Harvey Schneier

Linaclotide for Irritable Bowel Syndrome With Constipation: A 26-Week, Randomized, Double-blind, Placebo-Controlled Trial to Evaluate Efficacy and Safety

OBJECTIVES:Linaclotide is a minimally absorbed peptide guanylate cyclase-C agonist. The objective of this trial was to determine the efficacy and safety of linaclotide treatment in patients with irritable bowel syndrome with constipation (IBS-C) over 26 weeks.METHODS:This phase 3, double-blind, parallel-group, placebo-controlled trial randomized IBS-C patients to placebo or 290 μg of oral linaclotide once daily for a 26-week treatment period. The primary and the secondary efficacy assessments were evaluated over the first 12 weeks of treatment. Primary end points included the Food and Drug Administrations (FDAs) end point for IBS-C (responder: a patient who reported (i) improvement of ≥30% from baseline in average daily worst abdominal pain score and (ii) increase of ≥1 complete spontaneous bowel movement (CSBM) from baseline, both in the same week for ≥6/12 weeks) and three other primary end points, based on improvements in abdominal pain and CSBMs for 9/12 weeks. Adverse events (AEs) were monitored.RESULTS:In all, 804 patients (mean age=44 years, female=90%, white=78%) were evaluated; 33.7% of linaclotide-treated patients were FDA end point responders, vs. 13.9% of placebo-treated patients (P<0.0001) (number needed to treat=5.1, 95% confidence interval (CI): 3.9, 7.1). The pain responder criterion of the FDA end point was met by 48.9% of linaclotide-treated patients vs. 34.5% of placebo-treated patients (number needed to treat=7.0, 95% CI: 4.7, 13.1), and the CSBM responder criterion was met by 47.6% of linaclotide-treated patients, vs. 22.6% of placebo patients (number needed to treat=4.0, 95% CI: 3.2, 5.4). Remaining primary end points (P<0.0001) and all secondary end points (P<0.001), including abdominal pain, abdominal bloating, and bowel symptoms (SBM and CSBM rates, Bristol Stool Form Scale (BSFS) score, and straining), were also statistically significantly improved with linaclotide vs. placebo. Statistically significant differences from placebo were observed for responder and continuous end points over 26 weeks of treatment. AE incidence was similar between treatment groups, except for diarrhea, which caused discontinuation in 4.5% of linaclotide patients vs. 0.2% of placebo patients.CONCLUSIONS:Linaclotide 290 μg once daily significantly improved abdominal and bowel symptoms associated with IBS-C over 26 weeks of treatment.

A 12-Week, Randomized, Controlled Trial With a 4-Week Randomized Withdrawal Period to Evaluate the Efficacy and Safety of Linaclotide in Irritable Bowel Syndrome With Constipation

OBJECTIVES:Linaclotide is a minimally absorbed guanylate cyclase-C agonist. The objective of this trial was to determine the efficacy and safety of linaclotide in patients with irritable bowel syndrome with constipation (IBS-C).METHODS:This phase 3, double-blind, parallel-group, placebo-controlled trial randomized IBS-C patients to placebo or 290 μg oral linaclotide once daily in a 12-week treatment period, followed by a 4-week randomized withdrawal (RW) period. There were four primary end points, the Food and Drug Administrations (FDAs) primary end point for IBS-C (responder: improvement of ≥30% in average daily worst abdominal pain score and increase by ≥1 complete spontaneous bowel movement (CSBM) from baseline (same week) for at least 50% of weeks assessed) and three other primary end points, based on improvements in abdominal pain and CSBMs for 9/12 weeks. Adverse events (AEs) were monitored.RESULTS:The trial evaluated 800 patients (mean age=43.5 years, female=90.5%, white=76.9%). The FDA end point was met by 136/405 linaclotide-treated patients (33.6%), compared with 83/395 placebo-treated patients (21.0%) (P<0.0001) (number needed to treat: 8.0, 95% confidence interval: 5.4, 15.5). A greater percentage of linaclotide patients, compared with placebo patients, reported for at least 6/12 treatment period weeks, a reduction of ≥30% in abdominal pain (50.1 vs. 37.5%, P=0.0003) and an increase of ≥1 CSBM from baseline (48.6 vs. 29.6%, P<0.0001). A greater percentage of linaclotide patients vs. placebo patients were also responders for the other three primary end points (P<0.05). Significantly greater improvements were seen in linaclotide vs. placebo patients for all secondary end points (P<0.001). During the RW period, patients remaining on linaclotide showed sustained improvement; patients re-randomized from linaclotide to placebo showed return of symptoms, but without worsening of symptoms relative to baseline. Diarrhea, the most common AE, resulted in discontinuation of 5.7% of linaclotide and 0.3% of placebo patients.CONCLUSIONS:Linaclotide significantly improved abdominal pain and bowel symptoms associated with IBS-C for at least 12 weeks; there was no worsening of symptoms compared with baseline following cessation of linaclotide during the RW period.

