Efficacy of Linaclotide for Patients With Chronic Constipation

Transcription

1 GASTROENTEROLOGY 2010;138: Efficacy of Linaclotide for Patients With Chronic Constipation ANTHONY J. LEMBO,* CAROLINE B. KURTZ, JAMES E. MACDOUGALL, B. J. LAVINS, MARK G. CURRIE, DONALD A. FITCH, BRENDA I. JEGLINSKI, and JEFFREY M. JOHNSTON *Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (BIDMC); Ironwood Pharmaceuticals Inc., Cambridge, Massachusetts See editorial on page 813. BACKGROUND & AIMS: Linaclotide is a minimally absorbed peptide agonist of the guanylate cyclase-c receptor that stimulates intestinal fluid secretion and transit and reduces pain in animal models. We assessed the safety and efficacy of a range of linaclotide doses in patients with chronic constipation. METHODS: We performed a multicenter, double-blind, placebo-controlled, parallel-group study of 310 patients with chronic constipation. Patients were randomly assigned to groups given 75, 150, 300, or 600 g oral linaclotide or placebo once daily for 4 weeks. Symptom assessments included spontaneous bowel movements (SBMs), complete SBMs, stool consistency, straining, abdominal discomfort, and bloating. Severity of constipation, adequate relief of constipation, global relief of constipation, treatment satisfaction, quality of life, adverse events, clinical laboratory data, and electrocardiogram results were assessed. RESULTS: All doses of linaclotide improved the weekly rate of SBM (primary end point) compared with placebo; the increases in overall weekly number of SBMs from baseline were 2.6, 3.3, 3.6, and 4.3 for linaclotide doses of 75, 150, 300, and 600 g, respectively, compared with 1.5 for placebo (P.05 for each pair-wise comparison of a linaclotide dose to placebo). Likewise, linaclotide significantly improved the weekly rate of complete SBM, stool consistency, straining, abdominal discomfort, bloating, global assessments, and quality of life. The most common and only dose-related adverse event was diarrhea (only 6 patients discontinued treatment because of diarrhea). CONCLUSIONS: Linaclotide therapy was associated with few adverse events and produced rapid and sustained improvement of bowel habits, abdominal symptoms, global relief, and quality of life in patients with chronic constipation. Keywords: MD-1100; Guanylin; Uroguanylin; Secretion. fort, and a sense of incomplete evacuation. 4 CC not only adversely affects a person s quality of life, 5,6 but is associated with multiple potential comorbidities, 7 as well as significant direct and indirect costs Traditional treatments, such as lifestyle modifications, fiber supplements, and laxatives, have been aimed at increasing gastrointestinal (GI) motility and stool frequency rather than addressing the multiple symptoms associated with CC. 11 The need for more effective and well-tolerated therapies for CC is underscored by the finding that approximately 50% of individuals with CC were not completely satisfied with available treatments. 6 Two medications have been approved by the US Food and Drug Administration for the treatment of CC. Tegaserod, a 5-HT 4 partial agonist, was removed from the market in 2007 because of concerns of increased cardiovascular adverse events (AEs). 12 Lubiprostone, a chloride channel activator, has been shown to be effective in the treatment of CC when administered twice a day 13,14 ; however, a high incidence of nausea has been reported (29%), limiting its use by some patients with CC. Linaclotide (MD-1100) is a novel, minimally absorbed, 14 amino acid peptide that has been shown to increase fluid secretion and transit, as well as reduce abdominal pain in animal models. The actions of linaclotide are mediated through its binding to the guanylate cyclase-c (GC-C) receptor on the luminal surface of intestinal enterocytes. Activating GC-C receptors increases cyclic guanosine monophosphate, which triggers a signal transduction cascade that results in the activation of the cystic fibrosis transmembrane conductance regulator. 15 This activation causes a release of chloride and bicarbonate into the intestinal lumen, resulting in an increase in fluid secretion and acceleration of intestinal transit. 16,17 In addition, linaclotide has been shown to ame- The symptoms of chronic constipation (CC) are reported in approximately 15% of the general population. 1 The condition is particularly common in women and the elderly population. 2,3 The symptoms of CC include infrequent bowel movements (BMs), hard stools, straining during defecation, bloating, abdominal discom- Abbreviations used in this paper: AE, adverse event; BM, bowel movement; BSFS, Bristol Stool Form Scale; CC, chronic constipation; CSBM, complete spontaneous bowel movement; GC-C, guanylate cyclase-c; GI, gastrointestinal; PAC-QOL, Patient Assessment of Constipation Quality of Life; SBM, spontaneous bowel movement by the AGA Institute /10/$36.00 doi: /j.gastro

