3 GW Reserch, Inc., Chul Vist, Cliforni, USA ; 4 Genom Reserch Group, Inc., Mimi, Florid, USA ; 5 Advnce Medicl Reserch Service, Corp., Mimi, Florid, USA ; Synergy Phrmceuticls Inc., New York, New York, USA. Correspondence: L. Mgnus, MD, Synergy Phrmceuticls Inc., Suite 22, 42 Lexington Avenue, New York, New York 7, USA. E-mil: lmgnus@synergyphrm.com Received 8 August 2 ; ccepted 2 December 2 Officil journl of the Americn College of Gstroenterology

2 4 Miner et l. over-the-counter lxtives ( 4 ). Current guidelines suggest tht constipted ptients should be initilly treted with over-thecounter lxtives for episodic constiption ( 5, ). More recently, number of prescription phrmcotherpies hve been pproved in the United Sttes for the tretment of ptients with CIC, including linclotide (Linzess, Ironwood Phrmceuticls, Inc., Cmbridge, MA, USA) nd lubiprostone (Amitiz, Tked Phrmceuticl Compny, Osk, Jpn) ( 7,8 ). However, no single or combined tretment hs been shown to work in ll ptients nd thus there remins need for new tretment options ( 9 ). Plecntide is -mino cid peptide nlog of urogunylin. Urogunylin is n endogenous gonist tht binds nd ctivtes gunylte cyclse-c (GC-C) receptors expressed in the epithelil lining of the GI mucos in ph-sensitive mnner (, ). The sole difference between the two peptides is the replcement of one ph-sensing residue with nother, Asp with Glu, t the third position ner the N-terminus ( 2,3 ). Therefore, plecntide, like urogunylin, binds to nd ctivtes GC-C receptors in ph-sensitive mnner nd hs demonstrted eight times the binding potency of urogunylin in preclinicl models ( 4 ). GC-C receptor ctivtion stimultes cyclic gunosine monophosphte production, which increses cystic fibrosis trnsmembrne conductnce regultor ctivity ( 5 ), leding to chloride nd bicrbonte secretion into the intestinl lumen. In ddition, ctivtion of GC-C signling decreses the ctivity of the sodium-hydrogen exchnger, leding to decresed sodium bsorption ( ). The resulting ionic grdient llows for fluid secretion tht serves to hydrte the stool nd fcilitte BMs ( 7 ). GC-C ctivtion lso decreses other CICrelted symptoms by decresing viscerl hypersensitivity to relieve bdominl discomfort nd to ccelerte stool trnsit through the intestine, fcilitting BMs ( 8 23 ). Previous studies in helthy volunteers nd in ptients with CIC hve demonstrted plecntide to be sfe nd effective in relieving the symptoms of CIC ( 2,24 ). The objective of the present study ws to ssess, on lrger scle, the efficcy nd sfety of two plecntide doses when dministered to ptients with CIC for 2 weeks. METHODS Study design This study (NCT98224) ws rndomized, 2 weeks in durtion, double-blinded nd plcebo-controlled. Ptients with CIC ( N =,394) were rndomized t one of 4 clinicl centers (53 in the United Sttes nd in Cnd) between 3 December 23 nd 23 April 25 (lst ptient lst visit). Informed consent ws obtined from ech ptient before dmission into the study nd initition of ny study-relted procedures, ccording to the regultory nd legl requirements of the prticipting country (US or Cnd). The terms of the consent nd when it ws obtined were lso documented. Ech site-specific investigtor nd coordintor recruited nd enrolled prticipnts. The study ws conducted in ccordnce with the Interntionl Conference on Hrmonistion E Consolidted Guidnce for Good Clinicl Prctice, the United Sttes Code of Federl Regultions Title 2, Prts 5 nd 5, nd the ethicl principles of the Declrtion of Helsinki (s mended in 99). No importnt chnges to methods were mde fter the tril ws commenced. All uthors hd ccess to the study dt nd hd reviewed nd pproved the finl mnuscript. Following informed consent, ptients entered screening period. The lst 2 weeks of the screening period consisted of pre-tretment ssessment period to confirm eligibility nd estblish ech ptient s bseline for efficcy outcome mesurements. Ptients were instructed to use n electronic diry to mintin record of Dily BMs (number, time, consistency, completeness of evcution, nd rescue mediction use) nd Dily Symptoms. Recordings were to be mde for ech dy, with no llownce for returning to complete dt for previous dys. To mintin eligibility for prticiption in the tril, ptients were required to complete of the 7 required dily diry entries (mong other criteri) in ech of the two pre-tretment ssessment weeks. Ptients who mintined eligibility t the end of the 2-week pretretment ssessment were rndomized on dy of the 2-week tretment period in :: rtio (strtified by gender) to one of the following three tretment groups: plecntide 3 mg, plecntide mg, or plcebo. Rndomiztion ws dynmic by site, with ech site initilly ssigned two rndomiztion blocks (one for ech gender) of 9 per strt. At weeks 