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1 A 12-Week, Rndomized, Controlled Tril with 4-Week Rndomized Withdrwl Period to Evlute the Efficcy nd Sfety of Linclotide in Irritble Bowel Syndrome with Constiption The Hrvrd community hs mde this rticle openly vilble. Plese shre how this ccess benefits you. Your story mtters. Cittion Published Version Accessed Citble Link Terms of Use Ro, Stish, Anthony J. Lembo, Steven J. Shiff, Bernrd J. Lvins, Mrk G. Currie, Xinwei D. Ji, Kelvin Shi, et l A 12-week, rndomized, controlled tril with 4-week rndomized withdrwl period to evlute the efficcy nd sfety of linclotide in irritble bowel syndrome with constiption. The Americn Journl of Gstroenterology 107(11): doi: /jg June 30, :25:46 PM EDT This rticle ws downloded from Hrvrd University's DASH repository, nd is mde vilble under the terms nd conditions pplicble to Other Posted Mteril, s set forth t (Article begins on next pge)

2 1714 ORIGINAL CONTRIBUTIONS nture publishing group see relted editoril on pge 1726 CME A 12-Week, Rndomized, Controlled Tril With 4-Week Rndomized Withdrwl Period to Evlute the Efficcy nd Sfety of Linclotide in Irritble Bowel Syndrome With Constiption Stish Ro, MD 1, Anthony J. Lembo, MD 2, Steven J. Shiff, MD 3, Bernrd J. Lvins, MD 4, Mrk G. Currie, PhD 4, Xinwei D. Ji, PhD 3, Kelvin Shi, PhD 3, Jmes E. McDougll, PhD 4, Jmes Z. Sho, MS 4, Pul Eng, PhD 3, Susn M. Fox, PhD 3, Hrvey A. Schneier, MD 3, Croline B. Kurtz, PhD 4 nd Jeffrey M. Johnston, MD 4 OBJECTIVES: METHODS: Linclotide is minimlly bsorbed gunylte cyclse-c gonist. The objective of this tril ws to determine the efficcy nd sfety of linclotide in ptients with irritble bowel syndrome with constiption (IBS-C). This phse 3, double-blind, prllel-group, plcebo-controlled tril rndomized IBS-C ptients to plcebo or 290 μ g orl linclotide once dily in 12-week tretment period, followed by 4-week rndomized withdrwl (RW) period. There were four primry end points, the Food nd Drug Administrtion s (FDA s) primry end point for IBS-C (responder: improvement of 30 % in verge dily worst bdominl pin score nd increse by 1 complete spontneous bowel movement (CSBM) from bseline (sme week) for t lest 50 % of weeks ssessed) nd three other primry end points, bsed on improvements in bdominl pin nd CSBMs for 9 / 12 weeks. Adverse events (AEs) were monitored. RESULTS: The tril evluted 800 ptients (men ge = 43.5 yers, femle = 90.5 %, white = 76.9 % ). The FDA end point ws met by 136 / 405 linclotide-treted ptients (33.6 % ), compred with 83 / 395 plcebo-treted ptients (21.0 % ) ( P < ) (number needed to tret: 8.0, 95 % confidence intervl: 5.4, 15.5). A greter percentge of linclotide ptients, compred with plcebo ptients, reported for t lest 6 / 12 tretment period weeks, reduction of 30 % in bdominl pin (50.1 vs %, P = ) nd n increse of 1 CSBM from bseline (48.6 vs %, P < ). A greter percentge of linclotide ptients vs. plcebo ptients were lso responders for the other three primry end points ( P < 0.05). Significntly greter improvements were seen in linclotide vs. plcebo ptients for ll secondry end points ( P < 0.001). During the RW period, ptients remining on linclotide showed sustined improvement; ptients re-rndomized from linclotide to plcebo showed return of symptoms, but without worsening of symptoms reltive to bseline. Dirrhe, the most common AE, resulted in discontinution of 5.7 % of linclotide nd 0.3 % of plcebo ptients. CONCLUSIONS: Linclotide significntly improved bdominl pin nd bowel symptoms ssocited with IBS-C for t lest 12 weeks; there ws no worsening of symptoms compred with bseline following cesstion of linclotide during the RW period. Am J Gstroenterol 2012; 107: ; doi: /jg ; published online 18 September Section of Gstroenterology / Heptology, Georgi Helth Sciences University, August, Georgi, USA ; 2 Division of Gstroenterology, Deprtment of Medicine, Beth Isrel Deconess Medicl Center, Hrvrd Medicl School, Boston, Msschusetts, USA ; 3 Forest Reserch Institute, Jersey City, New Jersey, USA ; 4 Ironwood Phrmceuticls, Inc., Cmbridge, Msschusetts, USA. Correspondence: Jeffrey M. Johnston, MD, Ironwood Phrmceuticls, Inc., 301 Binney Street, Cmbridge, Msschusetts 02142, USA. E-mil: jjohnston@ironwoodphrm.com Portions of this mnuscript were presented s n orl presenttion t Digestive Disese Week, My 2011, Chicgo, IL. Received 2 April 2012; revised 20 June 2012; ccepted 24 June 2012 The Americn Journl of GASTROENTEROLOGY VOLUME 107 NOVEMBER

3 Linclotide in IBS-C 1715 INTRODUCTION Irritble bowel syndrome (IBS) is common gstrointestinl disorder chrcterized by frequent nd intermittent episodes of bdominl pin nd bdominl discomfort tht re ssocited with ltered bowel hbits ( 1,2 ). The symptoms of IBS not only dversely ffect ptient s helth-relted qulity of life ( 3 ) but lso plce significnt finncil burden on society due to reduced work productivity nd incresed use of helthcre-relted resources ( 4,5 ). IBS with constiption (IBS-C) ffects pproximtely one-third of IBS ptients ( 3 ), occurs more commonly in women thn men ( 6 ), nd frequently includes dditionl symptoms, such s bdominl bloting, hrd stools, strining, nd senstion of incomplete evcution ( 7,8 ). Trditionl therpies for IBS-C, generlly directed towrds the ptient s predominnt symptoms ( 9 ), re frequently ssocited with ptient disstisfction ( 10 ). More recent therpies, including tegserod nd lubiprostone, hve been shown to improve globl symptoms of IBS-C ( 9 ). Tegserod, 5-HT 4 prtil gonist pproved by the Food nd Drug Administrtion (FDA) for the short-term tretment of women with IBS-C, ws removed from the mrket in 2007 due to incresed crdiovsculr events in ptients receiving the mediction. Lubiprostone, chloride chnnel ctivtor tht ws