2 March 2010 LINACLOTIDE IN CC 887 liorate visceral hypersensitivity 18 ; this effect is also mediated by cyclic guanosine monophosphate through direct inhibition of afferent nerve firing. 19 In healthy human volunteers, linaclotide was well-tolerated at single oral doses of up to 3000 g and multiple oral doses (7 days of once daily treatment) of up to 1000 g, with no detectable serum levels. 20 In a Phase 2a study of 42 patients with CC, linaclotide administered for 2 weeks dose-dependently increased the change from pretreatment baseline in the number of spontaneous BMs (SBMs) and complete SBMs (CSBMs) per week, improved stool consistency, reduced straining, relieved abdominal discomfort, decreased constipation severity, and provided global relief, compared to placebo. 21 The objective of the current study was to assess the safety and efficacy of linaclotide administered at 75, 150, 300, and 600 g doses, compared to placebo, once daily for 4 weeks in a large number of patients with CC. Materials and Methods Study Design A randomized, double-blind, parallel-group, placebo-controlled, dose-range finding study was conducted at 57 clinical centers in the United States between November 2006 (first signed informed consent) and December 2007 (last patient visit). The study was performed in accordance with the Declaration of Helsinki and US21 Code of Federal Regulations. Written informed consent was obtained from all patients prior to their participating in the study. Each participating center s Institutional Review Board approved the study protocol and informed consent form. After informed consent was obtained, patients entered an initial screening period of up to 28 days for routine blood tests, urinalysis, and pregnancy testing, if appropriate, and washout of laxatives and other prohibited medications. Patients meeting the inclusion and exclusion criteria then entered a 14-day pretreatment baseline period. Patients eligible to continue on to the 4-week treatment period of the study were randomized using a validated computer system to receive a 75, 150, 300, or 600 g gelatin capsule of linaclotide or placebo orally once daily before the first meal of the day. After the treatment period, patients were followed for an additional 14 days off the study drug. Patients reported daily bowel and abdominal symptoms and weekly global assessments using an interactive voice response system. All personnel involved in the design and implementation of the study remained blinded. Study visits occurred during the screening period, pretreatment period (day 14), treatment period (days 0, 14, and 28), and posttreatment period (14 days after completion of treatment on day 42). Study Participants Patients were men and women at least 18 years of age who met modified Rome II criteria for CC, including having 3 SBMs per week and having one or more of the following symptoms for at least 12 weeks during the 12 months preceding the study: (1) straining during 25% of BMs; (2) lumpy or hard stools during 25% of BMs; or (3) sensation of incomplete evacuation during 25% of BMs. 22 Patients were asked to refrain from making any major lifestyle changes (eg, starting a new diet or changing their exercise pattern) during the study. Patients were excluded from the study if they met the Rome II criteria for irritable bowel syndrome, 23 had a history of pelvic floor dysfunction, needed to use manual maneuvers in order to achieve a BM, had a history of surgery of the colon at any time or other abdominal operations within 60 days prior to entry into the study, had a history of laxative abuse, or had other medical conditions (eg, neurological disorders, metabolic disorders, or other significant disease) that would impair their ability to participate in the study. Patients were excluded if they used prohibited medications, were pregnant or breastfeeding. Use of an investigational drug and any surgery within 30 days prior to the start of the study were also exclusionary. Patients were required to meet the colonoscopy requirements of the American Gastroenterological Association guidelines, which include patients successfully completing a colonoscopy within 10 years of the screening visit. 24 Likewise, patients of any age with clinically significant alarm symptoms (eg, lower GI bleeding, iron-deficiency anemia, unexplained weight loss, systemic signs of infection, or colitis) were required to complete a colonoscopy with nonsignificant findings after the onset of the alarm symptoms and within 5 years of entering into the study. Women of child-bearing age were required to have a negative serum pregnancy test; those sexually active were required to use oral or implanted contraceptives or double-barrier birth control. To confirm the presence of constipation during the 14-day pretreatment baseline period, patients were required to report an average of 3 CSBMs and 6 SBMs per week via the interactive voice response system. Patients reporting laxative, enema, and/or suppository usage for 2 days or any usage of a prohibited medication during the pretreatment period were disqualified from entering the study. Additionally, patients reporting watery stools (Type 7 on the Bristol Stool Form Scale [BSFS]), 25 for any SBM, or loose (mushy) stools (Type 6 on the BSFS) for 1 SBM were excluded. Rescue and Concomitant Medications Rescue medications were allowed for severe constipation (ie, at least 72 hours after the patient s previous BM), including oral Ducolax (bisacodyl; Boehringer Ingelheim GmbH, Ingelheim Rhein, Germany) up to 15 mg