Two Randomized Trials of Linaclotide for Chronic Constipation

BACKGROUND Linaclotide is a minimally absorbed peptide agonist of the guanylate cyclase C receptor. In two trials, we aimed to determine the efficacy and safety of linaclotide in patients with chronic constipation. METHODS We conducted two randomized, 12-week, multicenter, double-blind, parallel-group, placebo-controlled, dual-dose trials (Trials 303 and 01) involving 1276 patients with chronic constipation. Patients received either placebo or linaclotide, 145 μg or 290 μg, once daily for 12 weeks. The primary efficacy end point was three or more complete spontaneous bowel movements (CSBMs) per week and an increase of one or more CSBMs from baseline during at least 9 of the 12 weeks. Adverse events were also monitored. RESULTS For Trials 303 and 01, respectively, the primary end point was reached by 21.2% and 16.0% of the patients who received 145 μg of linaclotide and by 19.4% and 21.3% of the patients who received 290 μg of linaclotide, as compared with 3.3% and 6.0% of those who received placebo (P<0.01 for all comparisons of linaclotide with placebo). Improvements in all secondary end points were significantly greater in both linaclotide groups than in the placebo groups. The incidence of adverse events was similar among all study groups, with the exception of diarrhea, which led to discontinuation of treatment in 4.2% of patients in both linaclotide groups. CONCLUSIONS In these two 12-week trials, linaclotide significantly reduced bowel and abdominal symptoms in patients with chronic constipation. Additional studies are needed to evaluate the potential long-term risks and benefits of linaclotide in chronic constipation. (Funded by Ironwood Pharmaceuticals and Forest Research Institute; ClinicalTrials.gov numbers, NCT00765882 and NCT00730015.).

T1817 Results From the Randomized Withdrawal Period of a Phase 3 Clinical Trial of Linaclotide in Chronic Constipation

INTRODUCTION: Linaclotide, a first-in-class, minimally-absorbed guanylate cyclase typeC receptor agonist, statistically significantly improved bowel and abdominal symptoms in 2 recent Phase 3 trials in CC patients. One trial included a 4-week randomized withdrawal period (RW) following a 12-week treatment period (TP). AIM: To determine the effect of cessation of linaclotide treatment in CC patients during the RW. METHODS: For the TP, eligible patients met modified Rome II CC criteria, and during a 2-week baseline period had <3 complete spontaneous bowel movements (CSBM) and ≤6 SBM per week. For the RW, linaclotide patients were re-randomized to placebo (PBO) or to continue their TP dose; PBO patients were allocated to 266 mcg linaclotide. Thus, patient TP→RW treatment sequences were: 133→PBO, 266→PBO, 133→133, 266→266, or PBO→266. Symptoms assessed included CSBMs, SBMs, stool consistency, straining severity, constipation severity, abdominal discomfort, and bloating. RESULTS: A total of 538 of the 642 patients in the intent-to-treat population participated in the RW. CSBM rates for linaclotide-treated patients re-randomized to PBO decreased to rates similar to PBO rates during the TP (Figure). Conversely, CSBM rates for linaclotide patients continuing their dose during the RW were sustained at TP rates. CSBM rates in PBO patients allocated to 266 mcg linaclotide during the RW increased to levels seen in patients who remained on linaclotide. Similar trends were seen for other symptoms. AEs in the RW were similar to those seen during the TP. CONCLUSION: During the RW, there was no evidence of rebound CC symptoms or AEs following cessation of linaclotide treatment, while patients initiating linaclotide treatment had marked improvement in CC symptoms. Linaclotide treatment resulted in sustained improvements in bowel and abdominal symptoms over 16 weeks.