pproved by the FDA for the tretment of women with IBS-C in 2008, hs shown efficcy using globl end point (globl symptom relief) ( 11 ). Given the limited tretments currently vilble for ptients with IBS-C, dditionl therpeutic options would be of vlue. Linclotide, minimlly bsorbed 14-mino-cid peptide structurlly relted to the endogenous gunylin peptide fmily of hormones tht regulte fluid nd electrolyte homeostsis in the intestine, binds to nd ctivtes GCC (gunylte cyclse-c) on the luminl surfce of the intestinl epithelium. Activtion of GCC results in the genertion of cyclic gunosine monophosphte (cgmp), which is incresed in both the intrcellulr nd extrcellulr comprtments. The increse in cgmp within intestinl epithelil cells triggers signl trnsduction cscde ctivting the cystic fibrosis trnsmembrne conductnce regultor ( 12 ). This ctivtion cuses secretion of chloride nd bicrbonte into the intestinl lumen; sodium ions nd wter follow, resulting in incresed luminl fluid secretion nd reflex ccelertion of intestinl trnsit. Extrcellulr cgmp, ctively trnsported out of intestinl epithelil cells, is believed to reduce viscerl hyperlgesi by modulting the ctivity of fferent pin fibers ( 13 ). In niml models, linclotide tretment ccelerted gstrointestinl trnsit nd reduced viscerl nociception ( 14 ); in humn phse 2 clinicl studies, it ccelerted colonic trnsit ( 15 ) nd improved bdominl pin nd constiption ssocited with IBS-C ( 16 ). Likewise, in two lrge phse 3 trils in ptients with chronic constiption, linclotide significntly improved bowel nd bdominl symptoms over 12 weeks ( 17 ). The objective of this phse 3 clinicl tril ws to ssess the efficcy nd sfety of linclotide dministered once dily s n orl cpsule t dose of 290 μ g vs. plcebo to ptients with IBS-C. A 4-week rndomized withdrwl (RW) period ws included in this tril to ssess the effect of discontinuing tretment with linclotide. METHODS Tril design This multicenter, rndomized, double-blind, plcebo-controlled, prllel-group tril ws conducted t 118 outptient clinicl reserch centers (111 in the United Sttes, 7 in Cnd) from 14 July 2009 (first ptient enrolled) to 12 July 2010 (lst ptient completed). The protocol nd ll tril procedures were pproved by n Institutionl Review Bord, nd the tril ws designed, conducted, nd reported in ccordnce with the principles of Good Clinicl Prctice guidelines. All ptients gve written informed consent before their prticiption in the tril. After screening period of up to 21 dys followed by pretretment bseline period of dys, eligible ptients were rndomly ssigned with the use of n interctive voice-response system (IVRS) to receive once dily n orl cpsule of either linclotide 290 μ g or plcebo, in 1:1 rtio. Ptients who completed ll 12 weeks of the double-blind tretment period were eligible to enter the double-blind 4-week RW period in which ptients initilly rndomized to linclotide were re-rndomized (1:1) to linclotide 290 μ g or plcebo, nd ptients previously rndomized to plcebo were ssigned to receive linclotide 290 μ g once dy. Rndomiztion ssignments were generted in blocks of four nd strtified ccording to tril center. All sponsor stff involved in the tril, tril center personnel, nd ptients were blinded to the lloction of tril tretment. Tril visits were conducted t screening, t the strt of the pretretment bseline period, t rndomiztion (dy 1), throughout the tretment period (weeks 2, 4, 8, nd 12), nd t the beginning nd end of the RW period (weeks 13 nd 16 (end of tril)). Ptients mde dily clls to the IVRS to report their symptoms throughout the tril. Tril ptients Femle nd mle ptients were eligible to prticipte if they were t lest 18 yers of ge, nd met modified Rome II criteri for IBS ( 18 ). In the 12 months before the screening visit, eligible ptients were to hve for t lest 12 weeks, which need not be consecutive, bdominl pin, or bdominl discomfort tht hd 2 of these three fetures: (i) relieved with defection, (ii) onset ssocited with chnge in frequency of stool, nd (iii) onset ssocited with chnge in form (ppernce) of stool, before strting chronic tretment with tegserod or lubiprostone (if ptients hd tken these medictions); nd < 3 spontneous bowel movements (SBMs) per week (SBM = bowel movement (BM) occurring in the bsence of ny lxtive, suppository, or enem use during the preceding 24 h), nd hd t lest one dditionl bowel symptom (strining, lumpy or hrd stools, nd senstion of incomplete evcution during > 25 % of BMs), before strting chronic tretment with tegserod, lubiprostone, polyethylene glycol 3350, or ny lxtive (if ptients hd tken these medictions). In ddition, ptients hd to report n 2012 by the Americn College of Gstroenterology The Americn Journl of GASTROENTEROLOGY

4 1716 Ro et l. verge score 3.0 for dily bdominl pin t its worst (11- point NRS (numericl rting scle)) s well s n verge of < 3 complete SBMs (CSBMs) per week (CSBM = n SBM ssocited with sense of complete evcution, s reported by the ptient) nd 5 SBMs per week during the 14 dys immeditely before rndomiztion (i.e., the bseline period). Ptients were excluded if they reported loose (mushy) or wtery stools for > 25 % of their BMs during the 12 weeks before screening or, during the bseline period, BSFS (Bristol Stool Form Scle) ( 19 ) score of 7 (wtery, no solid pieces) for ny SBM, or BSFS score of 6 (fluffy pieces with rgged edges, mushy stool) for > 1 SBM. Other key exclusion criteri included history of cthrtic colon, lxtive or enem buse, ischemic colitis, or pelvic floor dysfunction (unless successful tretment hd been documented by norml blloon expulsion test); britric surgery for tretment of obesity or surgery to remove segment of the gstrointestinl trct t ny time before the screening visit, surgery of the bdomen, pelvis, or