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Clinical Gastroenterology and Hepatology 2014;-:-–-

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All studies published in Clinical Gastroenterology and Hepatology are embargoed until 3PM ET of the day they are published as correctedproofs on-line. Studies cannot be publicized as accepted manuscripts or uncorrected proofs.

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A Randomized Trial of 5-Hydroxytryptamine4–ReceptorAgonist, YKP10811, on Colonic Transit and Bowel Functionin Functional Constipation

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Andrea Shin,*,a Andres Acosta,*,a Michael Camilleri,* Amy Boldingh,* Duane Burton,*Michael Ryks,* Deborah Rhoten,* and Alan R. Zinsmeister‡

*Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Gastroenterology and Hepatology,Department of Medicine, ‡Division of Biomedical Statistics and Informatics, Department of Health Sciences Research,College of Medicine, Mayo Clinic, Rochester, Minnesota

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BACKGROUND & AIMS:

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YKP10811, a selective agonist of the serotonin receptor 5-hydroxytryptamine-4, increasesgastrointestinal (GI) motility. We investigated the safety and effects of YKP10811 on GI andcolonic transit and bowel movements (BMs) in patients with functional constipation in a ran-domized, double-blind, placebo-controlled study.

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METHODS:

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Patients with functional constipation, based on the Rome III criteria, were assigned randomly togroups given YKP10811 10 mg (n [ 15), 20 mg (n [ 16), 30 mg (n [ 15), or placebo (n [ 11)daily for 8 days. Transit of solids was measured by validated scintigraphy at baseline and ondays 7 to 9. Patients kept diaries on days 1 to 9, recording time to first BM, number of BMs/day,and stool consistency (based on the Bristol Stool Form Scale). To evaluate safety, we collecteddata on adverse events and clinical laboratory test and electrocardiograms results. The primaryefficacy end points were determined from an intent-to-treat analysis assessing colonic transit at24 hours and the half-time (t1/2) of gastric emptying, using analysis of covariance models.Secondary efficacy end points included measures of colonic transit (geometric center at 4 and24 hours), small-bowel transit (based on colon filling at 6 hours), t1/2 of ascending colonemptying, and bowel functions. We used the Dunnett test to compare the effects of each dosewith placebo. A per-protocol analysis (PPA) assessed the t1/2 of gastric emptying and time tofirst BM using proportional hazards models.

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RESULTS:

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Fifty-five participants completed the study. YKP10811 was associated with a significant accel-eration in colon filling at 6 hours (P < .05), t1/2 of ascending colon emptying, and colonic transitat 24 and 48 hours, as well as increased stool consistency over 8 days (based on intent-to-treatanalysis). In general, the 10-mg and 20-mg doses were the most effective in accelerating colonictransit. No serious adverse events were observed.

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CONCLUSIONS:

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YKP10811, a selective agonist of the serotonin receptor 5-hydroxytryptamine-4, accelerates GIand colonic transit and improves bowel functions in patients with functional constipation,compared with placebo. ClinicalTrial.Gov: NCT01523184.

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Keywords: Prokinetic; Clinical Trial; Drug; Benzamide.

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aAuthors share co-first authorship.

Abbreviations used in this paper: AC, ascending colon; ANCOVA, analysisof covariance; EC50, median effective concentration; FC, functional con-stipation; GC, geometric center; GE, gastric emptying; GI, gastrointestinal;5-HT, 5-hydroxytryptamine; IC50, median inhibitory concentration; ITT,intent-to-treat.

© 2014 by the AGA Institute1542-3565/$36.00

http://dx.doi.org/10.1016/j.cgh.2014.08.012

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The prevalence of functional constipation (FC) is16% in adults and almost double that number

(33.5%) in people older than age 60 years.1,2 Functionalconstipation can be subclassified as normal colonictransit, slow colonic transit, and/or defecatory disorder.1,3

Better understanding of the mechanisms of FC has ledto insights on receptors, neurotransmitters, fluid andelectrolyte secretion and reabsorption, and novel targets.Recently approved medications for the treatment ofFC include the secretagogues lubiprostone and linaclo-tide.4 These medications do not appear to activategastrointestinal muscle contraction directly.5,6 The

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5-hydroxytryptamine (5-HT)4 receptor is an establishedtarget for increasing smooth muscle contractility. Thus,when stimulated by 5-HT4–receptor ligands, there are

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increased levels of intracellular cyclic adenosine mono-phosphate facilitating cholinergic neurotransmission inthe myenteric plexus, thereby inducing contractions inthe gastrointestinal tract.7 There is a subgroup of pa-tients who do not achieve satisfactory relief of FC. Suchpatients appear to receive benefit from treatment with 5-HT4–receptor agonists such as prucalopride,8 which isapproved for prescription and marketing in severalcountries; however, it is not yet approved in the UnitedStates.