Tu1381 Effects of 26 Weeks of Linaclotide Treatment on Adequate Relief and IBS Severity in Patients With Irritable Bowel Syndrome With Constipation

Introduction There have been few long-term studies evaluating treatments for IBS. Linaclotide (LIN), a 14 amino acid, minimally absorbed, guanylate cyclase C agonist (GCCA), was evaluated in 2 Phase 3 trials in patients (pts) with IBS-C, including a double-blind trial with an extended 26 wk Treatment Period, in which statistically significant improvements in abdominal pain and complete spontaneous bowel movement (CSBM) frequency were sustained for up to 26 wks. In a subsequent analysis of this study, we assessed the effects of 26 wks of LIN treatment on adequate relief and IBS severity and the relationship between long-term improvement in adequate relief with improvements in abdominal pain and CSBM frequency. Methods Adult pts with IBS-C (Rome II criteria) were randomised to LIN 290 μg or placebo (PBO) qd po for 26 wks. Endpoints included daily pt rating of abdominal pain at its worst during the previous 24 h on an 11-point scale (0 = none, 10 = very severe) and CSBM frequency. Pts also rated adequate relief of IBS symptoms (yes/no) and IBS severity (5-point scale: 1 = none, 5 = very severe) weekly. An Adequate Relief Responder was defined as a pt with adequate relief of IBS symptoms for ≥13 of the 26 wks of the Treatment Period. Spearman correlations were performed for Adequate Relief Responders and individual symptom improvement. Results The study included 401 LIN- and 403 PBO-treated pts. With LIN, 49% of pts were Adequate Relief Responders vs 25% of PBO pts (difference 24.1; p Conclusion Significantly more LIN pts vs PBO pts reported adequate relief of IBS symptoms and improvement of IBS severity during 26 wks of treatment. Gains in the % of pts reporting adequate relief correlated strongly with improvements in abdominal pain and CSBM frequency. Supported by Ironwood Pharmaceuticals Inc and by Forest Laboratories Inc. Editing assistance was provided by Complete Medical Communications, funded by Almirall. Disclosure of Interest E. Quigley Speaker bureau with: Danone, Janssen, Procter and Gamble, sanofi-aventis, Shire and Yakult, Conflict with: Advisory boards for Almirall, Ironwood, Janssen, Norgine, Salix and Shire/Movetis, W. Chey Consultant for: Ironwood Pharmaceuticals and Forest Research Institute, B. Lavins Shareholder of: Ironwood Pharmaceuticals, Employee of: Ironwood Pharmaceuticals, M. Baird Shareholder of: Ironwood Pharmaceuticals, Employee of: Ironwood Pharmaceuticals, D. Fitch Shareholder of: Ironwood Pharmaceuticals, Employee of: Ironwood Pharmaceuticals, X. Hao Shareholder of: Ironwood Pharmaceuticals, Employee of: Ironwood Pharmaceuticals, K. Shi Employee of: Forest Laboratories, M. Currie Shareholder of: Ironwood Pharmaceuticals, Employee of: Ironwood Pharmaceuticals, H. Schneier Shareholder of: Forest Laboratories, Employee of: Forest Laboratories, J. Johnston Shareholder of: Ironwood Pharmaceuticals, Employee of: Ironwood Pharmaceuticals

OC-082 26-Week efficacy and safety of once-daily oral linaclotide in patients with irritable bowel syndrome with constipation (IBS-C): a European perspective