retroperitonel structures during the 6 months before the screening visit, ppendectomy or cholecystectomy during the 60 dys before the screening visit, or other mjor surgery during the 30 dys before the screening visit; history of diverticulitis or ny chronic condition tht could be ssocited with bdominl pin or discomfort nd could confound the ssessments in the tril (e.g., inflmmtory bowel disese, chronic pncretitis, polycystic kidney disese, ovrin cysts, endometriosis, lctose intolernce); fmily history of fmilil form of colorectl cncer. In generl, ptients were excluded if they were tking drugs tht could cuse constiption (e.g., nrcotics); however, ptients tking certin drugs for IBS tht might be constipting (e.g., tricyclic ntidepressnts) were eligible provided tht they were on stble dose for t lest 30 dys before the screening visit nd there ws no pln to chnge the dose fter the screening visit. Colonoscopy requirements were bsed on the Americn Gstroenterologicl Assocition guidelines ( 20 ). Women of childbering potentil were required to use contrceptives nd hve negtive serum pregnncy test. Ptients were sked to refrin from mking ny mjor lifestyle chnges (e.g., strting new diet or chnging their exercise pttern) during the tril. Rescue mediction (biscodyl 5 mg tblet or 10 mg suppository) ws llowed for severe constiption (i.e., 72 h fter the ptient s previous BM or when symptoms becme intolerble). Use of rescue mediction ws not llowed on the dy before, the dy of, nd the clendr dy fter the rndomiztion visit. Ptients on stble, continuous regimen of fiber, bulk lxtives, stool softeners, or probiotics during the 30 dys before the screening visit were llowed to continue, provided they mintined stble dosge throughout the tril. Efficcy ssessments nd end points Dily reports by ptients to IVRS included symptom rtings of worst bdominl pin, bdominl discomfort, bdominl crmping, bdominl fullness, nd bdominl bloting (ll bdominl symptoms were mesured using n 11-point NRS), s well s the number of BMs nd whether rescue mediction ws used. Ech BM ws ssessed for senstion of complete bowel emptying (yes /no), stool consistency (7-point BSFS with 1 = seprte hrd lumps like nuts to 7 = wtery, no solid pieces ), nd severity of strining (5-point ordinl scle). Weekly IVRS ssessments included IBS severity nd constiption severity (both using 5- point ordinl scle), degree of IBS relief (7-point blnced scle), nd dequte relief of IBS-C symptoms (yes / no). Assessment of stisfction with the tril-mediction s bility to relieve IBS symptoms (5-point ordinl scle) ws cptured t ll study visits following rndomiztion. Primry end points. There were four prespecified primry end points in the tril, which were ll responder end points. One of the four primry end points ws bsed on the FDA recommendtions for IBS-C tril design nd end points in the recently finlized guidnce for IBS clinicl trils (My 2012) ( 21 ); responder for this end point (to be referred to herefter s FDA end point ) ws defined s ptient who met both of the following criteri in the sme week for t lest 6 of the 12 weeks of the tretment period: (i) n improvement of 30 % from bseline in the verge of the dily worst bdominl pin scores (to be referred to herefter s bdominl pin ) nd (ii) n increse of 1 CSBM from bseline. This combined end point ws dded fter the initition of the tril, but before completion of enrollment nd dtbse lock, with protocol mendment (no unblinding hd occurred). The other three primry end points lso required ptients to meet weekly responder definitions, but for t lest 9 of the 12 weeks of the tretment period. These weekly responder definitions were (i) n improvement of 30 % in bdominl pin, (ii) 3 CSBMs nd n increse of 1 CSBM from bseline, nd (iii) combined end point tht defined responder s ptient who met criteri for both i nd ii in the sme week. Secondry end points. Th e secondry end points included 12-week chnge from bseline in bdominl pin, bdominl discomfort, bdominl bloting, stool frequency (CSBM nd SBM weekly rtes), stool consistency (BSFS), nd severity of strining; secondry responder end points included bdominl pin nd CSBM responders (using the individul components of the FDA end point). A number of other dditionl end points were lso ssessed, including 12-week chnge from bseline in bdominl fullness nd bdominl crmping, IBS symptom severity, constiption severity, dequte relief of IBS-C symptoms, degree of relief of IBS symptoms, nd tretment stisfction. Sfety ssessments At ech scheduled study visit, ll ptients were sked n openended question regrding dverse events (AEs). Ptients reported AEs by reclling instnces since the prior visit. The site investigtor ssessed ll ptient-reported AEs nd judged ech event for severity nd reltionship to the blinded tril mediction. Other sfety evlutions included physicl exmintions, electrocrdiogrm recordings, vitl sign mesurements, nd stndrd clinicl lbortory tests. The Americn Journl of GASTROENTEROLOGY VOLUME 107 NOVEMBER