4, 8, nd 2 of the tretment period nd 2 weeks following the lst dose of mediction (week 4), ptients returned to the clinic to undergo efficcy nd sfety ssessments. Ptients continued to complete dily diry entries throughout the tretment nd post-tretment periods. Ptient popultion Eligible for inclusion were mle nd femle (not pregnnt or lctting) ptients with CIC ged 8 8 yers who hd body mss index of 8 4 kg/m 2 nd were willing to prticipte in the 2-week pre-tretment ssessment, 2 weeks of tretment, nd 2-week post-tretment period. Ptients hd to meet the Rome III functionl constiption criteri, modified for this study, for t lest 3 months before the screening visit nd hd to demonstrte symptom onset for t lest months before the dignosis, which included history of fewer thn three BMs per week, no use of mnul mneuvers (such s digitl evcutions or support of pelvic floor) to fcilitte defections, nd t lest two of the following: strining during t lest 25% of defections, lumpy or hrd stool for t lest 25% of defections, senstion of incomplete evcution for t lest 25% of defections, nd senstion of norectl blockge/obstruction for t lest 25% of defections ( 25 ). Ptients were excluded if they met the Rome III criteri for irritble bowel syndrome or if they reported loose stool more thn rrely without the use of lxtives. Other key exclusion criteri were diseses or conditions ssocited with constiption, diseses or conditions tht could ffect GI motility or defection, medicl history of cncer, or other uncontrolled medicl conditions. Ptients were to mintin stble diet for t lest 3 dys prior to screening, use contrception where pplicble, nd were not to hve prticipted in previous plecntide clinicl tril. Ptients were llowed to continue the use of fiber if they were using high fiber diet or fiber supplements for the 3 dys before screening nd could enroll provided tht they greed to remin on tht diet VOLUME 2 APRIL 27

3 Plecntide in Ptients With CIC 5 or supplement for the durtion of the study. Following the completion of the 2-week pre-tretment ssessment, ptients hd to meet the following criteri before rndomiztion: less thn 3 complete spontneous bowel movements (CSBMs) per week, scores on the Bristol Stool Form Scle (BSFS) of or 7 in less thn 25% of spontneous bowel movements (SBMs), nd one of the following: BSFS of or 2 in t lest 25% of defections, strining vlue reported on t lest 25% of dys on which BM ws recorded, or t lest 25% of BMs resulting in sense of incomplete evcution. A full listing of inclusion nd exclusion criteri is listed in Supplementry Appendix A online. Tretments Ptients were rndomly ssigned to one of the three tretment groups (plecntide 3 mg, plecntide mg, or plcebo) utilizing web-bsed rndomiztion nd tril supply mngement (RTSM) system. All tretments were given orlly, once dily from dy through 2 weeks of the tretment period. Ptients received their ssigned study drug on the dy of rndomiztion (dy of week ), took their first dose t the clinic site, nd were instructed to tke their study mediction on dily bsis with or without food. At the dy, week 4, nd week 8 visits, the site performed drug-dispensing ctivities by logging into the RTSM system to get study drug kit lloction for ech ptient. No interruptions in dily therpy were permitted. Complince ws ssessed by pill count, with ptients who hd tken t lest 8% of ssigned doses to be considered complint. All study drugs were supplied in identicl blister pcks, nd tblets were similr in color, smell, tste, nd ppernce, thereby ssuring double-blind conditions for ll investigtors nd ptients. Ptients greed to mintin stble diet nd fluid intke over the course of the study. Ptients were provided biscodyl 5 mg tblets s rescue mediction nd were instructed to tke or 2 tblets only if they hd not hd BM for 3 or more dys. During the pre-tretment ssessment period, ptients were not to exceed 2 dys of rescue mediction use in ech week. BMs occurring within 24 h of rescue mediction use were not counted towrds the SBM or CSBM frequency endpoint. In the event of n emergency, the investigtor nd sub-investigtors t the clinicl site hd the bility to brek the tretment code using the RTSM system. No brek of the tretment code occurred in this study. Assessments nd endpoints Ptients were required to report ll BMs in the BM Diry in rel time or on dily bsis, indicting the time of the BM, with no bility to report dt from the previous dy. The primry efficcy endpoint ws the percentge of ptients who were durble overll CSBM responders during the 2-week tretment period. A CSBM weekly responder ws defined s ptient who hd 3 CSBMs for given week nd n increse from bseline of CSBM for tht sme week. An overll CSBM responder ws ptient who ws weekly