YKP10811 (C24H30ClFN4O4 HCl) is a novel benza-mide derivative with high binding affinity to the 5-HT4receptor. The aim of this phase II, single-center, ran-domized, parallel-group, multiple-dose, double-blind,placebo-controlled study was to evaluate the effects of8 days of treatment with 10, 20, and 30 mg YKP10811,once daily, on gastrointestinal and colonic transit, and onbowel functions in patients with FC. In addition, weaimed to assess the safety and tolerability of multipledoses of YKP10811.

Materials and Methods

Participants

Participants with functional constipation wererecruited by public advertisement. Eligible participantsprovided their written consent before initiation of thestudy. Each subject completed a validated bowel diseasequestionnaire9 and was evaluated for functional con-stipation by Rome III criteria10; in addition, there was noevidence of a rectal evacuation disorder as assessed byphysical examination11 conducted by the study in-vestigators. All participants met eligibility criteria,including the following: age 18 through 65 years, bodymass index of 18 through 40 kg/m2, reported fewer than3 bowel movements per week by daily bowel question-naire, baseline colonic transit by scintigraphy geometriccenter (GC) of 2.7 or less at 24 hours, failed availableconstipation medications including laxatives and fiber,and had a negative qualitative urine drug or alcohol testat screening. The study was approved by the Mayo ClinicInstitutional Review Board.

Study Design

We conducted a single-center, randomized, parallel-group, multiple-dose administration over 8 days,double-blind, placebo-controlled study. Allocation ofstudy drug was concealed from the clinical researchteam. We evaluated the effects of YKP10811 (10, 20, and30 mg once daily, approximately n ¼ 15 each) ongastrointestinal (GI) and colonic transit, and bowelfunction, safety, and tolerability in patients with FC. Thestudy was conducted in accordance with the Declarationof Helsinki and with Good Clinical Practice guidelines.Written informed consent was obtained from all patients

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before participation. The study was registered atClinicalTrial.Gov (NCT01523184). Treatment allocationand concealment were conducted by an independentMayo statistician who otherwise was not involved in thestudy. The randomization was communicated to andretained by the study research pharmacist, and wasconcealed from all study investigators until completionof the study and locking up of the data. Randomizationwas performed within blocks of consecutive patients.Only the independent Mayo statistician and pharmacistknew the block size being used. All randomized patientsand study center and contract research organizationpersonnel were blinded to study treatment allocationuntil data analyses.

In addition, participant eligibility was based on thebaseline measurement of colonic transit (GC measuredover 24 hours [GC24] � 2.7) using scintigraphy (whichalso assessed baseline gastric emptying [GE]). Thebaseline colonic transit at 24 hours of 2.7 or less (indi-cating that the average location of the isotope was in thelower part of the descending colon) was selected foreligibility to ensure that the patients had a similarspectrum of colonic transit, and it corresponded to theaverage colonic transit in healthy volunteers.12,13 Patientrandomization was stratified on sex and the baselineGC24 value (� 1.6 vs >1.6) to ensure that there wasbalance in the number of patients with slow colonictransit (GC24 < 1.6), which was the average colonictransit measurement in 61 patients with slow-transitconstipation in our laboratory.14

Patients underwent scintigraphic assessment ofgastric, small-bowel, and colonic transit of solids over the48-hour period from days 7 to 9. A bowel function diarywas kept from days 1 to 9; participants recorded thetime to first bowel movement after dosing, number ofstools per day, average stool consistency (Bristol StoolScale), ease of passage, and completeness of evacuation.