5 Linclotide in IBS-C 1717 Phrmcokinetic ssessments During the tretment period, subset of ptients hd blood smples tken t the rndomiztion nd week 4 visits to determine if linclotide or its ctive metbolite, MM , could be detected t quntifible levels in the plsm. Sttisticl methods nd dt nlysis The overll fmily-wise type I error rte for testing the primry nd secondry efficcy end points ws controlled t the 0.05 significnce level using five-step seril gte-keeping, multiple-comprison procedure. Bsed on this multiple-comprison procedure nd the results of previous phse 2b study ( 16 ), smple size of 400 ptients per tretment rm ws selected to provide >85 % overll power to simultneously detect difference between the plcebo nd linclotide groups for the primry end points. Responder end points were nlyzed using Cochrn Mntel Henszel (CMH) test controlling for geogrphic region. Continuous chnge-from-bseline end points were nlyzed using n ANCOVA (nlysis of covrince) model with fixed-effect terms for tretment group nd geogrphic region nd the corresponding bseline vlue s covrite. Lest-squres mens (i.e., mens djusted for the other effects) from the ANCOVA model bsed on ptients overll verge scores (except for SBMs nd CSBMs, for which the overll weekly rtes were clculted) re presented. Geogrphic region ws used s fctor in the nlyses rther thn individul tril centers due to the potentil for very smll numbers of ptients t some tril centers. If ptient dropped out of the tril or otherwise did not report efficcy dt for prticulr tretment-period week (ptients were required to complete t lest four IVRS clls during tretment week), the ptient ws not considered responder for tht week. An observed-cses pproch to missing dt ws pplied to the chnge-from-bseline secondry end points, such tht if ptient dropped out of the tril or otherwise did not report dt, the verge of the non-missing dt over the 12 weeks of the tretment period ws the ptient s vlue. Ptients were ssumed to hve not hd BMs nor tken rescue mediction if the corresponding dily Screening period Bseline period (2 3 weeks) Ptients screened (N=2424) Rndomized (n=803) Excluded (n=1,621) Screen filures (n=466) Pretretment filures (n=1,155) Did not meet inclusion/exclusion criteri (1,006) Adverse event (1) Protocol violtion (6) Withdrwl of consent (81) Lost to follow-up (34) Other (27) Plcebo (n=397) Linclotide 290 μg qd (n=406) Tretment period (12 weeks) Discontinued (n=62) Adverse event (n=10) Protocol violtion (n=9) Withdrew consent (n=25) Lost to follow-up (n=10) Insufficient therpeutic response (n=4) Other (n=4) Completed tretment period (n=335) Completed tretment period (n=312) Discontinued (n=94) Adverse event (n=32) Protocol violtion (n=10) Withdrew consent (n=25) Lost to follow-up (n=17) Insufficient therpeutic response (n=5) Other (n=5) Rndomized withdrwl (RW) period (4 weeks) Discontinued (n=10) Adverse event (n=2) Protocol violtion (n=1) Withdrew consent (n=2) Lost to follow-up (n=3) Insufficient therpeutic response (n=0) Other (n=2) Assigned Linclotide 290 μg qd (n=335) Discontinued (n=3) Adverse event (n=1) Protocol violtion (n=1) Withdrew consent (n=0) Lost to follow-up (n=0) Insufficient therpeutic response (n=1) Other (n=0) Plcebo (n=154) Rndomized Linclotide 290 μg qd (n=158) Discontinued (n=4) Adverse event (n=0) Protocol violtion (n=2) Withdrew consent (n=0) Lost to follow-up (n=2) Insufficient therpeutic response (n=0) Other (n=0) Completed RW period (n=325) Completed RW period (n=151) Completed RW period (n=154) Figure 1. Ptient flow through the study by the Americn College of Gstroenterology The Americn Journl of GASTROENTEROLOGY

6 1718 Ro et l. question ws not nswered. For the nlysis of dequte relief, degree of relief of IBS symptoms, nd tretment stisfction, lst observtion crried forwrd method ws used. All P vlues were bsed on two-sided tests. All rndomized ptients who took t lest one dose of tril mediction were included in sfety nlyses (sfety popultion). Efficcy nlyses were bsed on the ITT (intent-to-tret) popultion, which included ll ptients in the sfety popultion who hd t lest one post-rndomiztion entry of the primry efficcy ssessment (i.e., IVRS ssessment of bdominl pin or CSBMs). RESULTS Ptient disposition, demogrphics, nd bseline chrcteristics Of the 2,424 ptients who were screened for prticiption in this tril, 803 (33 % ) were rndomized to tretment ( Figure 1 ). Two ptients were rndomized t more thn one tril center but only dt from the tril center in which they were first rndomized were included in sttisticl nlyses. Of the 802 ptients who received double-blind tril mediction (sfety popultion), 800 ptients hd t lest one post-rndomiztion entry of the primry efficcy ssessment (ITT popultion). The demogrphics of the ITT popultion re shown in Tble 1. Following completion of the tretment period, totl of 647 (81 % ) ITT ptients entered the RW period of the tril, of which 645 received t lest one dose of tril mediction nd were included in the RW popultion. Men complince with the tril-mediction dosing (ssessed by counting pills returned t tril visits) up to tril discontinution / completion of the 12-week tretment period ws 95 nd 94 % for the plcebo nd linclotide groups, respectively. Complince with the dily IVRS cll-in (ptients who completed 80 % of scheduled clls) during the tretment period ws 73 nd 71 % for plcebo- nd linclotide-treted ptients, respectively. During the pretretment bseline period, 88 % of ptients experienced bdominl pin every dy nd 76 % of ptients hd no CSBMs. Efficcy results For ll primry nd secondry efficcy end points, the linclotide 290- μ g group demonstrted sttisticlly significnt improvement compred with the plcebo group, controlling for multiplicity. For the individul components of the FDA end point, significntly greter percentge of linclotide-treted ptients, compred with plcebo-treted ptients, reported reduction of 30 % in bdominl pin for t lest 6 out of the 12 weeks of the tretment period (50.1 vs %, P = (Figure 2 )) or n increse of 1 CSBM from bseline for t lest 6 out of the 12 weeks of the tretment period (48.6 vs %, P < (Figure 2 )). A totl of 136 of 405 ptients (33.6 % ) receiving linclotide compred with 83 of 395 ptients (21.0 % ) receiving plcebo (odds rtio: 1.9, 95 % confidence intervl: 1.4, 2.7; P < ) met the FDA end point ( Tble 2 ; Figure 2 ). A significntly greter percentge of linclotide-treted ptients thn plcebo-treted ptients lso met the responder requirements for the other three primry end points, Tble 