CSBM responder for t lest 9 of the 2 tretment weeks, nd durble overll CSBM responder ws lso weekly responder in t lest 3 of the lst 4 weeks. An SBM ws defined s BM tht occurs in the bsence of lxtive use (for exmple, rescue mediction; s entered in the diry) within 24 h of the BM, nd CSBM ws defined s n SBM with the sense of complete evcution. Secondry nd dditionl endpoints reported from the BM Diry included frequency of CSBMs nd SBMs within 24 h fter the first dose of study mediction nd stool consistency from the BSFS score for ech BM. No chnges in tril outcomes were mde. The Dily Symptom Diry ws completed for dditionl endpoints. This electronic diry ws completed ech dy in the evening nd cptured strining, bdominl bloting, nd bdominl discomfort on Likert scle of 4 (=none, 4=very severe). The Ptient Assessment of Constiption Symptoms (PAC-SYM) nd Ptient Assessment of Constiption Qulity of Life (PAC-QoL) questionnires, s well s the Ptient Globl Assessment questionnire, were lso completed t the clinic t weeks 4, 8, 2 (end of tretment), nd 4 (end of study). Sfety evlutions included physicl exmintions, electrocrdiogrph recordings, vitl sign mesurements, nd stndrd lbortory tests. Adverse events (AEs) were cptured, ssessed for severity, nd clssified for reltedness to study mediction. Sttisticl nlysis The intention-to-tret popultion ws used for the efficcy nlyses. The sfety popultion (defined s ll rndomized ptients who received t lest one dose of the study drug) ws used for sfety nlyses. The primry efficcy endpoint ws the percentge of ptients who were durble overll CSBM responders. The Cochrn Mntel Henszel test, strtified by gender, ws used to test hierrchicl comprison between plecntide mg nd plcebo nd between plecntide 3 mg nd plcebo. For this nlysis, ptients who hd fewer thn four complete diry dys were considered non-responders. The Holm-bsed tree-gtekeeping procedure ws used for djustment of P vlues to control the fmily-wise type I error rte t 5% (two-sided) by tking into ccount multiple doses nd multiple primry endpoints. For secondry efficcy endpoints, tretment comprisons of chnges from bseline were nlyzed using liner mixed-effects model with fixed effects for gender (strtifiction vrible), tretment, week, the interction of tretment nd week, nd the corresponding bseline vlue nd rndom intercept for ptients. Tretment comprisons of chnges from bseline for ech ptient-reported dily symptom were mde using liner mixedeffects model under the ssumption of normlly distributed residuls with tretment group, week, interction of tretment nd week, gender, nd the corresponding bseline vlue s fixed effects, nd rndom intercept for ptient. Comprisons of ptients symptoms, mesured using PAC-SYM nd PAC-QoL questionnires, were mde of chnges from bseline for the totl score between ech plecntide tretment nd plcebo using n nlysis of covrince (ANCOVA) liner mixed-effects model with fixed effects for gender (strtifiction vrible), tretment, week, the interction of tretment nd week, nd the corresponding bseline vlue, nd rndom intercept for ptient. The smple size for this study ws bsed on results of previously completed lrge, multicenter, 2-week dose-rnging study of Officil journl of the Americn College of Gstroenterology

4 Miner et l. Screened N=2,84 Evlution for sfety Evlution for efficcy Adverse events Tretment filure Lost to follow-up Lck of complince Physicin decision Protocol violtion Consent withdrwl Other during follow-up Figure. Disposition of the study popultion. n plecntide in ptients with CIC nd on considertion of overll sfety exposure requirements ( 2 ). The power clcultion for the primry endpoint ssumed tht the durble overll responder rtes for plecntide 3 nd mg were equl. Using these ssumptions nd bsed on χ 2 continuity-corrected test with the intention of providing ~9% power t 5% significnce level, enrollment of t lest 45 ptients per tretment rm ws required. Assuming 5% screen filure nd discontinution rte, 2,84 ptients were screened. No interim nlyses were plnned or conducted in this study. RESULTS Ptient disposition, complince, nd bseline demogrphics Of the 2,84 ptients screened ( Figure ),,34 comprised the intention-to-tret popultion (plecntide 3 mg, n =453; plecntide mg, n =44; plcebo, n =452). The sfety popultion included the,389 ptients who received t lest one dose of study drug. There were,53 ptients (82.7%) who completed tretment (plecntide 3 mg, n =39; plecntide mg, n =375; plcebo, n =388), nd,4 ptients (8.8%) completed the study (through week 4). The mjority of ptients in the intention-to-tret popultion were complint with study drug, with complince defined s 8% of ssigned doses nd clculted from returned pill counts. Mediction complince ws comprble cross ll groups (plecntide 3 mg, 9.5%; plecntide mg, 9.