3 888 LEMBO ET AL GASTROENTEROLOGY Vol. 138, No. 3 daily, Fleet enema (C. B. Fleet Company, Lynchburg, VA), or Ducolax suppository. No more than 2 uses of rescue medication were allowed during the baseline pretreatment period, provided also that there was no use within 3 days prior to the first dose of study medication. Patients were instructed to contact the investigator before taking a rescue medication for severe constipation, and all rescue medication usage was recorded. Patients on a stable, continuous regimen of fiber or bulk-forming agent therapy for at least 30 days prior to randomization were allowed to continue provided that they continued at a constant dose throughout the study. Assessments The primary end point of the study was the change in mean weekly SBM frequency from the 14-day pretreatment baseline period to the 4-week treatment period. Additional efficacy end points included daily assessments of other bowel habits (ie, CSBM frequency, stool consistency, straining) and abdominal symptoms (ie, discomfort and bloating), global assessments (ie, constipation severity, adequate and global relief of constipation, treatment satisfaction), and the Patient Assessment of Constipation Quality of Life (PAC-QOL) questionnaire. 26 Assessments were recorded by phone using an interactive voice response system. Each day, patients recorded the time study medication was taken, the number of BMs, and the time of each BM. Patients also recorded the characteristics of each BM, including: (1) stool consistency using the 7-point BSFS, (2) degree of straining using a 5-point ordinal severity scale (1 not at all, 2 a little bit, 3 a moderate amount, 4 a great deal, 5 an extreme amount), and (3) sensation of complete bowel emptying (yes/no). A BM was deemed an SBM if no laxative, enema, or suppository was taken in the preceding 24 hours, and a CSBM if the patient indicated that the SBM was associated with a sensation of complete bowel emptying. Each day patients also recorded the severity of abdominal discomfort and bloating using a 5-point ordinal severity scale (1 none, 2 mild, 3 moderate, 4 severe, 5 very severe). The following questions were asked at the end of the pretreatment baseline and weeks 1, 2, and 4 of the treatment period: (1) constipation severity using the 5-point ordinal severity scale (1 none, 2 mild, 3 moderate, 4 severe, 5 very severe), (2) adequate relief of constipation using a binary scale (yes/no), and (3) global relief of constipation using a 7-point balanced scale (1 completely relieved, 2 considerably relieved, 3 somewhat relieved, 4 unchanged, 5 somewhat worse, 6 considerably worse, 7 as bad as I can imagine). At the end of the treatment period, patients were asked to rate their overall satisfaction with the study medication s ability to relieve their constipation symptoms on a 5-point ordinal scale (1 not at all satisfied, 2 a little satisfied, 3 moderately satisfied, 4 quite satisfied, 5 very satisfied), and to provide an assessment of their health-related quality of life also asked the end of the pretreatment baseline using the PAC-QOL. 26 The site investigator assessed all patient-reported AEs and serious AEs and determined their relationship to study treatment. Safety evaluations included physical examinations, electrocardiograph recordings, vital sign measurements, and standard laboratory tests. Statistical Methods and Data Analysis Patients were randomized in approximately equal proportions to 1 of 5 treatment groups using central randomization balanced within each site using a block size of 5. A computer-generated randomization schedule was generated before the study began by a statistician not otherwise associated with the trial. The sponsor, all randomized patients, and study center personnel were blinded to study treatment allocation. The planned sample size was based on the results of a previous Phase 2a linaclotide study with the intention of providing 88% power to detect an overall difference of 2.53 SBMs per week with a standard deviation of The study design called for enrollment of at least 60 patients per treatment arm, anticipating 10 patients per arm withdrawing from the study. The primary efficacy end point was the change from the 14-day pretreatment baseline in overall weekly SBM rate during the 4-week treatment period. The overall weekly SBM rate during the 4-week treatment period was calculated as 7 times the number of SBMs divided by the number of days the patient reported bowel habits data (similarly for CSBMs). SBM frequency was also analyzed using a responder definition, with a responder defined as a patient who, for 3 of the 4 treatment weeks, had a weekly SBM rate 3 and an increase 1 relative to baseline. CSBM responders were similarly defined. Patients who were CSBM responders and had either an improvement in their BSFS or straining score of 1 for 3 of 4 weeks without worsening of either were considered to be constipation responders. An improvement in the abdominal discomfort and bloating score of 0.5 and constipation severity score of 1.0 was determined by patient-reported outcome assessments to be perceived as beneficial and, therefore, were used to assess responders for these end points. Change from baseline end points were analyzed using an analysis of covariance, with a fixed-effect term for treatment group and geographic region, and the corresponding baseline value as a covariate. The change from baseline means presented are the least-squares means from the analysis of covariance (ANCOVA) model based on the patient s overall average score during the 4-week treatment period (except for SBMs and CSBMs, where overall weekly rates were calculated). Responder end points were analyzed using a Cochran-Mantel-Haenszel