1. Summry of ptient demogrphic nd bseline chrcteristics (ITT popultion) Demogrphic dt Plcebo, N =395 Linclotide 290 µ g, N =405 Age (yers), men (rnge) 43.7 (18 84) 43.3 (19 81) 65 yers, n ( % ) 26 (6.6) 19 (4.7) Sex, n ( % ) Femle 357 (90.4) 367 (90.6) Mle 38 (9.6) 38 (9.4) Rce, n ( % ) White 301 (76.2) 314 (77.5) Blck 75 (19.0) 78 (19.3) Other 19 (4.8) 13 (3.2) BMI, men (s.d.) 27.6 (6.2) 28.3 (6.4) Abdominl symptoms, men (s.d.) Abdominl pin 5.6 (1.7) 5.7 (1.7) Abdominl discomfort 6.0 (1.7) 6.2 (1.6) Abdominl bloting 6.5 (1.9) 6.7 (1.8) Abdominl fullness 6.5 (1.8) 6.8 (1.7) Abdominl crmping 5.4 (1.9) 5.4 (1.9) Bowel symptoms, men (s.d.) CSBMs / week 0.2 (0.5) 0.2 (0.5) SBMs / week 1.9 (1.4) 1.9 (1.4) Stool consistency b 2.4 (1.0) 2.3 (1.0) Strining c 3.4 (0.8) 3.6 (0.8) Constiption severity d 3.7 (0.6) 3.8 (0.6) IBS severity d 3.7 (0.6) 3.7 (0.6) BMI, body mss index; CSBM, complete SBM; IBS, irritble bowel syndrome; ITT, intent-to-tret; SBM, spontneous bowel movement. Assessed using n 11-point Numericl Rting Scle: 0=none; 10=very severe. b Assessed using the BSFS: 1=seprte hrd lumps, like nuts (hrd to pss); 2=susge-shped, but lumpy; 3=like susge but with crcks on its surfce; 4=like susge or snke, smooth nd soft; 5=soft blobs with cler cut edges (pssed esily); 6=fl uffy pieces with rgged edges, mushy stool; 7=wtery, no solid pieces (entirely liquid). c Assessed using 5-point ordinl scle: 1=not t ll; 2= little bit; 3= moderte mount; 4= gret del; 5=n extreme mount. d Assessed using 5-point ordinl scle: 1=none; 2=mild; 3=moderte; 4=severe; 5=very severe. All demogrphic chrcteristics were similr between tretment groups. For bseline clinicl chrcteristics, signifi cnt differences were observed for bdominl fullness ( P =0.011), stool consistency ( P =0.046), nd strining ( P =0.020). which required improvement in bdominl pin (i.e., reduction of 30 % in bdominl pin), CSBM rte (i.e., 3 CSBMs nd n increse of 1 CSBM), or both for t lest 9 of the 12 weeks of the tretment period ( Tble 2 ). The NNT (number needed to tret) for the primry end points rnged from 7.6 to The Americn Journl of GASTROENTEROLOGY VOLUME 107 NOVEMBER

7 Linclotide in IBS-C 1719 Linclotide-treted ptients lso experienced sttisticlly significntly greter improvements compred with plcebo-treted ptients for the secondry nd dditionl end points ( Tble 3 ). During the first week of tretment nd for ech subsequent week of tretment, linclotide-treted ptients reported greter improvements in worst bdominl pin nd CSBM frequency compred % Responders % Responders % Worst bdominl pin reduction for 6/12 weeks (secondry) 50.1%*** 37.5% Plcebo Lin 290 μg NNT = 7.9 Increse 1 CSBM from bseline for 6/12 weeks (secondry) 29.6% 48.6%**** with plcebo-treted ptients ( P < 0.001; Figure 3 ). At week 12, the men decrese from bseline in worst bdominl pin ws 2.4 % for linclotide vs. 1.5 % for plcebo ( P < ), nd the men increse from bseline in the weekly CSBM rte ws 2.4 nd 0.9 for linclotide nd plcebo, respectively ( P < ). At the end of the Tretment Period (week 12), 52 % of linclotide-treted ptients % Respoders FDA end point (primry) %**** % Plcebo Lin 290 μg NNT= Plcebo Lin 290 μg NNT= 5.3 ***P<0.001 ****P< P vlues for ll nlyses bsed on comprison of linclotide versus plcebo groups using the Cochrn-Mntel-Henszel test Figure 2. FDA end point nd components. FDA end point: 30 % bdominl pin reduction nd increse 1 CSBM from bseline in the sme week for 6 / 12 weeks. * * * * P vlue < , * * * < for linclotide vs. plcebo (Cochrn Mntel Henszel (CMH) test). P vlues met the criterion for sttisticl significnce bsed on the multiple-comprison procedure. CSBM, complete spontneous bowel movement; FDA, Food nd Drug Administrtion; Lin, linclotide; NNT, number needed to tret. Tble 2. Primry efficcy prmeter results (ITT popultion) Primry efficcy prmeters FDA end point (ech week, 30 % decrese in worst bdominl pin + n increse 1 CSBM from bseline for t lest 6 / 12 weeks) 30 % Decrese in worst bdominl pin (ech week, 30 % decrese in bdominl pin from bseline for t lest 9 / 12 weeks) 3 CSBMs nd n increse of 1 CSBM (ech week, 3 CSBM + n increse 1 CSBM from bseline for t lest 9 / 12 weeks) Combined responder (ech week 30 % decrese in worst bdominl pin + 3 CSBM + n increse 1 CSBM from bseline for t lest 9 / 12 weeks) Plcebo responder ( N =395), n ( % ) Linclotide responder ( N =405), n ( % ) Difference Odds rtio (95 % CI) P vlue NNT (95 % CI) 83 (21.0) 136 (33.6) (1.4, 2.7) < (5.4, 15.5) 107 (27.1) 139 (34.3) (1.0, 1.9) (7.4, 116.1) 25 (6.3) 79 (19.5) (2.3, 5.9) < (5.6, 11.6) 20 (5.1) 49 (12.1) (1.5, 4.5) (9.2, 31.3) CI, confi dence intervl; CSBM, complete spontneous bowel movement; FDA, Food nd Drug Administrtion; ITT, intent-to-tret; NNT, number needed to tret. P vlues were bsed on comprison of linclotide vs. the plcebo group using the Cochrn Mntel Henszel test by the Americn College of Gstroenterology The Americn Journl of GASTROENTEROLOGY