%; nd plcebo, 98.%). Demogrphic chrcteristics of the study popultion were comprble nd blnced cross the three tretment groups ( Tble ). The proportion of femles (8.8%) nd those identifying s blck/ Africn Americn (25.%) were comprble to those found in the generl CIC ptient popultion ( 2,4 ). Efficcy mesures The primry efficcy mesure ws chieved with both plecntide doses ( Figure 2 ). Both plecntide 3 nd mg resulted in Rndomized N=,394 (%) n (.) (98.7) (.9) (.3) (3.) (.7) () (.4) (.) (4.) (5.4) (.) Evlution for sfety Evlution for efficcy Adverse events Tretment filure Lost to follow-up Lck of complince Physicin decision Protocol violtion Consent withdrwl Other during follow-up (%) n (.) (95.) (7.2) (4.9) (.8) (3.2) (.2) (.2) (.3) (3.) (3.) (.3) Evlution for sfety Evlution for efficcy Adverse events Tretment filure Lost to follow-up Lck of complince Physicin decision Protocol violtion Consent withdrwl Other during follow-up significntly greter percentge of ptients who were durble overll CSBM responders compred with those in the plcebo group (plecntide 3 mg, 2.%; plecntide mg, 9.5%; plcebo,.2%; P <. for ech drug dose vs. plcebo). The percentge of weekly CSBM responders in both plecntide groups ws greter thn with plcebo within the first week of tretment (plecntide 3 mg, 35.8%; plecntide mg, 29.3%; plcebo,.%; P <. for ech drug dose vs. plcebo), nd this difference ws mintined for the durtion of the 2-week tretment period ( Figure 2 b ). Following cesstion of plecntide dministrtion (follow-up period), the proportions of CSBM weekly responders in both plecntide dose groups decresed nd were comprble with plcebo. Both plecntide doses significntly incresed the weekly CSBM nd SBM frequencies from bseline ( Figure 3,b ). Increses from bseline were evident within the first week of tretment nd were sttisticlly different from the increse resulting from plcebo tretment. These sttisticlly significnt increses were mintined throughout the durtion of tretment. Over the 2-week tretment period, there were cliniclly nd sttisticlly significnt lest squres (LS) men chnges from bseline in weekly CSBM frequencies with 3- nd -mg doses of plecntide (2.5 nd 2.2/week, respectively) s compred with plcebo (.2/week; P <. for ech dose). By week 4, 2 weeks following the cesstion of tretment, the vlues for plecntide tretment returned towrd those of plcebo tretment nd did not go lower thn bseline levels. Sttisticlly significnt chnges in SBMs/week, similr to the ptterns of chnge in CSBMs/ week, lso resulted with both doses of plecntide. The LS men increse in weekly SBM frequency over the 2-week tretment period ws 3.2 nd 3. for plecntide 3 nd mg, respectively, nd.3/week for plcebo ( P <. for ech dose compred with plcebo). The onset of plecntide ctivity ws rpid nd occurred within the first week of tretment. Both doses of plecntide sttisticlly incresed the percentge of ptients (%) (.) (9.5) (7.8) (5.3) (.7) (.5) (.2) () (2.) (2.9) (4.) (.9) VOLUME 2 APRIL 27

5 Plecntide in Ptients With CIC 7 Tble. Summry of demogrphics nd bseline ptient chrcteristics ( N = 452) Plecntide 3 mg ( N = 453) Plecntide mg ( N = 44) Age (yers) Rnge (8 78) (8 79) (8 79) Gender (% femle) Rce (% of popultion) White Blck Other Body mss index 28.± ± ±5.3 CSBMs/week.4±..3±.5.3±.5 SBMs/week 2.2±2. 2.±.8.8±.8 Stool consistency b 2.±. 2.5±. 2.±.2 Strining score c 2.3±.8 2.3±.8 2.3±.9 Abdominl discomfort score d Abdominl bloting score e.8±.9.8±.8.8±.9.9±.9.9±.9.9±. CSBM, complete spontneous bowel movement; ITT, intention-to-tret; SBM, spontneous bowel movement. Vlues re men±s.d. in the ITT popultion unless otherwise stted. b Stool consistency ws ssessed with the use of the 7-point Bristol Stool Form Scle, where indictes seprte, hrd lumps, like nuts (hrd to pss); 2 susge-shped but lumpy; 3 like susge but with crcks on the surfce; 4 like susge or snke, smooth nd soft; 5 soft blobs with cler-cut edges (pssed esily); fluffy pieces with rgged edges or mushy stool; nd 7 wtery, no solid pieces (entirely liquid). c Assessed using the Dily Symptom Diry; ptients who indicted hving bowel movement for tht dy were sked: For tody, when you hd bowel movement, rte your strining t its worst on scle of to 4. Strining ws rted on 5-point Likert scle where =none, =mild, 2=moderte, 3=severe, nd 4=very severe. d Assessed using the Dily Symptom Diry; ptients were sked: For tody, rte your bdominl discomfort t its worst on scle of to 4. Abdominl discomfort ws rted on 5-point Likert scle where =none, =mild, 2=moderte, 3=severe, nd 4=very severe. e Assessed using the Dily Symptom Diry; ptients were sked: For tody, rte your bdominl bloting t its worst on scle of to 4. Abdominl