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Jeffrey M Johnston - One of the best experts on this subject based on the ideXlab platform.

  • safety and tolerability of Linaclotide for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation pooled phase 3 analysis
    Expert Review of Gastroenterology & Hepatology, 2019
    Co-Authors: Judy Nee, S J Shiff, Jeffrey M Johnston, Elizabeth P Shea, Courtney E Walls, Kenneth Tripp, Susan M Fox, Wieslaw Bochenek, Darren Weissman, Mark G Currie
    Abstract:

    ABSTRACTBackground: Linaclotide is approved for treating irritable bowel syndrome with constipation (IBS-C; 290 µg QD) and chronic idiopathic constipation (CIC; 145 µg or 72 µg QD). These analyses aimed to assess Linaclotide safety in a large, pooled Phase 3 population.Methods: In six randomized controlled trials (RCTs), patients received Linaclotide (72 µg, 145 µg, 290 µg) or placebo daily for 12–26 weeks; in two long-term safety (LTS) studies, patients received open-label Linaclotide for ≤78 additional weeks. Laboratory values, vital signs, and treatment-emergent adverse events (TEAEs) were assessed.Results: Overall, 3853 patients received ≥1 dose of Linaclotide. The most common TEAE was diarrhea (majority [90.5% in RCTs] mild/moderate). Linaclotide patients experienced 1.1 diarrhea TEAE per patient-year in the RCTs (0.2 in placebo), and 0.3 in the LTS studies. In RCTs, 6.9% Linaclotide and 3.0% placebo patients discontinued due to any adverse event (AE); 4.0% Linaclotide and 0.3% placebo patients disco...

  • Safety and tolerability of Linaclotide for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation: pooled Phase 3 analysis
    2019
    Co-Authors: Judy W. Nee, S J Shiff, Jeffrey M Johnston, Elizabeth P Shea, Courtney E Walls, Kenneth Tripp, Susan M Fox, Wieslaw Bochenek, Darren Weissman, Mark G Currie
    Abstract:

    Background: Linaclotide is approved for treating irritable bowel syndrome with constipation (IBS-C; 290 µg QD) and chronic idiopathic constipation (CIC; 145 µg or 72 µg QD). These analyses aimed to assess Linaclotide safety in a large, pooled Phase 3 population. Methods: In six randomized controlled trials (RCTs), patients received Linaclotide (72 µg, 145 µg, 290 µg) or placebo daily for 12–26 weeks; in two long-term safety (LTS) studies, patients received open-label Linaclotide for ≤78 additional weeks. Laboratory values, vital signs, and treatment-emergent adverse events (TEAEs) were assessed. Results: Overall, 3853 patients received ≥1 dose of Linaclotide. The most common TEAE was diarrhea (majority [90.5% in RCTs] mild/moderate). Linaclotide patients experienced 1.1 diarrhea TEAE per patient-year in the RCTs (0.2 in placebo), and 0.3 in the LTS studies. In RCTs, 6.9% Linaclotide and 3.0% placebo patients discontinued due to any adverse event (AE); 4.0% Linaclotide and 0.3% placebo patients discontinued due to diarrhea. In LTS studies, 9.4% patients discontinued due to any AE, and 3.8% due to diarrhea. Serious AEs (SAEs) were rare and similar across treatment groups; there were no SAEs of diarrhea. Conclusion: These pooled analyses of patients treated for ≤104 weeks confirm Linaclotide’s overall safety.

  • high dose Linaclotide is effective and safe in patients with chronic constipation a phase iii randomized double blind placebo controlled study with a long term open label extension study in japan
    Neurogastroenterology and Motility, 2019
    Co-Authors: Shin Fukudo, Jeffrey M Johnston, Hiroto Miwa, Atsushi Nakajima, Yoshikazu Kinoshita, Masanori Kosako, Kenta Hayashi, Hiraku Akiho, Kentaro Kuroishi, Mark G Currie
    Abstract:

    BACKGROUND A previous phase II dose-ranging study of Linaclotide in a Japanese chronic constipation (CC) population showed that 0.5 mg was the most effective dose. This study aimed to verify the hypothesis that 0.5 mg of Linaclotide is effective and safe in Japanese CC patients. METHODS This was a Japanese phase III randomized, double-blind, placebo-controlled (part 1), and long-term, open-label extension (part 2) study of Linaclotide. CC patients (n = 186) diagnosed using the Rome III criteria were randomly assigned to Linaclotide 0.5 mg (n = 95) or placebo (n = 91) for a 4-week double-blind treatment period in part 1, followed by an additional 52 weeks of open-label treatment with Linaclotide in part 2. The primary efficacy endpoint was the change from baseline in weekly spontaneous bowel movement (SBM) frequency at the first week. Secondary endpoints included responder rate for complete SBM (CSBM), changes in stool consistency, and severity of straining. KEY RESULTS Part 1: Change in weekly mean SBM frequency in the first week of treatment with Linaclotide (4.02) was significantly greater than that with placebo (1.48, P < 0.001). Linaclotide produced a higher CSBM responder rate (52.7%) compared to placebo (26.1%, P < 0.001). Part 2: Patients continued to show improved SBM frequency with Linaclotide. Through parts 1 and 2, the most common drug-related adverse event was mild and occasionally moderate diarrhea. CONCLUSIONS AND INFERENCES The results of this study indicate that a Linaclotide dose of 0.5 mg/day is effective and safe in Japanese CC patients.