8 1720 Ro et l. Tble 3. Other efficcy prmeter results (ITT popultion) Worst bdominl pin Plcebo, N =395 Men (11-point NRS scle) Linclotide 290 µ g, N =405 Difference P vlue Chnge from bseline, men b,c < % of ptients with 30 % decrese in worst bdominl pin for t lest 6 / 12 weeks d Abdominl discomfort Men (11-point NRS scle) NNT (95 % CI) (5.1, 17.1) Chnge from bseline, men b,c < % of ptients with 30 % decrese in bdominl discomfort for t lest 6 / 12 weeks d (5.6, 22.8) Abdominl bloting Men (11-point NRS scle) Chnge from bseline, men b,c < % of ptients with 30 % decrese in bdominl bloting for t lest 6 / 12 weeks d < (5.0, 14.3) Abdominl fullness Men (11-point NRS scle) Chnge from bseline, men b,c < % of ptients with 30 % decrese in bdominl fullness for t lest 6 / 12 weeks d Abdominl crmping Men (11-point NRS scle) (5.6, 23.0) Chnge from bseline, men b,c < % of ptients with 30 % decrese in bdominl crmping for t lest 6 / 12 weeks d CSBMs Men CSBMs / week (5.8, 28.3) Chnge from bseline, men b,c < CSBM 24 h fi rst dose (%) c < (4.0, 7.4) % of ptients w / CSBM rte increse 1 per week for t lest 6 / 12 weeks d < (3.9, 8.1) SBMs Men SBMs / week Chnge from bseline b,c < SBM 24 h fter fi rst dose (%) c < (3.3, 5.9) % of ptients w / SBM rte increse 2 per week from bseline for t lest 6 / 12 weeks d < (2.9, 4.6) Stool consistency Men BSFS score (1 7) Chnge from bseline, men b,c < Men weekly % of SBMs without hrd or lumpy stools (BSFS 3) < Strining Men strining score (1 5) Chnge from bseline, men b,c < Men weekly % of SBMs without signifi cnt strining (i.e., score 3) < Tble continued on following pge The Americn Journl of GASTROENTEROLOGY VOLUME 107 NOVEMBER

9 Linclotide in IBS-C 1721 Tble 3. Continued Constiption severity Plcebo, N =395 Men constiption severity score (1 5) Linclotide 290 µ g, N =405 Difference P vlue Chnge from bseline, men b,c < NNT (95 % CI) % of ptients with decrese of 1 for t lest 6 / 12 weeks d < (4.2, 9.9) IBS severity Men IBS severity score (1 5) Chnge from bseline, men b,c < % of ptients with decrese of 1 for t lest 6 / 12 weeks d < (3.9, 8.3) Adequte relief % of ptients reporting dequte relief of IBS symptoms for t lest 75 % of the weeks (i.e., 9 / 12 weeks) d % of ptients reporting dequte relief of IBS symptoms for t lest 50 % of the weeks (i.e., 6 / 12 weeks) d Degree of relief e % of ptients reporting Somewht Relieved, Considerbly Relieved, or Completely Relieved for 100 % of the weekly scores or Considerbly Relieved or Completely Relieved for t lest 50 % of the weekly scores d < (4.6, 10.7) < (4.7, 12.6) < (4.3, 9.5) BSFS, Bristol Stool Forms Scle; CI, confi dence intervl; CSBM, complete SBM; IBS, irritble bowel syndrome; ITT, intent-to-tret; NNT, number needed to tret; NRS, numericl rting scle; SBM, spontneous bowel movement. Secondry end point. b Chnges from bseline re the lest-squres mens from the nlysis of covrince (ANCOVA) model. c P vlues were bsed on comprison of linclotide vs. the plcebo group using the ANCOVA model. d P vlues were bsed on comprison of linclotide vs. the plcebo group using the Cochrn Mntel Henszel test. e Degree of Relief scle: 1=completely relieved; 2=considerbly relieved; 3=somewht relieved; 4=unchnged; 5=somewht worse; 6=considerbly worse; 7=s bd s I cn imgine. were either very stisfied or quite stisfied with tretment compred with 23 % of plcebo-treted ptients ( P < ). During the 4-week RW Period, ptients who were re-rndomized from linclotide to plcebo showed n increse in worst bdominl pin nd decrese in CSBMs to levels similr to those observed in the plcebo group during the Tretment Period. The ptients who continued to tke linclotide showed sustined improvement in worst bdominl pin nd CSBMs similr to tht previously observed during the Tretment Period. These improvements were sttisticlly significnt compred to ptients re-rndomized to plcebo for weeks for CSBMs ( P < 0.001) nd weeks for worst bdominl pin ( P < 0.05). Ptients who switched from plcebo to linclotide showed levels of improvement similr to those experienced by linclotide-treted ptients during the Tretment Period ( Figure 3 ). Sfety A totl of 228 of 406 linclotide-treted ptients (56.2 % ) reported t lest one tretment-emergent AE (TEAE) compred with 210 of 396 plcebo-treted ptients (53.0 % ) in the 12-week tretment period ( Tble 4 ). Most TEAEs were mild or moderte in severity (93.8 %, linclotide; 98.1 %, plcebo). The incidences of dirrhe ( P < ), fltulence ( P = ), nd bdominl pin ( P = ) TEAEs were significntly greter in the linclotide-treted ptients compred with plcebo-treted ptients. The most common TEAE in the 12-week tretment period ws dirrhe, experienced by 19.5 % of linclotide-treted ptients compred with 3.5 % of plcebo-treted ptients. The occurrences of dirrhe were reported to be mild or moderte in 71 of 79 linclotide-treted ptients (89.9 % ) nd 13 of 14 plcebotreted ptients (92.9 % ) who experienced dirrhe. There were no SAEs of dirrhe reported during the tril. None of the ptients who reported dirrhe experienced cliniclly significnt sequele (e.g., orthosttic hypotension or dehydrtion). More thn hlf of linclotide-treted ptients who experienced dirrhe hd onset within the first 2 weeks of tretment. Dirrhe ws the most common AE resulting in tretment discontinution in linclotidetreted ptients (5.7 vs. 0.3 % in plcebo-treted ptients); overll, AEs resulted in the premture discontinution of 32 ptients (7.9 % ) nd 11 ptients (2.8 % ) tking linclotide nd plcebo, respectively, in the tretment period. Rtes of serious AEs (SAEs) did not differ between linclotide nd plcebo groups (two ptients in ech group (0.5 % )). In the linclotide group, the SAEs consisted of one ptient who 2012 by the Americn College of Gstroenterology The Americn Journl of GASTROENTEROLOGY