Study Medication

Pharmacology. YKP10811 (C24H30ClFN4O4 HCl) is anovel substituted benzamide derivative, small moleculewith high binding affinity to the 5-HT4 receptor (Ki¼ 4.96nmol/L). In cellular functional assays conducted with the5-HT4 receptor, YKP10811 showed weak agonist activitythat was dose dependent and reproducible (medianeffective concentration [EC50] ¼ 0.78 nmol/L). These re-sults indicated that YKP10811 acts as a partial agonist ofthe 5-HT4 receptor. YKP10811 did not show any signifi-cant off-target binding to any other receptors, enzymes, orserotonin-receptor subtypes at 1 mmol/L, except forbinding to the 5-HT2A receptor (Ki¼ 600 nmol/L) and the5-HT2B receptor (Ki ¼ 31 nmol/L). Thus, YKP10811 has120-fold and 6-fold lower affinity, respectively, for 5-HT2Aand 5-HT2B receptors than for 5-HT4. In cellular functionalassays, YKP10811 showed antagonist activity at the5-HT2B receptor with a median inhibitory concentration

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(IC50) of 2.1 mmol/L and no significant activity at the5-HT2A receptor up to 10 mmol/L. YKP10811 showed noactivity against serotonin-receptor subtypes 5-HT1B,5-HT1D, or 5-HT2A at 1 nmol/L to 10 mmol/L, or forserotonin-receptor subtype 5-HT7 at 10 nmol/L to30 mmol/L (data on file; SK Life Sciences, Inc). Thus, re-sults from binding assays and functional assays fullysupport the conclusion that YKP10811 is a specific andselective 5-HT4–receptor agonist.

Preclinical studies. In rats, YKP10811 acceleratedcolonic transit by 37% at a dose as low as 1 mg/kg. Indogs, 0.3 mg/kg YKP10811 accelerated colonic transit by45.5% at 2 hours after dosing. The accelerated colonictransit in dogs was associated with significantly increasedcolon contractions and defecation. YKP10811 signifi-cantly reduced visceral hypersensitivity in multiple painmodels in rats.

Safety. The study of the specificity and selectivity ofYKP10811 for the 5-HT4 receptor would predict a safepharmacologic profile with potential for pharmacody-namic and clinical efficacy.15 In a phase I, double-blind,randomized, 9-day, placebo-controlled, multiple-ascending dose study in healthy volunteers at doses of 5,15, 30, and 45 mg once daily, YKP10811 was welltolerated with minimal side effects (data on file; SK LifeSciences, Inc).

Pharmacokinetics. After oral administration of either10, 20, or 30 mg YKP10811 daily for 7 days, the vari-ability for Cmax was 42.9% to 78.5% and for the areaunder the concentration-time curve (0-tau) was 29.7% to58.8%. The geometric mean values of both Cmax and thearea under the concentration-time curve (0-tau)increased with increasing dose of YKP10811. The medianTmax of YKP10811 ranged from 1.00 to 2.00 hours, withindividual values ranging from 0.47 to 2.17 hours afterdosing across the 3 YKP10811 dose levels.

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Administration of Study Medication

Patients received multiple oral doses of YKP10811 orplacebo once daily for 8 days. The doses given were 10,20, and 30 mg, or matching placebo. Drugs wereadministered with a total of 240 mL water. No food wasallowed for at least 1.5 hours after dosing. The selecteddoses were based on phase I and preclinical studies (dataon file; SK Life Science, Inc).

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Gastrointestinal and Colonic Transit

A validated scintigraphic method with known perfor-mance characteristics was used to measure gastricemptying, small-bowel transit, and colonic transit over 48hours, using dual-isotope gamma camera scanning ofabdominal images. This scintigraphic method is wellvalidated and established,12,16 with published COVinter

and COVintra to plan phase IIA studies according to effectsizes desirable for pharmacodynamics and bowel function

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end points in patients with lower functional gastrointes-tinal disorders associated with constipation such as FC.17

Briefly, participants reported to the Clinical ResearchUnit, fasted, on themorning of testing as directed by studypersonnel. A urine pregnancy test was performed, whenapplicable, within 48 hours of the start of the test. 111Inabsorbed on activated charcoal particles was delivered tothe colon by means of a methacrylate-coated, delayed-release capsule. The capsule was ingested after an over-night fast, 1.5 hours before a breakfast test meal duringbaseline transit assessments. Then, 99mTc-sulfur colloidwas used to label 2 scrambled eggs that were eaten with 1slice of whole wheat bread and 1 glass of whole milk (296kcal, 30% fat). This meal facilitated measurement ofgastric and small-bowel transit. Patients ingested stan-dardized meals for lunch and dinner immediately beforethe 4- and 8-hour scans. For measurement of gastricemptying, small-bowel, and colonic transit, scans wereacquired before ingestion of the radiolabeled test meal,followed by scans taken immediately after (time 0) and at30 minutes, and at 1, 1.5, 2, 4, 6, 8, 24, and 48 hours afterthe radiolabeled breakfast (egg meal).