Introduction Linaclotide, a minimally absorbed guanylate cyclase-C receptor agonist, is an investigational drug treatment for IBS-C. As part of the European Medicines Authority submission we evaluated the efficacy and safety of linaclotide 290 μg, administered once daily for 26 weeks (wks), in a Phase 3 trial of patients with IBS-C. Methods In a randomised, double-blind, Phase 3 trial, IBS-C patients (modified Rome II criteria) with an overall complete spontaneous bowel movement (CSBM) frequency of <3/wk, an overall spontaneous bowel movement (SBM) frequency of ≤5/wk and an average abdominal pain score of ≥3 (0–10 scale) during a 2 wk baseline period were randomised to linaclotide or placebo for 26 wks of treatment. Efficacy parameters were analysed at 12 and 26 wks. Results In total, 804 patients (female 90%; median age 44 years) received linaclotide (n=401) or placebo (n=403). During the 2 wk baseline period, 87% had abdominal pain every day (mean score 5.6; 0–10 scale) and 76% had no CSBMs (mean rate 0.2/wk). Significant improvements in linaclotide-treated patients were seen for both co-primary and all 12 secondary parameters. For the first co-primary parameter (≥30% reduction from baseline in mean abdominal pain or discomfort score with neither score worsening for ≥6 of the first 12 wks), 54.1% of linaclotide-treated patients and 38.5% of placebo-treated patients were responders (p<0.0001). For the second co-primary parameter (“considerably relieved” or “completely relieved” on the weekly degree-of-relief of IBS symptoms question for ≥6 of the first 12 wks), 39.4% of linaclotide-treated patients and 16.6% of placebo-treated patients were responders (p<0.0001). Similar improvements in both co-primary endpoints were seen at 26 wks (53.6% vs 36.0%, 37.2% vs 16.9%; both p<0.0001). Also, rates for sustained abdominal pain/discomfort response and sustained IBS degree-of-relief response at 12 and 26 wks were significantly greater in linaclotide-treated vs placebo-treated patients (all p<0.0001). Linaclotide significantly improved CSBMs, stool consistency, straining, bloating, SBMs, abdominal pain and abdominal discomfort vs placebo over 12 and 26 wks (p<0.0001). The most common adverse event (AE) was diarrhoea, causing discontinuation in 4.0% of linaclotide-treated and 0.2% of placebo-treated patients. Conclusion Treatment of IBS-C with linaclotide produced statistically significant improvements in abdominal and bowel symptoms at 12 wks and were sustained over 26 wks. Diarrhoea was the most common AE. Competing interests A J Lembo grant/research support from: Ironwood Pharmaceuticals, consultant for: Ironwood Pharmaceuticals/Salix/Prometheus/Alkermes/Ardelyx/GSK/Theravance, conflict with: lecture fees from Ironwood Pharmaceuticals, J Fortea Shareholder with: Almirall, Employee of: Almirall, C Diaz Employee of: Almirall, M Falques Employee of: Almirall, J Shao Employee of: Ironwood Pharmaceuticals, B J Lavins Employee of: Ironwood Pharmaceuticals, H A Schneier Employee of: Forest Research Institute, J M Johnston Employee of: Ironwood Pharmaceuticals.

Clarification of trial end points presented in a recent review of linaclotide

Response to: Roque MV, Camilleri M. Linaclotide, a synthetic guanylate cyclase C agonist, for the treatment of functional gastrointestinal disorders associated with constipation. Expert Rev. Gastroenterol. Hepatol. 5(3), 301–310 (2011).