4 March 2010 LINACLOTIDE IN CC 889 Table 1. Summary of Demographics and Baseline Patient Characteristics (Intent-to-Treat Population) Linaclotide All Placebo 75 g 150 g 300 g 600 g n Demographic data Age, mean (SD) 47.3 (13.7) 46.1 (15.6) 46.4 (14.2) 46.4 (11.7) 47.9 (12.8) 49.6 (13.7) Gender, female, n (%) 282 (92) 60 (88) 55 (93) 54 (96) 58 (94) 55 (89) Race, n (%) African American 36 (12) 8 (12) 6 (10) 6 (11) 6 (10) 10 (16) White 259 (84) 57 (84) 50 (85) 50 (89) 54 (87) 48 (77) Pretreatment baseline, mean (SD) SBMs/week 2.3 (1.5) 2.3 (1.5) 2.0 (1.3) 2.3 (1.5) 2.2 (1.5) 2.5 (1.7) CSBMs/week 0.4 (0.7) 0.5 (0.6) 0.3 (0.6) 0.4 (0.7) 0.5 (0.7) 0.3 (0.6) Stool consistency a 2.4 (1.0) 2.5 (1.1) 2.0 (0.9) 2.4 (1.1) 2.6 (1.1) 2.4 (0.9) Straining b 3.2 (0.8) 3.0 (0.8) 3.5 (0.8) 3.2 (0.9) 2.9 (0.9) 3.2 (0.8) Abdominal discomfort c 2.4 (0.9) 2.4 (0.9) 2.4 (0.9) 2.5 (1.0) 2.4 (0.8) 2.4 (0.9) Bloating c 2.8 (0.9) 2.7 (1.0) 2.7 (0.9) 2.8 (1.0) 2.8 (1.0) 2.8 (0.8) Constipation severity d 3.5 (0.8) 3.3 (0.9) 3.6 (0.8) 3.5 (0.8) 3.5 (0.7) 3.3 (0.7) CSBM, complete spontaneous bowel movement; SD, standard deviation; SBM, spontaneous bowel movement. a Stool consistency was assessed using the 7-point Bristol Stool Form Score (1 separate hard lumps, like nuts (hard to pass); 7 watery, no solid pieces). b Straining was assessed on a 5-point ordinal scale (1 not at all; 5 an extreme amount). c Abdominal bloating and discomfort were assessed daily using a 5-point ordinal severity scale (1 none, 5 very severe). d Constipation severity was assessed weekly on a 5-point ordinal severity scale (1 none; 5 very severe). (CMH) test controlling for geographic region. Geographic regions were used as a factor in the analyses as opposed to trial center due to the potential of trial centers having small numbers of patients. Time-to-event data were analyzed using log-rank tests. An observedcases approach to missing data was applied (ie, a patient s missing values were not imputed). All P values are based on 2-sided tests. In this Phase 2b dose-range finding study, the reported P values were not adjusted for multiple comparisons. Safety results are reported for the Safety Population (n 309), defined as all randomized patients who took at least 1 dose of study medication. Efficacy analyses are reported for the Intent-to-Treat population (n 307, see Table 1), defined as patients in the safety population who had 1 postrandomization entry of the primary efficacy assessment. Results Participant Flow and Demographics Of the 639 patients who signed consent, 120 were screen failures, 209 were pretreatment failures, and 310 patients were randomized to 1 of the 5 arms of the study. One patient randomized to 150 g linaclotide withdrew prior to receiving the study medication (safety population, n 309), 2 additional patients withdrew prior to any postdose evaluation of the primary efficacy assessment (Intent-to-Treat population, n 307) and 32 additional patients discontinued while receiving study medication (reasons shown in Supplementary Figure 1). The number of patients who withdrew from the study was generally comparable across all 5 dose groups, although there was a slightly higher number of patients at the highest dose of linaclotide (600 g daily). The majority of the patients were white (84%) and female (92%), with a mean age of 47.3 years (range, years). Generally, treatment groups were wellbalanced with respect to baseline demographics and pretreatment baseline bowel habit characteristics. Bowel Function Stool frequency. Frequency of weekly SBMs increased significantly with increasing linaclotide dosage (Figure 1). The change from the 14-day pretreatment baseline to the 4-week treatment period in overall mean weekly SBM frequency showed a linear doseresponse with increases of 2.6, 3.3, 3.6, and 4.3 for linaclotide doses of 75, 150, 300, and 600 g, respectively, compared to 1.5 for placebo (P.05 for each pairwise comparison of a linaclotide dose to placebo, a test for linear-trend was significant P.0001). In addition, a greater percentage of patients receiving linaclotide doses of 75, 150, 300, and 600 g experienced an SBM within the first 24 hours (50.8%, 55.4%, 54.8%, and 75.8%, respectively) compared with placebo (36.8%, P.05 for each of the linaclotide doses, except 75 g vs placebo). The median time in hours to first SBM was 24.0, 21.9, 23.1, and 13.0 for linaclotide doses of 75, 150, 300, and 600 g, respectively, vs 32.6 for placebo (P.0005 for overall log-rank test). SBM responder rates, defined as a patient who reported a weekly SBM rate 3 and an increase 1 relative to

5 890 LEMBO ET AL GASTROENTEROLOGY Vol. 138, No. 3 Figure 1. Effects of linaclotide on bowel function, including spontaneous bowel movements (SBM), complete spontaneous bowel movements (CSBM), straining, and stool consistency. BSFS, Bristol Stool Form Scale. baseline for 3 of 4 of the treatment weeks, were 59.3%, 55.4%, 61.3%, and 67.7% for linaclotide doses of 75, 150, 300, and 600 g, respectively, compared to 32.4% for placebo (P.01 for each of the linaclotide doses) (Figure 2). Linaclotide also improved the frequency of SBMs associated with a sensation of complete emptying of the bowels. The mean number of CSBMs per week was greater with all doses of linaclotide compared with placebo (Figure 1). The change from the 14-day pretreatment baseline to the 4-week treatment period in overall mean weekly CSBM frequency was dose-responsive with increases of 1.5, 1.6, 1.8, and 2.3 for linaclotide doses of 75, 150, 300, and 600 g, respectively, compared to 0.5 for placebo (P.01 for each of the linaclotide doses). A greater percentage of patients receiving linaclotide doses of 75, 150, 300, and 600 g experienced a CSBM within the first 24 hours (25.4%, 14.3%, 22.6%, and 35.5%, re- Figure 2. Percentage of spontaneous bowel movements (SBM) and complete spontaneous bowel movement (CSBM) responders. CSBM and SBM responders were defined as a patient who, for 3 of the 4 treatment weeks, had a weekly CSBM (or SBM) rate 3 and an increase 1 relative to baseline.