Daily Symptom Assessments

During the study, participants completed a daily diaryto record their bowel functions for each bowel movementincludingconsistency (Bristol Stool FormScale scoreswereas follows: 1, hard lumps; 2, lumpy sausage; 3, crackedsausage; 4, smooth sausage; 5, soft lumps; 6, mushy; and 7,watery), ease of passage (1,manual disimpaction; 2, enemaneeded; 3, straining needed; 4, normal; 5, urgent withoutpain; 6, urgent with pain; 7, incontinent), and sense ofcompleteness of evacuation (yes/no).18–20

The on-study bowel habit diary cards were dispensedat day 1 and the completed cards were collected at theend of the study visit on day 9. Stool consistency wasappraised using the validated Bristol Stool Form Scale.18

For each of these symptom end points, the averagenumber or score for the treatment period was calculatedfor each individual participant, as in prior studies.19,20

Safety Assessments

Safety was determined by evaluating adverse events,vital signs (pulse rate, supine blood pressure, orthostaticblood pressure, oral temperature, and respiration rate),physical examinations, multiple 12-lead electrocardio-grams at baseline and standard times after dosing, andclinical laboratory assessments (chemistry, hematology,coagulation, and urinalysis).

Study End Points, Statistical Methods,and Data Analysis

Data in this article show median and interquartileranges, unless otherwise stated. The primary efficacy

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analysis was based on an intent-to-treat (ITT) analysis ofcolonic GC at 24 hours and the t1/2 of gastric emptyingfor solids using analysis of covariance (ANCOVA) modelswith baseline GC24 and baseline GE t1/2, respectively,and treatment group in the statistical models. The Dun-nett test was used for multiple comparisons of activedrug with placebo. The secondary efficacy variables werecolonic GC at 4 and 48 hours, colonic filling at 6 hours(CF6), and the t1/2 for ascending colon (AC) emptying.The ITT analyses imputed the missing values in 2 sub-jects using the overall mean (CT, CF6, AC t1/2, and boweldiary scores) and the overall median (GE t1/2 and time tofirst bowel movement after the initial dose). The degreesof freedom for error in the ANCOVA models wereadjusted (subtracting one for each missing valueimputed) to compensate for the imputations. In someinstances, response end points first were transformed torank scale to accommodate nongaussian distributions ofthe ANCOVA model residuals.

In addition, a per-protocol analysis using propor-tional hazards models examined treatment effects on theGE t1/2 and time to first bowel movement in 55 of the 57participants who completed all studies. The study (withat least 12 patients per treatment arm) was powered todetect an effect size of 43% in colonic transit GC24 and26% in gastric emptying t1/2 (Table 1).

All authors had access to the study data and reviewedand approved the final manuscript.

Results

Participants, Demographics, andBaseline Parameters

Supplementary Figure 1 shows the CONSORT flowchart of participants in the study. Fifty-seven participantswere randomized to the study, with 11, 15, 16, and 15participants, respectively, randomized to placebo, 10 mg,

Table 1. Effect Size Shown Based on PerformanceCharacteristics and Variance in Main End Points inthe Proposed Study

Assumingn¼12/ group

Response type Mean SD CV%

Effect size,a %detectablewith 80%

power (a ¼ .05)

GE solids t1/2 min(N ¼ 63)

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Colonic filling at 6 h, %(N ¼ 63)

44 29 66 79

GC at 24 h (N ¼ 62) 2.36 0.85 36 43Ascending colon t1/2 h

(N ¼ 50)15.0 8.0 53 63

NOTE. Table data are based on data from previous studies using similarmethods. Note that the effect size shown may be smaller for each dosecontrast (n ¼ 18) vs placebo (n ¼ 12).aEffect size is the difference between means as a percentage of the listedmean.