10 1722 Ro et l. experienced sthm nd second ptient who experienced pericrdil effusion nd pericrditis leding to withdrwl from the tril. In the plcebo group, the SAEs consisted of one ptient who Chnge in CSBM Rte b Tretment Period* RW Period** 0 BL Tretment Period Plcebo Linclotide 290 μg 0 Weeks RW Tretment Sequence Tretment Period* Plcebo / Linclotide 290 μg Linclotide 290 μg / Linclotide 290 μg Linclotide 290 μg / Plcebo Lest-squres men chnge in CSBM rte ± stndrd error *P< for linclotide ptients compred to plcebo ptients for ech of the 12 Tretment Period weeks (ANCOVA) **P<0.001 for linclotide-linclotide ptients compred to linclotide-plcebo ptients for RW Period weeks (ANCOVA) RW Period** experienced chronic cholecystitis nd second ptient who experienced duodenitis, gstroenteritis, hitl herni, esophgitis, renl cyst, nd urinry trct infection. There were no deths during the tretment period; one screened ptient died s result of crdiorespirtory rrest nd ventriculr fibrilltion due to possible drug overdose, but this ptient died before rndomiztion nd did not receive tril mediction. There were no cliniclly significnt differences between the linclotide nd plcebo groups in the incidence of bnorml lbortory prmeters, vitl signs, or electrocrdiogrm prmeters. Serum bicrbonte levels were below the lower limit of norml t the end of tretment in seven ptients receiving linclotide compred with one ptient receiving plcebo. None of these ptients reported dirrhe s n AE or other AEs tht were considered to be relted to low bicrbonte levels. In the subset of ptients who were ssessed for linclotide exposure, no quntifible plsm levels of linclotide were detected following tril-mediction dosing t the rndomiztion nd week 4 tril visits. All ptients tested (72 plcebo nd 64 linclotide) hd levels lower thn the limit of quntifiction for linclotide ( < 0.2 ng /ml) nd its primry metbolite, MM ( < 2.0 ng /ml). Chnge in Worst Abdominl Pin c % Chnge in Worst Abdominl Pin BL Tretment Period Plcebo Linclotide 290 μg Weeks RW Tretment Sequence Plcebo / Linclotide 290 µg Linclotide 290 μg / Linclotide 290 μg Linclotide 290 μg / Plcebo Lest-squres men chnge in worst bdominl pin ± stndrd error *P<0.001 for linclotide ptients compred to plcebo ptients for ech of the 12 Tretment Period weeks (ANCOVA) **P<0.05 for linclotide-linclotide ptients compred to linclotide-plcebo ptients for RW Period weeks 14, 15, nd 16 (ANCOVA) Tretment Perioed* RW Period** 60 BL Weeks Tretment Period RW Tretment Sequence Plcebo Linclotide 290 μg Plcebo / Linclotide 290 μg Linclotide 290 μg / Linclotide 290 μg Linclotide 290 μg / Plcebo Lest-squres men percent chnge in worst bdominl pin ± stndrd error *P<0.001 for linclotide ptients compred to plcebo ptients for ech of the 12 Tretment Period weeks (ANCOVA) **P<0.05 for linclotide-linclotide ptients compred to linclotide-plcebo ptients for RW Period week 14 (ANCOVA) Tble 4. Tretment-emergent dverse events (sfety popultion) Adverse event (preferred term) Ptients with t lest 1 TEAE Plcebo ( N =396), n ( % ) Linclotide 290 µ g ( N =406), n ( % ) P vlue 210 ( 53.0) 228 ( 56.2) Dirrhe 14 (3.5) 79 (19.5) < Abdominl pin 10 (2.5) 22 (5.4) Fltulence 6 (1.5) 20 (4.9) Hedche 14 (3.5) 20 (4.9) Abdominl distension 3 (0.8) 9 (2.2) Tretment-emergent dverse events (TEAEs) reported in 2 % of linclotidetreted ptients nd t n incidence greter thn reported in plcebo-treted ptients during the tretment period. P vlue ws bsed on Fisher s exct test compring linclotide nd plcebo. Figure 3. Weekly results for complete spontneous bowel movement (CSBM) frequency (, * P < for linclotide ptients compred with plcebo ptients for ech of the 12 Tretment-Period weeks, * * P < for linclotide linclotide ptients compred with linclotide plcebo ptients for RW Period weeks 13 16); reduction in worst bdominl pin ( b, * P < for linclotide ptients compred with plcebo ptients for ech of the 12 Tretment Period weeks, * * P < 0.05 for linclotide linclotide ptients compred with linclotide plcebo ptients for RW Period weeks 14 16); nd percent reduction in worst bdominl pin ( c, * P < for linclotide ptients compred with plcebo ptients for ech of the 12 Tretment Period weeks, * * P < 0.05 for linclotide linclotide ptients compred with linclotide plcebo ptients for RW Period week 14). All P vlues were derived from n nlysis of covrince model. The Americn Journl of GASTROENTEROLOGY VOLUME 107 NOVEMBER

11 Linclotide in IBS-C 1723 During the RW period, TEAEs occurred in 22.2 % of linclotide linclotide ptients, 22.1 % of linclotide plcebo ptients, nd 30.6 % of plcebo linclotide ptients. With the exceptions of dirrhe nd bdominl pin, the incidence of TEAEs ws similr cross the three tretment sequences. The incidence of dirrhe ws 1.9, 0.6, nd 11.7 %, in linclotide linclotide, linclotide plcebo, nd plcebo linclotide ptients, respectively. The incidence of bdominl pin ws 1.3 % in the linclotide linclotide ptients nd 2.4 % in the plcebo linclotide ptients; there were no TEAEs of bdominl pin in the linclotide plcebo ptients. There ws no evidence of rebound (i.e., worsening in IBS-C symptoms compred with the bseline period in the linclotide plcebo ptients). No SAEs were reported during the RW period. DISCUSSION In this lrge phse 3 clinicl tril, greter percentge of IBS-C ptients who were treted with linclotide chieved sttisticlly significnt improvement in the key symptoms of IBS-C, including bdominl pin nd constiption, compred with plcebo. Four primry outcomes mesures were ssessed, including the FDA end point. This end point required tht ptients experience benefit of t lest 30 % when compred with bseline in bdominl pin nd n increse of 1 CSBM from bseline in the sme week for t lest 6 out of the 12 weeks of the tretment period. In spite of the rigor of this end point, 33.6 % of linclotide-treted ptients were responders compred with 21.0 % of plcebo-treted ptients ( P < ). Furthermore, sttisticlly significnt differences in responder rtes were lso demonstrted for the three other primry end points, which required (i) decrese in bdominl pin of 30 %, (ii) both n bsolute vlue of 3 CSBMs nd n increse of 1 CSBM from bseline, nd (iii) both bdominl pin nd CSBM criteri for t lest 9 of the 12 weeks of the tretment period. Although IBS is disorder with multiple symptoms, bdominl pin is one of the crdinl mnifesttions nd strongly correltes with IBS severity ( 22 ) nd utiliztion of helthcre resources ( 23 ). Also, n improvement in bdominl pin of 30 % hs been shown to be cliniclly importnt in IBS ptients ( 23 ), nd in