6 March 2010 LINACLOTIDE IN CC 891 spectively) compared with placebo (7.4%, P.05 for each of the linaclotide doses except 150 g vs placebo). The median time in days to a CSBM was 5.9, 4.6, 4.0, and 3.0 for linaclotide doses of 75, 150, 300, and 600 g, respectively, vs 8.3 for placebo (P.03 for overall log-rank test). CSBM responder rates, defined similarly to SBM responder, were higher for all doses of linaclotide (18.6%, 26.8%, 32.3%, and 29.0%, for 75, 150, 300, and 600 g dose groups, respectively) compared with placebo (7.4%; P.05 for each of the linaclotide doses except 75 g vs placebo) (Figure 2). Stool consistency. The mean change from baseline in overall stool consistency across the 4-week treatment period was greater in patients receiving linaclotide than in patients receiving placebo (Figure 1). The change was dose-dependent at 1.35, 1.57, 1.68, and 2.00 for linaclotide doses of 75, 150, 300, and 600 g, respectively, compared to a 0.50 mean change for patients receiving placebo (P.0005 for each of the linaclotide doses). Straining. The mean change from baseline in overall straining across the 4-week treatment period showed dose-dependent improvement in patients receiving linaclotide compared to placebo ( 0.71, 0.97, 1.11, and 1.14 for linaclotide 75, 150, 300, and 600 g, respectively, vs 0.52 for placebo, P.001 for each of the linaclotide doses, except for 75 g vs placebo) (Figure 1). Constipation responders. The percentage of patients who were CSBM responders and had either an improvement in their BSFS or straining score of 1for3of4 weeks of the study without worsening of either symptom were 18.6%, 23.2%, 27.4%, and 25.8% for linaclotide doses of 75, 150, 300, and 600 g, respectively, vs 4.4% for placebo (P.05 for each of the linaclotide doses). Posttreatment effects. During the 14-day posttreatment period, bowel habits trended toward baseline and were similar to placebo, suggesting that linaclotide does not cause rebound worsening of constipation symptoms (Figure 1). Abdominal Symptoms Discomfort. The mean change from baseline in overall abdominal discomfort across the 4-week treatment period improved in patients receiving linaclotide ( 0.32, 0.30, 0.24, and 0.28 for linaclotide doses of Figure 3. Effects of linaclotide on abdominal symptoms (discomfort and bloating), constipation severity, and global relief of constipation.

7 892 LEMBO ET AL GASTROENTEROLOGY Vol. 138, No. 3 75, 150, 300, and 600 g, respectively, vs 0.04 for placebo, P.05 for each of the linaclotide doses) (Figure 3). The percentage of patients who reported a decrease in the abdominal discomfort score of 0.5 for 3 of 4 weeks was 30.5%, 28.6%, 27.4%, and 32.3% for linaclotide doses of 75, 150, 300, and 600 g, respectively, vs 11.8% for placebo (P.05 for each of the linaclotide doses). Bloating. The mean change from baseline in overall bloating across the 4-week treatment period improved in patients receiving linaclotide compared to placebo ( 0.40, 0.42, 0.27, and 0.26 for linaclotide doses of 75, 150, 300, and 600 g, respectively, vs 0.02 for placebo, P.05 for each of the linaclotide doses) (Figure 3). The percentage of patients who reported a decrease in the bloating score of 0.5 for 3 of 4 weeks was 28.8%, 39.3%, 32.3%, and 30.6% for linaclotide doses of 75, 150, 300, and 600 g, respectively, vs 11.8% for placebo (P.05 for each of the linaclotide doses). Global Measures of Constipation Constipation severity. The mean change in overall constipation severity score across the 4-week treatment period from baseline improved significantly for each of the linaclotide doses vs placebo during the treatment period ( 0.78, 0.89, 0.88, and 0.95 for linaclotide doses of 75, 150, 300, and 600 g, respectively, vs 0.17 for placebo; P.0001 for each of the linaclotide doses) (Figure 3). The percentage of patients with improvement of 1 on the constipation severity score at week 4 was significantly greater for patients receiving linaclotide compared to placebo (63.4%, 66.7%, 69.6%, and 71.8% for linaclotide doses of 75, 150, 300, and 600 g, respectively, vs 34.9% for placebo, P.05 for each of the linaclotide doses). Adequate relief of constipation. A greater percentage of patients receiving linaclotide reported adequate relief of constipation at week 4 compared with placebo (58.5%, 75.8%, 60.9%, and 69.2% for linaclotide doses of 75, 150, 300, and 600 g, respectively, vs 32.6% for placebo; P.05 for each of the linaclotide doses). Likewise, a greater percentage of patients receiving linaclotide reported adequate relief of constipation for at least 2 weeks in the treatment period compared with placebo (40.7%, 58.9%, 41.9%, and 56.5% for linaclotide doses of 75, 150, 300, and 600 g, respectively, vs 27.9% for placebo; P.001 for 150 and 600 g doses only vs placebo). Global relief of constipation. The change from baseline in the overall global relief of constipation score across the 4-week treatment period showed statistically significant dose-dependent improvement for all doses of linaclotide ( 0.99, 1.12, 1.13, and 1.26 for linaclotide doses of 75, 150, 300, and 600 g, respectively) compared to placebo ( 0.50, P.01 for each of the linaclotide doses) (Figure 3). The mean change from baseline in the global relief of constipation improved significantly for