bloting ws rted on 5-point Likert scle where =none, =mild, 2=moderte, 3=severe, nd 4=very severe. experiencing CSBMs nd SBMs within 24 h compred with plcebo ( Figure 3 c ). Plecntide significntly improved stool consistency nd symptom-relted secondry endpoints over the 2-week tretment period compred with plcebo ( Figure 4,b nd Tble 2 ). Stool consistency improved from bseline with both plecntide doses by.5 points on the BSFS scle over the 2-week tretment period s compred with.8 points for plcebo ( P <. for ech dose compred with plcebo). These improvements resulted in BSFS stool scores of 4. (men) over 2 weeks for both the plecntide 3- nd -mg doses. Sttisticl improvements in men weekly Dily Symptom Diry scores were observed with plecntide tretment compred Durble overll CSBM responders (percentge of ptients) b CSBM weekly responders (percentge of ptients) P<..2% 2.% 9.5% Tretment time (weeks) with plcebo ( Tble 2 ). Improvements in strining score were observed erly in tretment nd were mintined throughout the study. The LS men chnges in weekly strining scores over the 2-week tretment period were.9 for plecntide 3 mg nd.9 for plecntide mg, while the plcebo chnge ws. ( P <. for ech dose compred with plcebo). The symptoms of bdominl bloting nd bdominl discomfort were lso significntly improved over the 2-week tretment period with plecntide compred with plcebo. The LS men chnges in bdominl bloting were.4 for plcebo,.5 for plecntide 3 mg ( P =.2), nd.4 for plecntide mg ( P =.45), nd the LS men chnges in bdominl discomfort were.4 for plcebo,.5 for plecntide 3 mg ( P <.), nd.5 for plecntide mg ( P =.4). Severl ptient ssessment tools demonstrted tht plecntide tretment, t both doses, significntly improved ptient symptoms nd helth-relted qulity of life. Evlution of Ptient Globl Assessments showed tht constiption severity ws significntly reduced with both plecntide doses compred with plcebo ( Tble 2 ). Furthermore, significntly greter percentge P<. Follow-up period Figure 2. ( ) Percentge of ptients in ech tretment group ssessed s durble overll complete spontneous bowel movement (CSBM) responder in the intention-to-tret (ITT) popultion, the primry efficcy endpoint. Durble overll CSBM responders were defined s ptients who fulfilled both 3 CSBMs per week nd n increse of CSBM from bseline, in the sme week, for 9 of the 2 tretment weeks, including 3 of the lst 4 weeks of tretment. Error brs represent 95% confidence intervls. ( b ) Weekly evolution of the percentge of CSBM responders in the ITT popultion. Vlues re LS mens; brs represent 95% confi dence intervls. P =., P =.3, P =.5, P =. vs. plcebo. Officil journl of the Americn College of Gstroenterology

6 8 Miner et l. Chnge from bseline in CSBM (number/week) b Chnge from bseline in SBM (number/week) c Ptients with CSBM within 24 hours (%) CSBM 7 5 SBM P<. P<. P<. 4 P< % 28.7% 25.2% 39.8% 59.2% 52.% 3 mg mg 3 mg mg Plecntide Plecntide of ptients treted with plecntide 3 mg (7.5%) nd plecntide mg (8.7%) responded tht they experienced reductions in their ssessment of constiption severity when compred with plcebo (5.9%). Ptient stisfction with tretment nd their intention to continue tretment ws sttisticlly greter with the plecntide tretment groups thn with the plcebo group ( Tble 2 ). Scores between the two doses were comprble. The LS men improvement in PAC-SYM Totl Score ws.7 for plcebo nd.9 for both plecntide doses, respectively ( P <. for ech dose compred with plcebo; negtive vlues represent improvement). Similrly, PAC-QoL Totl Score improved by.7 for plcebo nd. for both plecntide doses, respectively ( P <. for ech dose compred with plcebo; negtive vlues represent improvement). Ptients with SBM within 24 hours (%) Follow-up period Tretment time (weeks) Follow-up period Tretment time (weeks) Figure 3. ( ) Chnges from bseline in weekly complete spontneous bowel movement (CSBM) frequency. Vlues re lest squres (LS) men; brs represent s.e. P <. vs. plcebo. ( b ) Chnges from bseline in men weekly spontneous bowel movement (SBM) frequency. Vlues re LS men; brs represent s.e. P <. vs. plcebo. ( c ) Percentge of ptients experiencing CSBM or SBM within 24 h fter the fi rst dose of study mediction. P <. vs. plcebo. Chnge in stool consistency from bseline b 7 Men Bristol Stool Form Scle score Follow-up period Tretment time (weeks) Follow-up period Sfety Approximtely one-third of ptients experienced t lest one AE during the course of the 2-week tretment period (plecntide 3 mg, 35.4%; plecntide mg, 33.%; plcebo, 32.8%; Tble 3 ). The mjority of AEs were mild to moderte in severity. A totl of 5 ptients (.