ptients reporting pin relief in generl ( 24 ). In this tril, more thn hlf of linclotide-treted ptients reported n improvement in bdominl pin of 30 % for t lest 6 out of 12 weeks compred with 37.5 % of plcebo-treted ptients, for n NNT of 7.9. Improvement in bdominl pin begn within the first week of therpy, nd once reching mximum t 6 8 weeks, ws sustined throughout the reminder of the tretment period. By the lst week of the tretment period (week 12), linclotide-treted ptients reported men improvement of 43.2 % in bdominl pin compred with 27.5 % for plcebo-treted ptients. During the 4-week RW period, ptients re-rndomized to remin on linclotide hd continued relief of bdominl pin, showing durbility of response, while those re-rndomized from linclotide to plcebo showed grdul worsening of bdominl pin symptoms to the level experienced by ptients receiving plcebo during the tretment period, but without signs of rebound or worsening of symptoms reltive to bseline. In ddition to bdominl pin, linclotide improved severl other importnt bdominl symptoms tht re frequently reported by IBS-C ptients, including bdominl bloting nd bdominl discomfort, beginning during the first week of tretment nd continuing throughout the 12-week tretment period. Linclotide lso improved bowel function, including SBM nd CSBM frequency, strining, stool consistency, nd constiption severity. However, in contrst to the grdul improvement in bdominl symptoms, improvement in bowel function occurred more rpidly. Most linclotide-treted ptients experienced n SBM within 24 h of the first dose of linclotide (67.4 vs % for plcebo, P < ); mximl improvement in bowel function usully occurred within the first week. Thus, improvement with linclotide in bdominl (sensory) symptoms such s bdominl pin my be ttributble to more thn improvement in bowel function lone. Preclinicl dt suggest tht cgmp, which is relesed intr- nd extrcellulrly following GCC ctivtion by linclotide, cn reduce the firing of pin-sensing viscerl fferent fibers ( 13 ). Further studies re under wy tht my provide better understnding of the mechnisms by which linclotide exerts its beneficil effects directly on bdominl sensory symptoms. Dirrhe ws the most common TEAE in linclotide-treted ptients nd ppers to be n extension of linclotide s phrmcologicl effects. Although dirrhe ws reported in 19.5 % of linclotide-treted ptients, only 2 % reported tht they hd severe dirrhe nd only 5.7 % discontinued the drug due to dirrhe. The incidence of SAEs ws similr between linclotidend plcebo-treted ptients ( n = 2 ptients in ech group); dirrhe ws not reported s n SAE. In conclusion, linclotide significntly improved bdominl nd bowel symptoms in this phse 3 tril (12-week tretment period + 4-week RW period). ACKNOWLEDGMENTS Annie Neild, PhD, of Ironwood Phrmceuticls, provided editoril ssistnce. CONFLICT OF INTEREST Gurntor of the rticle : Jeffrey M. Johnston, MD. Specific uthor contributions: Wrote the initil drft of the mnuscript, ssisted in the interprettion of dt, nd provided criticl revision: Stish Ro nd Anthony J. Lembo; designed the tril: Jeffrey M. Johnston, Bernrd J. Lvins, Hrvey A. Schneier, nd Steven J. Shiff; ssisted in the interprettion of dt nd criticl revision of the mnuscript for importnt intellectul content: Jeffrey M. Johnston, Bernrd J. Lvins, Croline B. Kurtz, Mrk G. Currie, Hrvey A. Schneier, nd Steven J. Shiff; provided sttisticl design, nlyses, nd interprettion: Jmes E. McDougll, Xinwei D. Ji, Kelvin Shi, nd Jmes Z. Sho; coordinted cquisition of dt nd tril supervision: Pul Eng nd Susn M. Fox. Finncil support: This tril ws funded by Forest Reserch Institute nd Ironwood Phrmceuticls, Inc by the Americn College of Gstroenterology The Americn Journl of GASTROENTEROLOGY

12 1724 Ro et l. Potentil competing interests: Jeffrey M. Johnston, Croline B. Kurtz, Jmes E. McDougll, Jmes Z. Sho, Bernrd J. Lvins, nd Mrk G. Currie re employees of Ironwood Phrmceuticls nd own stock / stock options in Ironwood Phrmceuticls. Hrvey A. Schneier, Steven J. Shiff, Pul Eng, Susn M. Fox, Xinwei D. Ji, nd Kelvin Shi re employees of Forest Lbortories nd own stock / stock options in Forest Lbortories. Anthony J. Lembo nd Stish Ro re pid consultnts to Ironwood Phrmceuticls nd Forest Reserch Institute. Study Highlights WHAT IS CURRENT KNOWLEDGE 3 The hllmrk symptoms of irritble bowel syndrome with constiption (IBS-C) re bdominl pin nd constiptionrelted complints including hrd stools, strining, nd sense of incomplete evcution. 3 There re few effective tretments for IBS-C. 3 Linclotide is minimlly bsorbed, 14-mino-cid peptide gunylte cyclse-c gonist (GCCA). 3 In phse 2 clinicl studies, linclotide ccelerted colonic trnsit nd improved bdominl pin nd constiption ssocited with IBS-C. WHAT IS NEW HERE 3 In this phse 3 tril, ptients treted with linclotide experienced sttisticlly significnt improvements in bdominl symptoms (including bdominl pin) nd bowel function (including incresed frequency of bowel movements). 3 Linclotide improved other importnt irritble bowel syndrome with constiption (IBS-C) symptoms including bloting, stool consistency, nd strining. 3 Linclotide led to significntly greter proportion of ptients reporting dequte relief of their IBS-C symptoms thn plcebo. 3 Ptients who completed 12 weeks of linclotide tretment nd were then re-rndomized to plcebo experienced return of IBS-C symptoms, without experiencing rebound symptoms (worsening of symptoms beyond bseline levels). 3 The most common dverse event with linclotide tretment ws dirrhe. REFERENCES 1. L ong st ret h G F, Thomps on WG, C he y W D et l. Func t i on l b owel disorders. Gstroenterology 2006 ;130 : Hellstrom PM, Sito YA, Bytzer P et l. 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