each week of the study, except at week 2 for the 75- g dose (P.0626) (results not shown). Treatment satisfaction. Patient satisfaction with the study medication s ability to relieve constipation symptoms was significantly higher in the linaclotide dose groups vs the placebo group (3.09, 3.33, 3.25, 3.28, for linaclotide doses of 75, 150, 300, and 600 g, respectively, vs 2.33 for placebo; P.01 for each of the linaclotide doses). Health-Related Quality of Life The improvement from baseline in the PAC-QOL for all linaclotide dose groups was greater than for the placebo group ( 0.72, 0.80, 0.67, and 0.83 for linaclotide doses of 75, 150, 300, and 600 g, respectively, vs 0.41 for placebo; P.05 for each of the linaclotide doses, except 300 g, for which the P.0515 vs placebo) (Table 2). The percentage of patients with an improvement from baseline of 1 in their overall PAC-QOL score was 42.4%, 44.6%, 30.6%, and 48.4% for linaclotide doses of 75, 150, 300, and 600 g, respectively, vs 26.5% for placebo-treated patients (P.05 for each of the linaclotide doses except 300 g vs placebo). Improvement in the 4 individual domains of the PAC-QOL (ie, physical discomfort, psychosocial discomfort, worries/concerns, and satisfaction with treatment) was greater for all linaclotide doses compared to placebo and was statistically significant vs placebo for each of the linaclotide doses for the physical discomfort (P.05) and satisfaction (P.01) domains. Rescue Medication There was no significant change in rescue medication use between placebo and linaclotide groups or between periods of the study. AEs Overall, the percentage of patients reporting at least 1 AE was 33.8% in patients receiving linaclotide compared with 31.9% in patients receiving placebo. The rate of AEs was slightly greater in patients receiving 600 g linaclotide (38.1%) compared with the other linaclotide groups (29.0% to 35.0%) (Table 3). The most commonly reported AEs were GI-related (Table 3). Of the GI AEs, diarrhea was the most common, with 5.1%, 8.9%, 4.8%, and 14.3% of patients receiving linaclotide 75, 150, 300, and 600 g, respectively, reporting diarrhea vs 2.9% of patients receiving placebo. One-half of the reports of diarrhea were within 2 days of starting the study medication. Most of the diarrhea AEs were graded by the investigator as mild or moderate in intensity; only 2 were graded as severe; both were in the 600- g group and both discontinued treatment as a result of diarrhea. Of interest, treatment satisfaction was similar in linaclotide patients with diarrhea who did not discontinue study

8 March 2010 LINACLOTIDE IN CC 893 Table 2. Patient Assessment of Constipation Quality of Life (PAC-QOL) Mean PAC-QOL Placebo 75 g 150 g 300 g 600 g (n 68) (n 59) (n 56) (n 62) (n 62) Overall score Baseline Week Change from BL a P value b Physical Discomfort Subscale Baseline Week Change from BL a P value b Psychosocial Discomfort Subscale Baseline Week Change from BL a P value b Worries and Concerns Subscale Baseline Week Change from BL a P value b Satisfaction Subscale Baseline Week Change from BL a P value b a Change from baseline (BL) means are the least-squares means from the ANCOVA. b P values were based on a comparison of each linaclotide group vs the placebo group using the ANCOVA model. medication vs those who did not experience diarrhea (mean score of 3.38 vs 3.37, respectively). No clinically significant adverse sequelae, such as dehydration requiring intravenous fluid or electrolyte changes, were observed. All other AEs occurred with a similar incidence in the linaclotide-treated groups compared with the placebo group. Nine patients discontinued treatment due to AEs, 2 in the placebo group, 0 in the linaclotide 75 g group, 2 in the linaclotide 150 g group, 2 in the linaclotide 300 g group, and 3 in the linaclotide 600 g group. One patient in the linaclotide 150 g treatment group withdrew due to a balance disorder that was reported by the investigator to be unlikely related to the study medication. All others who withdrew did so because of a GI AE. The most common AE leading to study discontinuation was diarrhea (1, 2, and 3 patients receiving linaclotide doses of 150, 300, and 600 g, respectively). There were 3 serious AEs reported in 2 patients in this study; both patients received placebo. One patient sustained a proximal humerus fracture while ice skating and the other patient experienced pneumonia and atrial fibrillation. Discussion In this dose-range finding study in patients with CC, linaclotide, a minimally absorbed GC-C receptor Table 3. Summary of Gastrointestinal Adverse Events Experienced by 2% of the Linaclotide-Treated Patients (Safety Population) System organ class MedDRA-preferred term Placebo (n 69) 75 g (n 59) 150 g (n 56) Linaclotide 300 g (n 62) 600 g (n 63) All (n 240) Any AE, n (%) 22 (31.9) 21 (35.6) 18 (32.1) 18 (29.0) 24 (38.1) 81 (33.8) Gastrointestinal disorders, n (%) 9 (13.0) 11 (18.6) 13 (23.2) 8 (12.9) 15 (23.8) 47 (19.6) Diarrhea 2 (2.9) 3 (5.1) 5 (8.9) 3 (4.8) 9 (14.3) 20 (8.3) Abdominal pain 3 (4.3) 2 (3.4) 5 (8.9) 2 (3.2) 2 (3.2) 11 (4.6) Flatulence 4 (5.8) 2 (3.4) 3 (5.4) 2 (3.2) 2 (3.2) 9 (3.8) Nausea 1 (1.4) 2 (3.4) 2 (3.6) 1 (1.6) 2 (3.2) 7 (2.9) AE, adverse event; MedDRA, Medical Dictionary for Regulatory Activities.