%) experienced serious AE (SAE) cross the tretment groups, with comprble rtes between tretments ( Tble 3 ); two of the reported SAEs (both in the plecntide 3 mg group) were pregnncies (sites were instructed to cpture ll pregnncies s SAEs). Of the 3 ctul SAEs, 4 occurred with plecntide 3 mg, 5 with plecntide mg, nd 4 with plcebo group. SAEs in the system orgn clss of infections nd infesttions were reported by the highest percentge of ptients: 2 (.4%) in the plecntide -mg group nd 3 (.7%) in the plcebo group (none reported with plecntide 3 mg). Of the 3 SAEs reported overll, only one event, diverticulitis (plcebo group), ws considered to be possibly relted to study drug. The rte of discontinuing study mediction due to n AE ws 5.% with plecntide 3 mg, 5.3% with plecntide mg, nd.3% with plcebo. Rtes of discontinution due to dirrhe were 2.7% for plecntide 3 mg, 2.% for plecntide mg, nd.4% for plcebo. No unexpected sfety signls were observed in this tril nd no deths were reported. The most common AE ws dirrhe ( Tble 3 ), which ws of mild to moderte severity in the mjority of ptients. Dirrhe occurred in 5.9% of ptients treted with plecntide 3 mg, 5.7% in ptients treted with plecntide mg, nd.3% of ptients Tretment time (weeks) Figure 4. ( ) Chnges from bseline in weekly stool consistency. Stool consistency ws mesured by the Bristol Stool Form Scle (BSFS). Vlues re lest squres (LS) men; brs represent s.e. P <. vs. plcebo. ( b ) Weekly BSFS scores during the study. Vlues re LS men. VOLUME 2 APRIL 27

7 Plecntide in Ptients With CIC 9 Tble 2. Chnges from bseline in stool consistency nd symptoms ssocited with tretment over the 2-week tretment period ( N = 452) ( N = 453) P vlue b ( N = 44) P vlue b Stool consistency Bseline 2. (.) 2.5 (.) 2. (.2) Chnge.8 (.).5 (.) <..5 (.) <. Dily symptoms scores Strining c Bseline 2.3 (.8) 2.3 (.8) 2.3 (.9) Chnge. (.).9 (.) <..9 (.) <. Abdominl bloting c Bseline.9 (.9).9 (.9).9 (.) Chnge.4 (.).5 (.).2.4 (.).45 Abdominl discomfort c Bseline.8 (.9).8 (.9).8 (.9) Chnge.4 (.).5 (.) <..5 (.).4 Ptient globl ssessments d Constiption severity e Bseline 3.5 (.9) 3. (.9) 3.5 (.) Chnge. (.).4 (.) <..4 (.) <. Tretment stisfction score f 2.8 (.) 3. (.) <. 3.5 (.) <. Tretment continution score f 3.4 (.) 3.8 (.) <. 3.8 (.) <. LS, lest squres. Bseline vlues re men (s.d.). Chnge vlues re LS men (s.e.). b P vlue compred with plcebo group. c The severity of strining, bloting, nd discomfort during bowel movements ws ssessed on 5-point Likert scle where =none, =mild, 2=moderte, 3=severe, nd 4=very severe. d Assessments t week 2. e Assessments of constiption severity: ptients were sked to rte their constiption severity on 5 scle, with higher score indicting more severe constiption. f Assessments of tretment stisfction nd continution: ptients were sked to rte how stisfi ed they were with tretment on 5 scle, with higher score indicting higher stisfction. The sme scoring system ws used for ssessing tretment continution. Vlues re men (s.e.). who received plcebo. Dirrhe ws followed in incidence by nsophryngitis nd sinusitis. No plecntide dose dependency ws observed for ny AE. Overll, the incidence of AEs in ny preferred term ws low. Lbortory findings, vitl signs, nd physicl exmintion were ll unremrkble, with low incidence of ny cliniclly importnt chnges. DISCUSSION Th is double-blind, phse III, rndomized study in ptients with CIC demonstrted the efficcy of plecntide in the tretment of CIC. Plecntide, t both doses tested, resulted in significntly greter percentge of ptients defined s durble overll CSBM responders versus plcebo. In ddition, plecntide improved the frequency of CSBMs/week nd SBMs/week, stool consistency, strining, other symptomtic endpoints ssocited with CIC, nd helth-relted qulity of life. Ptients treted with plecntide expressed stis fction with their tretment nd n intention to continue tretment. Plecntide tretment ws ssocited with low frequency of AEs. The incidence of dirrhe ws no more thn 5.9% nd no other cliniclly meningful sfety findings were observed. Plecntide is the first urogunylin nlog to be pproved for the tretment of CIC or other functionl GI disorders. It is lso the first tretment for CIC to be evluted in clinicl study using the stringent criteri of durble overll CSBM responder rte. This endpoint requires clinicl response in t lest 3 of the 4 lst weeks of tretment in ddition to the previously required 9 out of 2 weeks overll to evlute the durbility of efficcy. In meeting this revised regultory endpoint, plecntide hs successfully demonstrted significnt durble efficcy. In ddition, plecntide demonstrted rpid onset of efficcy (within the first week of tretment) with significnt increse in the weekly CSBM responders s well s other Officil journl of the Americn College of Gstroenterology