Response to Miner et al.

of events ( 2 ). It appears that a diff erent approach to reporting of AEs was applied in the plecanatide phase 3 CIC trials. According to the FDA’s summary basis of approval for plecanatide, patient reports of diarrhea were recorded only if the events were considered “bothersome”: “Since an increase in the number of BMs from baseline was an expected pharmacodynamic eff ect of plecanatide and would be coded as diarrhea, sites were instructed to only record an AE of diarrhea if the patient reports that it was bothersome [e.g., watery/ mushy stool (Bristol Stool Form Scale [BSFS] score of 6 or 7), with a sense of urgency, etc.] or if the event required treatment or hospitalization.” ( 3 ) Th is description of the methodology used for diarrhea AE collection is not completely clear and raises questions, including: • If the patient reported diarrhea, but did not specify whether it was bothersome, was the patient further questioned about the event, or was it simply not recorded? • If the sites determined bothersomeness, how was this done? • Did a reportable diarrhea event require specifi c BSFS values and/ or a sense of urgency? In the spirit of good scientifi c exchange, we ask the authors to provide, in a response letter for American Journal of Gastroenterology , answers to these questions, as well as the specifi c instructions given to sites for determining which diarrhea events were to be recorded as AEs. If diarrhea and diarrhea-like events deemed “non-bothersome” were collected, the overall (i.e., with and without “bothersomeness”) diarrhea rates should also be provided.

PTH-136 Two years on linaclotide: tolerability and treatment satisfaction in patients with irritable bowel syndrome with constipation with and without diarrhoea

Introduction Linaclotide (LIN) has been shown to improve abdominal pain and stool frequency and was well tolerated in Phase 3 clinical trials of patients (pts) with irritable bowel syndrome with constipation (IBS-C). Here we evaluate the most common LIN adverse event (AE), diarrhoea, and assess tolerability and treatment satisfaction (Tx sat) in IBS-C pts who rolled over (RO) from a Phase 3 trial into a long-term study (LTS) of LIN. Method Pts meeting modified Rome II IBS-C criteria were randomised to oral 290 µg LIN or placebo daily in a 6 month Phase 3 trial. RO pts completed Phase 3 and entered an open-label 18 month LTS. Tx sat (not at all, a little, moderately, quite, very) and AEs, including any reports of diarrhoea, were recorded at all study visits; AE severity was assessed by the investigator based on pt description. In the LTS, pts could interrupt, reduce (145 µg) or withdraw from dosing due to AEs. Tx sat was assessed in pts with and without diarrhoea. Abstract PTH-136 Table 1 Severity of diarrhoea AEs (LTS), n (% of pts with diarrhoea AEs) [N=171] Mild Moderate Severe 80 (46.8) 81 (47.4) 10 (5.8) Results Of 535 IBS-C RO pts in the LTS, 79% had ≥1 AE; 45 pts (8%) withdrew due to an AE; 24 pts (4.5%) reported ≥1 serious AE (SAE). Diarrhoea, the most common AE (171 pts; 32%; 0.29/pt-year), was mostly mild or moderate in severity and led to withdrawal in 18 pts (3%) [Table 1]. There were no diarrhoea-related SAEs. 131 pts (24%) decreased and/or interrupted their LIN dose due to diarrhoea; the majority of these pts continued in the study (Table 2). Pts averaged at least moderate Tx sat; >70% of pts were moderately to very satisfied with LIN treatment regardless of whether they had diarrhoea (figure 1). Abstract PTH136 Figure 1 Conclusion During up to 2 years on LIN, IBS-C pts were moderately to quite satisfied with treatment on average. Diarrhoea AEs were generally mild or moderate in severity and infrequently led to study withdrawal. TX sat was similar in LIN-treated pts who did and did not report diarrhoea. LIN was well tolerated. Disclosure of Interest H. Schneier: None Declared, S Shiff Conflict with: Allergan plc, Conflict with: Allergan plc, X Hao Conflict with: Ironwood Pharmaceuticals, J Chickering Conflict with: Ironwood Pharmaceuticals, Conflict with: Ironwood Pharmaceuticals and Allergan plc, Conflict with: Ironwood Pharmaceuticals, C Kurtz Conflict with: Ironwood Pharmaceuticals, M Currie Conflict with: Ironwood Pharmaceuticals, Conflict with: Ironwood Pharmaceuticals, J Johnston Conflict with: Ironwood Pharmaceuticals, Conflict with: Ironwood Pharmaceuticals