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20 mg, and 30 mg YKP10811. The demographic charac-teristics of the participants were as follows: 56 womenand 1 man, mean age of 42.8 � 1.3 years, mean bodymass index of 25.3 � 0.5 kg/m2, and a baseline GE t1/2 of125.0 � 4.3 minutes and a GC24 of 1.83 � 0.05 (Table 2).A total of 55 patients completed the study, with earlydiscontinuation in 2 participants (1 participant receivingplacebo and 1 participant receiving 20 mg YKP10811).

Gastrointestinal and Colonic Transit

Overall, the YKP10811 treatment effect on functionalconstipation was associated with accelerated small-boweland colonic transit (Table 3). When assessing the overalleffect of YKP10811, there was accelerated gastricemptying (t1/2) on per-protocol analysis (P ¼ .031; ITTanalysis on ranks, P ¼ .16). Overall treatment effects alsowere observed for CF6h (P < .001). The Dunnett testbased on ranks for CF6h was significant for YKP10811 at20 mg and 30 mg (P < .001).

The overall assessment of treatment effects ofYKP10811 showed significant acceleration of ACemptying (t1/2) and colonic transit at 24 and 48 hours.Specifically, the ANCOVA models based on ranks indi-cated an accelerated AC emptying (t1/2, P ¼ .016) andcolonic transit at GC 4, 24, and 48 hours (P ¼ .062,P < .01, and P ¼ .019, respectively). The Dunnett testbased on ranks indicated AC t1/2 was associated signifi-cantly with accelerated transit for all 3 doses individuallywhen compared with placebo (Dunnett test, P < .05 forall). In addition, 10 mg YKP10811 was associated withaccelerated transit at all GC time points (eg, at 24 hours)(Figure 1) when compared with placebo (Dunnett test,P < .05), and with borderline accelerated colonic transitat 48 hours (Dunnett test, P ¼ .08) in the 30 mg groupwhen compared with placebo (Table 3).

Daily Stool and Abdominal Symptoms

Overall, YKP10811 treatment effect on functionalconstipation (relative to placebo) was associated withsignificantly accelerated time to pass a BM after firstdosing (P < .01) and with borderline increased differ-ences in stool consistency over the 8-day treatment period(P¼ .064) (Table 4). The Dunnett test on ranks for time topass BM after first dosing was associated significantlywith all 3 doses of YKP10811 when compared with pla-cebo (Dunnett test P < .05). Stool consistency (form)(Table 4) significantly improved (softer) with 20 and30 mg doses of YKP10811 when compared with placebo(Dunnett test, P< .05). Therewas no significant differencein the number of BMs per day (Table 4).

Adverse Events

There were no deaths and no serious adverse events.Two subjects discontinued prematurely (1 on placebo, 1

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Table 2. Patient Demographics and Baseline Values

Placebo 10 mg YKP10811 20 mg YKP10811 30 mg YKP10811

N 11 15 16 15Age, y 39.1 � 2.0 44.0 � 3.2 47.0 � 2.2 41.0 � 2.6Females 100% 100% 94% 100%BMI, kg/m2 24.0 � 1.3 26.0 � 0.8 26.4 � 0.9 24.9 � 0.9Baseline GE t1/2 min 136.7 (117.7–149) 113.2 (105–152.9) 115.3 (89.6–127.5) 118 (109–136.5)Baseline colonic transit GC24 1.79 (1.46–1.99) 2.16 (1.57–2.31) 1.84 (1.57–2.1) 1.73 (1.49–1.97)

NOTE. Means � SEM are shown except baseline GE and GC24: median (interquartile range).BMI, body mass index.

- 2014 YKP10811 in Functional Constipation 5

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on 20mg YKP10811) secondary to prolongation of QTc onone electrocardiography each; the prolongation was lessthan 5 ms greater than the prespecified limit of 470 ms.Table 5 shows the adverse events associated withYKP10811. There were no significant differences betweenthe treatment groups. There was an overall borderlinetreatment effect on diarrhea (Cochran–Armitage test fortrend [dose effect] was P ¼ .15). One subject on 10 mgYKP10811 had “watery stools,” 1 subject on 20 mg had“explosive watery stools,” and 4 subjects on 30 mg had“diarrhea.” One subject on placebo had “diarrhea.”