8 2 Miner et l. Tble 3. Summry of TEAE Ptients with t lest one TEAE Ptients with t lest one severe TEAE Ptients with t lest one serious TEAE Ptients with t lest one TEAE leding to discontinution ( N = 458) Plecntide 3 mg ( N = 474) Plecntide mg ( N = 457) 5 (32.8) 8 (35.4) 5 (33.) 7 (.5) 3 (2.7) 7 (3.7) 4 (.9) (.3) 5 (.) (.3) 24 (5.) 24 (5.3) TEAEs with incidence in >2% of the plecntide ptients Dirrhe (.3) 28 (5.9) 2 (5.7) Nsophryngitis 8 (.7) 4 (.8) (2.4) Sinusitis 3 (.7) (2.) 3 (.7) TEAE, tretment-emergent dverse events. Vlues re number of ptients (%). 2 of the serious dverse events occurring in the plecntide 3 mg group were non-serious pregnncies; therefore, only 4 (.8%) serious dverse events occurred in this tretment group. Abdominl pin did not exceed 2% of the plecntide ptients (plcebo,.9%; plecntide 3 mg,.8%; plecntide mg,.3%). secondry endpoints compred to plcebo. Further, the rpid onset of effect ws demonstrted with sttisticlly greter percentge of plecntide ptients vs. plcebo ptients who experienced CSBMs nd SBMs within the first 24 h of tretment. The secondry nd dditionl endpoints in this study support the utility of plecntide in the mngement of CIC. Plecntide improved stool consistency to men BSFS score of 4 t ech of the tretment visits throughout the 2-week tretment period. Strining, common to CIC, ws lso reduced, which my be relted to the improvement in stool consistency. There ws sttisticlly significnt reduction in strining score with plecntide vs. plcebo (.9 for both plecntide 3 nd mg;. for plcebo; P <. for both doses). Abdominl symptoms such s bloting nd discomfort were lso significntly reduced compred to plcebo. These chnges were sso cited with n overll improvement in constiption symptoms s observed by reduction in the constiption severity score in the Ptient Globl Assessment questionnire. In this study, the bility of plecntide to improve symptoms ws confirmed independently by the use of the PAC-SYM nd PAC-QoL instruments. All prmeters ssessed in this study improved within the first week of tretment nd were mintined for s long s plecntide ws dministered. Following discontinution of plecntide, no worsening of these prmeters to below bseline levels ws observed in the follow-up period. Side effects ssocited with plecntide tretment were miniml. Dirrhe ws the most common side effect, observed in 5.9% (3 mg) nd 5.7% ( mg) of plecntide-treted ptients compred with plcebo (.3%). Furthermore, the rte of discontinution of plecntide tretment due to dirrhe ws low (2.7% for plecntide 3 mg, 2.% for plecntide mg, nd.4% for plcebo). Although this study provides informtion bout the short-term sfety of plecntide, long-term, open-lbel study ws lso completed to exmine the long-term sfety profile of plecntide. Results from the Ptient Globl Assessment questionnire s Tretment Stisfction nd Tretment Continution questions indicte greter overll stisfction with plecntide compred with plcebo nd greter intention to continue tretment in ptients receiving plecntide. As n nlog of urogunylin, plecntide-medited ctivtion of GC-C receptors is ph-sensitive with higher ctivity in the slightly cidic environment of the smll intestine thn in the neutrl or more bsic environments of the distl GI trct ( 2 ). Activtion of GC-C receptors leds to fluid secretion tht serves to hydrte the stool nd fcilittes regulr bowel function, s well s decreses viscerl hypersensitivity, which cn relieve bdominl discomfort nd ccelerte stool trnsit through the intestine. In ddition, plecntide is not bsorbed into the systemic circultion ( 2 ); therefore, it exerts its biologic ctivity only in the intestinl trct. It is hypothesized here tht the regulted (locl) biologic ctivity, miniml bsorption, nd ph-sensitive GC-C receptor ctivtion by plecntide my contribute to the fvorble efficcy profile nd the low incidence of AEs (including dirrhe) observed in this tril. CONCLUSION Plecntide, orlly dministered once dily for 2 weeks, significntly incresed the percentge of ptients with CIC defined s durble overll CSBM responders compred with plcebo. Significnt improvements in BM frequency nd stool consistency were ccompnied by significnt improvements in strining nd bdominl symptoms. Plecntide ws well tolerted, exhibiting limited AE profile, including low incidence of dirrhe. Plecntide ppers to be promising new tretment for ptients with CIC. ACKNOWLEDGMENTS We thnk the ptients with CIC who prticipted in this study nd the clinicins who contributed their efforts to the conduct of the study. The contributions of S. Comiskey nd R. Feng in the development of room temperture-stble formultion nd in mnufcturing of plecntide nd plcebo tblets used in this study re thnkfully cknowledged. Medicl writing support ws provided by Medicl Dynmics, New York, NY, with editoril nd submission support from The Medicine Group, New Hope, PA. CONFLICT OF INTEREST Gurntor of the rticle: Leslie Mgnus, MD. Specific uthor contributions: Study concept: Drs Miner nd Shilubhi; study design: Drs Miner, Brrow, nd Griffin; dt cquisition: Drs Miner, Koltun, Wiener, De L Portill, nd Prieto; dt nlysis: Drs Miner, Brrow, nd Griffin nd Ms Lyton; dt interprettion, drfting of the mnuscript, criticl revision of the VOLUME 2 APRIL 27