PWE-029 Characterisation and Association of Abdominal Pain With Anxiety or Depression in Patients with Irritable Bowel Syndrome with Constipation (IBS-C): Abstract PWE-029 Table

Introduction The Short-Form McGill Pain Questionnaire (SF-MPQ-2) assesses and characterises pain. It consists of 22 items (rated from 0 = none to 10 = worst possible) in 4 subscales (continuous pain, intermittent pain, neuropathic pain [sensory descriptors], and affective descriptors [emotional aspects of pain, eg cruel/exhausting]). The SF-MPQ-2 has not yet been validated in abdominal pain and, therefore, its use in functional gastrointestinal disorders like IBS is limited. Also, little is known about pain quality in IBS. We used the SF-MPQ-2 to characterise baseline abdominal pain in IBS-C and to determine whether subscale scores were associated with significant baseline anxiety or depression. Methods Over a 2-wk baseline period in 2 Phase 3 trials of linaclotide (LIN), patients (pts) with IBS-C (Rome II criteria; N = 1523) rated daily their worst abdominal pain over the past 24 h on an 11-point scale (0 = none, 10 = very severe) and completed the SF-MPQ-2. Summary statistics were calculated for each SF-MPQ-2 item and subscale. Pts were grouped by their highest-scored pain subscale and the pain subscale reported by the highest % of pts was defined as the predominant pain type. Association of each subscale with baseline abdominal pain score was determined by ANCOVA. Baseline anxiety and depression were assessed on the Hospital Anxiety and Depression Scale (HADS-A and HADS-D); pts were categorised as normal/borderline (0–10) or abnormal (11–21). Association of each subscale with abnormal HADS was analysed by logistic regression. Results Continuous pain was the predominant pain type (77% of pts); the item with the highest average score in this subscale was cramping pain. Baseline abdominal pain score was significantly associated with McGill continuous pain (p < 0.0001), intermittent pain (p = 0.004) and affective descriptors (p = 0.012), but not with neuropathic pain (p = 0.526). Only the affective descriptors subscale was significantly associated with abnormal HADS score (Table). Abstract PWE-029 Table Odds ratio Abnormal HADS Pain subscale Point estimate 95% CI p a HADS-A Continuous 1.04 0.96, 1.13 0.35 Intermittent 0.96 0.89, 1.04 0.33 Neuropathic 1.00 0.92, 1.09 0.99 Affective descriptors 1.15 1.07, 1.23 < 0.0001 HADS-D Continuous 1.11 0.94, 1.30 0.23 Intermittent 0.92 0.80, 1.05 0.21 Neuropathic 1.12 0.97, 1.29 0.12 Affective descriptors 1.24 1.10, 1.41 < 0.001 aWald χ2 test Conclusion These data indicate that continuous pain is predominant in IBS-C and that anxiety and depression are related to the emotional response to pain, not to pain itself. Support: Ironwood Pharmaceuticals Inc & Forest Laboratories Inc. Editing: CMC funded by Almirall Disclosure of Interest E. Quigley Speaker bureau with: Danone, Janssen, Procter and Gamble, sanofi-aventis, Shire and Yakult, Conflict with: Advisory boards for Almirall, Ironwood, Janssen, Norgine, Salix and Shire/Movetis, B. Lavins Shareholder of: Ironwood Pharmaceuticals, Employee of: Ironwood Pharmaceuticals, S. Shiff Shareholder of: Forest Laboratories, Employee of: Forest Laboratories, K. Shi Employee of: Forest Laboratories, X. Hao Shareholder of: Ironwood Pharmaceuticals, Employee of: Ironwood Pharmaceuticals, C. Kurtz Shareholder of: Ironwood Pharmaceuticals, Employee of: Ironwood Pharmaceuticals, M. Currie Shareholder of: Ironwood Pharmaceuticals, Employee of: Ironwood Pharmaceuticals, H. Schneier Shareholder of: Forest Laboratories, Employee of: Forest Laboratories, J. Johnston Shareholder of: Ironwood Pharmaceuticals, Employee of: Ironwood Pharmaceuticals