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Discussion

In this single-center, randomized, parallel-group,double-blinded, placebo-controlled study in patientswith functional constipation, YKP10811, a selective 5-HT4–receptor agonist, enhanced gastrointestinal andcolonic transit and improved bowel function during an 8-day treatment trial. The effect of YKP10811 on colonictransit was mirrored by improvements in softer stoolconsistency and faster time to first bowel movement,suggesting that YKP10811 has encouraging effects onthese clinical end points. In addition to pharmacodynamic

Table 3.Gastrointestinal and Colonic Transit

Placebo10

YKP1

N 11 1GE T1/2 mina 123.4 (104–172) 112 (10GE 4 h 0.97 (0.81–1) 1 (0.9CF6, %b 28.5 (19–47) 58 (20AC T1/2, h

d 20.5 (19.59–20.9) 15.17 (3.5Colonic transit GC4e 0 (0–0.94) 1 (0–1Colonic transit GC24b 1.67 (1.62–1.81) 3.18 (2.2Colonic transit GC48f 2.70 (2.25–2.99) 4.1 (3.4

NOTE. Data are presented as medians and interquartile ranges.aP ¼ .031 by per-protocol analysis (ITT, P ¼ .16 on rank scale).bAnalysis of variance on rank P < .01.cP < .05 by the Dunnett test (corrected for multiple comparisons).dAnalysis of variance on rank P ¼ .016.eAnalysis of variance on rank P ¼ .062.fAnalysis of variance on rank P¼ .019.gAnalysis of variance on rank P ¼ .08.

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effects in patients with functional constipation, the im-provements in bowel functions are validated andmeasurable end points recommended for treatment offunctional constipation.20 These findings suggest thatYKP10811 may be a potential new medication for thetreatment of functional constipation.

YKP10811 had a robust effect on accelerating, by30% to 40%, the AC emptying when compared withplacebo. Ascending colon emptying has been reported tohave the greatest contribution to overall colonic transit21

because the ascending and transverse colon constitutethe “reservoir” or storage regions of the human colon.22

In addition, YKP10811 accelerated colonic transit at24 and 48 hours, and this was associated with faster timeto first bowel movement after the first dose and looserstool consistency during 8 days of treatment. Among theother 5-HT4–receptor agonists previously studied withthe same method, 4 mg prucalopride23 and 30 and 50 mgvelusetrag24 also accelerated AC emptying. The overalleffect of naronapride (ATI-7505) on AC t1/2 suggestedborderline treatment differences (P ¼ .075), with onlyone pairwise comparison between 10 mg and placebo 3times daily being borderline significant (unadjustedP ¼ .042), whereas 3 mg and 20 mg doses 3 times dailydid not accelerate AC t1/2.

25

mg0811

20 mgYKP10811 30 mg YKP10811

5 16 150–136.6) 98 (85.38–117) 106 (91.6–122.4)6–1.0) 1 (1.0–1.0) 1 (1.0–1.0)–78) 82 (62–95)c 80 (55–89)c

0–16.99)c 14.72 (7.19–17.2)c 14.86 (9.78–17.88)c

.57)c 1 (0–1.0) 1 (0.85–1.0)c

6–3.52)c 2.60 (1.79–3.74)c 2.06 (1.81–2.91)7–4.96)c 4.15 (3.64–5)c 3.28 (2.85–4.88)g

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Figure 1. Colonic transit GC24h, presented as medians(interquartile range).

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YKP10811 had no significant effect on the number ofspontaneous bowel movements or bowel movements perweek. However, the short duration of the study and thesample size of the study were based on the plan to showan effect size of 43% in the primary end point, colonic GCat 24 hours. The study showed the effect of YKP10811 oncolonic transit and gastric emptying. Emptying of theproximal colon correlates linearly with fecal weight,26

which reflects largely stool water content, and, as ex-pected based on prior studies,16 the overall colonictransit was correlated linearly with stool consistency,with less significant association with the number ofbowel movements per day. Our prior studies also esti-mated that the sample size required in a phase IIA studyto show a 30% effect on stool consistency would be 24patients per treatment arm, and similar effects on stoolnumber would require 34 patients per treatment arm.17

In fact, the effect size of YKP10811 on stool consistencywas approximately 50% and, hence, showed a statisti-cally significant effect with approximately 15 patientsper treatment arm.