9 894 LEMBO ET AL GASTROENTEROLOGY Vol. 138, No. 3 agonist, significantly improved bowel habits and abdominal symptoms associated with constipation. Linaclotide s effects on bowel habits were observed within 24 hours after the start of the medication and maintained throughout the 4 weeks of treatment, with no evidence of rebound constipation after discontinuation of the medication during the 14-day follow-up period. There was evidence of a dose-dependent improvement in bowel habit symptoms with linaclotide, and all doses of linaclotide improved bowel habit symptoms compared with placebo, including SBMs, CSBMs, stool consistency, and straining. Abdominal symptoms commonly associated with constipation, such as abdominal discomfort and bloating, also improved with linaclotide within the first week of treatment compared to placebo. These results are underscored by results of linaclotide on the global assessments of constipation, including global relief of constipation, adequate relief of constipation, constipation severity, and treatment satisfaction. On the overall PAC-QOL scale, there was a significantly greater percentage of patients in each linaclotide dose group (except 300 g) who had a high level of therapeutic responsiveness with improvement of 1 point. 13,26,27 Taken together, these results, along with the improvement in abdominal symptoms and bowel habits, show a robust effect of linaclotide for the treatment of CC. Linaclotide was well-tolerated in this study of adult patients with CC. No serious AEs occurred in patients receiving linaclotide. AEs occurred in approximately onethird of patients receiving linaclotide (33.8%) and placebo (31.9%). Because linaclotide has no detectable systemic bioavailability at the doses administered in this study, most of the AEs were nonsystemic and were related to the GI tract. Diarrhea, which is an expected result of linaclotide s pharmacology, was the most commonly reported AE; most events of diarrhea were mild to moderate in severity. Among patients who completed the study, there was no difference in overall treatment satisfaction in the subgroup reporting an AE of diarrhea and those who did not, suggesting that diarrhea was not always considered adverse by the patient. The 2 cases of severe diarrhea occurred in the 600- g group and resulted in discontinuation from the study. As with most cases, the diarrhea in both patients began within the first week of treatment and resolved without clinical intervention. Similarly, the mild and moderate cases of diarrhea AEs were also self-limited and did not require interventions such as intravenous hydration or hospitalization, and none was associated with clinically significant changes in serum electrolytes. Similar to other studies in the United States in patients with CC, 13,27 the vast majority of patients in this study were females. The high percentage of female patients is partially due to the higher prevalence of CC among females, as well as to their tendency to enter functional GI clinical trials more often than males. Likewise, relatively small numbers of non-white (n 48) and elderly (n 30) patients enrolled in this study. Linaclotide appeared to be equally effective in these subgroups as in the entire study population. The effect of linaclotide was sustained during the 4-week treatment period; however, longer-duration studies are needed to confirm long-term maintenance of treatment effect. The efficacy of linaclotide generally improved with increasing doses from 75 g to600 g per day. Interestingly, abdominal discomfort and bloating did not show a dose-dependent effect, perhaps due to the relatively low baseline scores, which decreases the power of linaclotide to improve these symptoms (ie, floor effect ), and may explain the relatively small improvement seen on these end points. Nevertheless, the clinical significance of linaclotide on abdominal discomfort and bloating is unclear. Although the greatest effect on bowel function occurred at the 600- g/day dose of linaclotide, patients receiving this dose experienced more side effects, especially diarrhea, including 3 patients who discontinued due to diarrhea (2 of whom had diarrhea rated as severe). In summary, the results of this well-controlled, doserange finding, Phase 2b study support further development of oral, once-daily linaclotide for treatment of adults with CC. The 150 and 300 g daily doses of linaclotide appear to provide an appropriate balance of improvement in symptoms and few AEs and will, therefore, be assessed in future Phase 3 trials for CC. Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Gastroenterology at and at doi: /j.gastro References 1. Stewart WF, Liberman JN, Sandler RS, et al. Epidemiology of constipation (EPOC) study in the United States: relation of clinical subtypes to sociodemographic features. Am J Gastroenterol 1999;94: Higgins PD, Johanson JF. Epidemiology of constipation in North America: a systematic review. Am J Gastroenterol 2004;99: Lembo A, Camilleri M. Chronic constipation. N Engl J Med 2003; 349: Pare P, Ferrazzi S, Thompson WG, et al. An epidemiological survey of constipation in Canada: definitions, rates, demographics, and predictors of health care seeking. Am J Gastroenterol 2001;96: Wald A, Scarpignato C, Kamm MA, et al. The burden of constipation on quality of life: results of a multinational survey. Aliment Pharmacol Ther 2007;26: Johanson JF, Kralstein J. Chronic constipation: a survey of the patient perspective. Aliment Pharmacol Ther 2007;25: Talley NJ, Lasch KL, Baum CL. A gap in our understanding: chronic constipation and its comorbid conditions. Clin Gastroenterol Hepatol 2009;7: Talley NJ. Functional gastrointestinal disorders as a public health problem. Neurogastroenterol Motil 2008;20(Suppl 1):

10 March 2010 LINACLOTIDE IN CC Nyrop KA, Palsson OS, Levy RL, et al. Costs of health care for irritable bowel syndrome, chronic constipation, functional diarrhoea and functional abdominal pain. Aliment Pharmacol Ther 2007;26: Martin BC, Barghout V, Cerulli A. Direct medical costs of constipation in the United States. Manag Care Interface 2006;19: Tack J, Muller-Lissner S. Treatment of chronic constipation: current pharmacologic approaches and future directions. Clin Gastroenterol Hepatol 2009;7: ; quiz Schiller LR, Johnson DA. Balancing drug risk and benefit: toward refining the process of FDA decisions affecting patient care. Am J Gastroenterol 2008;103: Johanson JF, Morton D, Geenen J, et al. Multicenter, 4-week, double-blind, randomized, placebo-controlled trial of lubiprostone, a locally-acting type-2 chloride channel activator, in patients with chronic constipation. Am J Gastroenterol 2008;103: Johanson JF, Ueno R. Lubiprostone, a locally acting chloride channel activator, in adult patients with chronic constipation: a double-blind, placebo-controlled, dose-ranging study to evaluate efficacy and safety. Aliment Pharmacol Ther 2007;25: Forte LR Jr. Uroguanylin and guanylin peptides: pharmacology and experimental therapeutics. Pharmacol Ther 2004;104: Currie MG, Fok KF, Kato J, et al. Guanylin: an endogenous activator of intestinal guanylate cyclase. Proc Natl Acad Sci U S A 1992; 89: Andresen V, Camilleri M, Busciglio IA, et al. Effect of 5 days linaclotide on transit and bowel function in females with constipation-predominant irritable bowel syndrome. Gastroenterology 2007;133: Bueno L, Beaufraud C, Mahajan-Miklos S, et al. Antinocicetive actions of MD-1100, a novel therapeutic agent for C-IBS, in animal models of visceral pain. Am J Gastroenterol 2004; 99(Suppl 2):A Ustinova E, Bryant A, Reza T, et al. Oral cyclic guanosine monophosphate (cgmp) desensitizes colonic afferents in an animal model of experimental pain. Am J Gastroenterol 2008;103(Suppl 1):S Kurtz CB, Fitch D, Busby RW, et al. Effects of multidose administration of MD-1100 on safety, tolerability, exposure, and pharmacoldynamics in healthy subjects. Gastroenterology 2006; 130(Suppl 2):A Johnston JM, Kurtz CB, Drossman DA, et al. Pilot study on the effect of linaclotide in patients with chronic constipation. Am J Gastroenterol 2009;104: Thompson WG, Longstreth GF, Drossman DA, et al. Functional bowel disorders and functional abdominal pain. Gut 1999; 45(Suppl 2):II43 II Longstreth GF, Thompson WG, Chey WD, et al. Functional bowel disorders. Gastroenterology 2006;130: Winawer S, Fletcher R, Rex D, et al. Colorectal cancer screening and surveillance: clinical guidelines and rationale update based on new evidence. Gastroenterology 2003;124: Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J Gastroenterol 1997;32: Marquis P, De La Loge C, Dubois D, et al. Development and validation of the Patient Assessment of Constipation Quality of Life questionnaire. Scand J Gastroenterol 2005;40: Camilleri M, Kerstens R, Rykx A, et al. A placebo-controlled trial of prucalopride for severe chronic constipation. N Engl J Med 2008;358: Received August 19, Accepted December 8, Reprint requests Address requests for reprints to: Jeffrey M. Johnston, Ironwood Pharmaceuticals, Inc., 320 Bent Street, Cambridge, Massachusetts jjohnston@ironwoodpharma.com Acknowledgments The authors thank the investigators for their participation in this study. The statistical analysis of the entire data sets pertaining to efficacy (specifically primary and major secondary efficacy end points) and safety (specifically, serious adverse events as defined in federal guidelines) have been independently confirmed by a biostatistician not employed by the corporate entity. Clinicaltrials.gov ID NCT Conflicts of interest The authors disclose the following: Jeffrey Johnston, Caroline Kurtz, James MacDougall, Bernard Lavins, Donald Fitch, Brenda Jeglinski, and Mark Currie are employees of Ironwood Pharmaceuticals. Anthony Lembo is a consultant to Ironwood Pharmaceuticals. Funding This study was funded by Ironwood Pharmaceuticals.

11 895.e1 LEMBO ET AL GASTROENTEROLOGY Vol. 138, No. 3 Supplementary Figure 1. Diagram of patient flow through study.