9 Plecntide in Ptients With CIC 2 mnuscript for importnt intellectul content, nd finl pprovl of the mnuscript: ll uthors. Finncil support: Funding for this tril nd mnuscript support were provided by Synergy Phrmceuticls Inc. Synergy Phrmceuticls Inc. lso provided the plecntide nd plcebo used for the study. Potentil competing interests: Drs Shilubhi, Brrow, Mgnus, nd Griffin nd Ms Lyton re employees nd stockholders of Synergy Phrmceuticls Inc. Drs Miner, Koltun, Wiener, De L Portill, nd Prieto were study investigtors pid for their prticiption in this clinicl tril. Dr Koltun hs received funding for either dvisory bords or speking from the following institutions: Synergy Phrmceuticls, Symiomix Therputics, Ferring Phrmceuticls, Enteris Phrmceuticls, nd Shionogi Inc. Dr Miner hs received funding for dvisory bord meetings. Trnscript Profiling: does not pply. Study Highlights WHAT IS CURRENT KNOWLEDGE Chronic idiopthic constiption (CIC) is one of the most common functionl gstrointestinl disorders. Ptients with CIC often report disstisfction with trditionl tretment options. Plecntide is novel nlog of urogunylin, vitl peptide in pproprite gut motility. WHAT IS NEW HERE Plecntide significntly incresed the percentge of durble overll complete spontneous bowel movement (BM) responders in ptients with CIC. Plecntide significntly improved BM frequency, stool consistency, strining, nd bdominl symptoms. Plecntide exhibited fvorble sfety nd tolerbility profile, with low incidence of dirrhe. REFERENCES. Sures NC, Ford AC. Prevlence of, nd risk fctors for, chronic idiopthic constiption in the community: systemtic review nd met-nlysis. Am J Gstroenterol 2 ; : Higgins PD, Johnson JF. Epidemiology of constiption in North Americ: systemtic review. Am J Gstroenterol 24 ;99 : Americn College of Gstroenterology Chronic Constiption Tsk Force. An evidence-bsed pproch to the mngement of chronic constiption in North Americ. Am J Gstroenterol 25 ; (Suppl ):S Johnson JF, Krlstein J. Chronic constiption: survey of the ptient perspective. Aliment Phrmcol Ther 27 ;25 : Bhr u ch A E, D or n SD, L e mb o A et l. Americn Gstroenterologicl Assocition medicl position sttement on constiption. Gstroenterology 23 ;44 :2 7.. Bhruch AE, Pemberton JH, Locke GR 3rd. Americn Gstroenterologicl Assocition technicl review on constiption. Gstroenterology 23 ;44 : FDA Approves Linzess To Tret Certin Cses Of Irritble Bowel Syndrome And Constiption [press relese] Silver Spring, MD, US Food nd Drug Administrtion (FDA) : FDA Approves New Prescription Drug For Adults For Tretment of Chronic "Idiopthic" Constiption [press relese] Silver Spring, MD, US Food nd Drug Administrtion (FDA) : Wld A. Constiption: dvnces in dignosis nd tretment. JAMA 2 ;35 : Kit T, Smith CE, Fok KF et l. Chrcteriztion of humn urogunylin: member of the gunylin peptide fmily. 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Linclotide inhibits colonic nociceptors nd relieves bdominl pin vi gunylte cyclse-c nd extrcellulr cyclic gunosine 3ʹ,5ʹ-monophosphte. Gstroenterology 23 ;45 :334-4.e. 24. Miner PB, Surowitz R, Fogel R et l. 925g Plecntide, novel gunylte cyclse-c (GC-C) receptor gonist, is efficcious nd sfe in ptients with chronic idiopthic constiption (CIC): results from 95 ptient, 2 week, multi-center tril [bstrct]. Gstroenterology 23 ; 44 : S Drossmn DA. The functionl gstrointestinl disorders nd the Rome III process. Gstroenterology 2 ;3 : Study SP34-22: A Rndomized, 2-Week, Double-Blind, - Controlled, Repet-Dose, Orl, Dose-Rnging Study to Assess the Sfety nd Efficcy of Plecntide in Ptients With Chronic Idiopthic Constiption. In: CliniclTrils.gov [Internet]. Bethesd (MD): Ntionl Librry of Medicine (US). 22, Accessed on 25 August 25. Avilble t This work is licensed under Cretive Commons Attribution-NonCommercil-ShreAlike 4. Interntionl License. The imges or other third prty mteril in this rticle re included in the rticle s Cretive Commons license, unless indicted otherwise in the credit line; if the mteril is not included under the Cretive Commons license, users will need to obtin permission from the license holder to reproduce the mteril. To view copy of this license, visit The Author(s) 27 Officil journl of the Americn College of Gstroenterology