The findings of shorter gastric emptying t1/2 andincreased CF6 (small-bowel transit) suggest prokineticeffects in the stomach, even in patients with functionalconstipation whose baseline gastric emptying was 125.0� 4.3 minutes (SEM), which is comparable with the data

Table 4. Daily Stool and Abdominal Symptoms

Placebo 10 mg YKP1

N 11 15Time to first BM, ha 25.5 (24.4–28.4) 2.8 (1.95–BMs/day, n 0.8 (0.64–1.5) 1.46 (1.3–2BM formc 2.6 (1.75–3.43) 4 (3.2–4

NOTE. Data are presented as medians and interquartile ranges.aAnalysis of variance on rank P < .01.bP < .05 by the Dunnett test (corrected for multiple groups).cAnalysis of variance on rank P ¼ .064.

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from 319 healthy participants studied in the same lab-oratory with the same meal (121.7 � 1.7 min).27 Theacceleration of stomach and small-bowel transit isconsistent with preclinical studies that showed that 1hour after dosing, YKP10811 radiolabeled with 14C wasfound mainly in the small intestine (55%) and cecum(38%) (unpublished data; SK Life Science, Inc). Thissignificant effect (approximately 20% acceleration ofgastric emptying t1/2 with the 20 and 30 mg doses ofYKP10811) suggests that there is a prokinetic effect ofpotential relevance on gastric motility disorders, such asgastroparesis and functional dyspepsia.28,29

Interestingly, the results showed a lack of doseresponse in the treatment groups receiving YKP10811.Furthermore, YKP10811, 30 mg, had no significant effecton colonic transit GC24h and GC48h. These results maybe the result of the dual action (agonist/antagonist) ofYKP10811 seen in in vitro studies. YKP10811 facilitatedthe electrical field stimulation–induced neurogenictwitch of guinea pig ileum at lower concentrations(<1 mmol/L: EC50, 1.97 nmol/L) but inhibited electricalfield stimulation–induced contractions at higher con-centrations (>10 mmol/L: IC50, 30.42 mmol/L). This typeof dual action (agonist/antagonist) of YKP10811 underthe same assay conditions also was shown in the peri-staltic reflex test with an EC50 of 0.5 mmol/L and an IC50of 21 mmol/L. There is a significant gap in concentrationranges (>40-fold difference) for stimulatory vs inhibi-tory effects of YKP10811 in vitro (unpublished data; SKLife Science, Inc).

Overall, YKP10811 was well tolerated and withoutany major side effects in our study. Two participants, 1receiving placebo and 1 receiving 20 mg YKP10811 hadprolonged QTc (>470 ms). Both participants dis-continued the study on the advice of the investigators,even though the QTc prolongation was minimal (<475ms). The effect of YKP10811 on QTc F intervals attherapeutic doses should be evaluated and monitoredcarefully in subsequent studies. In addition, the commonside effect of YKP10811, diarrhea, is essentially a desiredpharmacologic effect in most patients, although a coupleof patients reported short-lived, watery or explosivediarrhea.

In conclusion, YKP10811 accelerated transit at alllevels in the gastrointestinal tract and improved bowel

0811 20 mg YKP10811 30 mg YKP10811

16 153.3)b 1.8 (1.3–3.5)b 2.4 (1.2–5.7)b

) 1.6 (1.2–2.4) 1.46 (0.7–2.4).7) 4.3 (3.3–4.9)b 3.8 (3.3–5.1)b

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Table 5. Detailed Adverse Events and Treatment Discontinuation

Placebo 10 mg YKP10811 20 mg YKP10811 30 mg YKP10811

N 11 15 16 15Discontinuation 1 0 1 0QTc prolongation 1 0 1 0Headache 8 6 11 10Nausea 2 4 0 3Flatulence/gassy (intermittent) 1 4 2 2Diarrhea (intermittent) 1 0 1 4Abdominal cramping/pain 1 4 3 3Stomach gurgling 0 4 2 5Loose stools 0 2 1 1Sinus congestion/stuffy nose/nasal congestion 0 2 0 1Bloating (stomach) 0 2 2 1Fatigue 0 2 1 0Felt flushed/hot flashes 0 2 0 0Gas pain (intermittent) 0 0 2 0Light headed 0 1 1 2Belching (intermittent) 0 1 0 2Dizziness 0 0 1 3Heartburn 0 1 0 3None 1 2 2 0

- 2014 YKP10811 in Functional Constipation 7

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functions in patients with functional constipation. Thus,YKP10811 is likely to be of benefit to patients with func-tional constipation without rectal evacuation disorders.The safety and efficacy of this novel agent should bestudied in larger multicenter clinical trials. With furtherstudies, the current data suggest that YKP10811 wouldexpand the therapeutic options beyond the recentlyapproved secretagogue medications for treatment offunctional constipation, lubiprostone4 and linaclotide.30,31

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Supplementary Material

Note: To access the supplementary material accom-panying this article, visit the online version of ClinicalGastroenterology and Hepatology at www.cghjournal.org,and at http://dx.doi.org/10.1016/j.cgh.2014.08.012.

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3. Camilleri M. Peripheral mechanisms in irritable bowel syndrome.N Engl J Med 2012;367:1626–1635.

4. Camilleri M. Pharmacological agents currently in clinical trials fordisorders in neurogastroenterology. J Clin Invest 2013;123:4111–4120.

5. Sweetser S, Busciglio IA, Camilleri M, et al. Effect of a chloridechannel activator, lubiprostone, on colonic sensory and motorfunctions in healthy subjects. Am J Physiol 2009;296:G295–G301.

6. Whitehead WE, Palsson OS, Gangarosa L, et al. Lubiprostonedoes not influence visceral pain thresholds in patients with

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irritable bowel syndrome. Neurogastroenterol Motil 2011;23:944–e400.

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8. Camilleri M, Kerstens R, Rykx A, et al. A placebo-controlled trialof prucalopride for severe chronic constipation. N Engl J Med2008;358:2344–2354.

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18. Heaton KW, Radvan J, Cripps H, et al. Defecation frequency andtiming, and stool form in the general population: a prospectivestudy. Gut 1992;33:818–824.

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19. Andresen V, Camilleri M, Busciglio I, et al. Effect of 5 dayslinaclotide on transit and bowel function in females withconstipation-predominant irritable bowel syndrome. Gastroen-terology 2007;133:761–768.

20. Manini ML, Camilleri M, Goldberg M, et al. Effects of velusetrag(TD-5108) on gastrointestinal transit and bowel function inhealth and pharmacokinetics in health and constipation. Neu-rogastroenterol Motil 2010;22:42–49, e47–e48.

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26. Vassallo M, Camilleri M, Phillips SF, et al. Transit through theproximal colon influences stool weight in the irritable bowelsyndrome. Gastroenterology 1992;102:102–108.

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27. Camilleri M, Iturrino J, Bharucha AE, et al. Performance char-acteristics of scintigraphic measurement of gastric emptying ofsolids in healthy participants. Neurogastroenterol Motil 2012;24:1076–e1562.

28. Zeng J, Zuo XL, Li YQ, et al. Tegaserod for dyspepsia and refluxsymptoms in patients with chronic constipation: an exploratoryopen-label study. Eur J Clin Pharmacol 2007;63:529–536.

29. Portincasa P, Mearin F, Robert M, et al. Efficacy and tolerability ofcinitapride in the treatment of functional dyspepsia and delayedgastric emptying. Gastroenterol Hepatol 2009;32:669–676.

30. Videlock EJ, Cheng V, Cremonini F. Effects of linaclotide inpatients with irritable bowel syndrome with constipation orchronic constipation: a meta-analysis. Clin Gastroenterol Hep-atol 2013;11:1084–1092.

31. Rao SS, Quigley EM, Shiff SJ, et al. Effect of linaclotide on se-vere abdominal symptoms in patients with irritable bowel syn-drome with constipation. Clin Gastroenterol Hepatol 2014;12:616–623.

Reprint requestsAddress requests for reprints to: Michael Camilleri, MD, Clinical EntericNeuroscience Translational and Epidemiological Research, Division ofGastroenterology and Hepatology, Department of Medicine, Mayo Clinic,Charlton 8-110, 200 First Street SW, Rochester, Minnesota 55905. e-mail:camilleri.michael@mayo.edu; fax: (xxx) xxx-xxxx.

Conflicts of interestThe authors disclose no conflicts.

FundingThis research was supported by SK Life Science, Inc, and the Korea DrugDevelopment Fund was funded by MSIP, MOTIE, and MOHW (KDDF-201210-13, Republic of Korea).

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Supplementary Figure 1. CONSORT flow diagram.

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