  • a randomized controlled and long term Linaclotide study of irritable bowel syndrome with constipation patients in japan
    Neurogastroenterology and Motility, 2018
    Co-Authors: Shin Fukudo, Jeffrey M Johnston, Hiroto Miwa, Atsushi Nakajima, Masanori Kosako, Hiraku Akiho, Ken Haruma, Ayako Nakagawa, Yusuke Yamaguchi, Mark G Currie
    Abstract:

    BACKGROUND Clinical testing was required to verify the effect of Linaclotide 0.5 mg/d in patients with irritable bowel syndrome with constipation (IBS-C) in Japan. METHODS This was a randomized, double-blind, placebo-controlled (Part 1) and long-term, open-label extension (Part 2) study of Linaclotide at 60 hospitals and clinics in Japan. Patients with IBS-C diagnosed using Rome III criteria (n = 500) were randomly assigned to Linaclotide 0.5 mg (n = 249) or placebo (n = 251) for a 12-week treatment period followed by open-label treatment with Linaclotide (n = 324) for an additional 40 weeks. The primary endpoints were the responder rate of global improvement of IBS symptoms and complete spontaneous bowel movement (CSBM) during 12 weeks. The secondary endpoints included responder rates of SBM and abdominal pain/discomfort relief. KEY RESULTS Part 1: The responder rates for global improvement and for CSBM frequency were significantly higher for Linaclotide compared to placebo (P < 0.001). Secondary endpoints including responder rates for SBM and abdominal pain/discomfort relief in the Linaclotide group were also significantly greater than those in the placebo group. Part 2: Patients switched from placebo to Linaclotide showed similar responder rates for global improvement and CSBM frequency to those in patients who continued to receive Linaclotide, supporting sustained efficacy. Diarrhea was seen in 14.5% of patients; all cases were mild or moderate. CONCLUSIONS AND INFERENCES This study suggests that a Linaclotide dose of 0.5 mg is effective and safe for IBS-C patients in Japan.

  • dose finding study of Linaclotide in japanese patients with chronic constipation a phase ii randomized double blind and placebo controlled study
    Neurogastroenterology and Motility, 2018
    Co-Authors: Shin Fukudo, Jeffrey M Johnston, Hiroto Miwa, Atsushi Nakajima, Yoshikazu Kinoshita, Masanori Kosako, Hiraku Akiho, Kentaro Kuroishi, Ayako Nakagawa, Mark G Currie
    Abstract:

    BACKGROUND Based on the previous phase II/III studies of irritable bowel syndrome with constipation (IBS-C) in Japan that demonstrated the efficacy and safety of Linaclotide 0.5 mg/d, we evaluated Linaclotide at doses of 0.5 mg/d and lower in the treatment of Japanese patients with chronic constipation (CC). METHODS This was a phase II randomized, double-blind, placebo-controlled, dose-finding study of Linaclotide for Japanese patients with CC (n = 382, 64 men, 318 women, age 20-75). After a baseline period of two weeks, patients were randomized to receive placebo (n = 80), or 0.0625 mg (n = 82), 0.125 mg (n = 71), 0.25 mg (n = 73) or 0.5 mg (n = 76) of Linaclotide during a two-week treatment period. The primary efficacy endpoint was change from baseline in weekly spontaneous bowel movement (SBM) frequency during the first week. Secondary endpoints included complete SBM (CSBM) responder rates and IBS-QOL. Safety and adverse events were also evaluated. KEY RESULTS The change in SBM frequency during the first week (mean) was 3.89, 3.11, 3.87, and 3.85 for 0.0625 mg, 0.125 mg, 0.25 mg, and 0.5 mg for Linaclotide, significantly higher than for placebo (1.91, P < 0.05). The CSBM responder, which is an important parameter, showed the greatest improvement at the 0.5 mg during the 2 week. The most frequent adverse event in the Linaclotide groups was diarrhea. CONCLUSIONS & INFERENCES Our results suggest that 0.0625, 0.125, 0.25, and 0.5 mg/d are effective doses of Linaclotide for treating CC in Japanese patients. ClinicalTrials.gov: NCT02425722, supported by Astellas Pharma, Inc.

Mark G Currie - One of the best experts on this subject based on the ideXlab platform.

  • safety and tolerability of Linaclotide for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation pooled phase 3 analysis
    Expert Review of Gastroenterology & Hepatology, 2019
    Co-Authors: Judy Nee, S J Shiff, Jeffrey M Johnston, Elizabeth P Shea, Courtney E Walls, Kenneth Tripp, Susan M Fox, Wieslaw Bochenek, Darren Weissman, Mark G Currie
    Abstract:

    ABSTRACTBackground: Linaclotide is approved for treating irritable bowel syndrome with constipation (IBS-C; 290 µg QD) and chronic idiopathic constipation (CIC; 145 µg or 72 µg QD). These analyses aimed to assess Linaclotide safety in a large, pooled Phase 3 population.Methods: In six randomized controlled trials (RCTs), patients received Linaclotide (72 µg, 145 µg, 290 µg) or placebo daily for 12–26 weeks; in two long-term safety (LTS) studies, patients received open-label Linaclotide for ≤78 additional weeks. Laboratory values, vital signs, and treatment-emergent adverse events (TEAEs) were assessed.Results: Overall, 3853 patients received ≥1 dose of Linaclotide. The most common TEAE was diarrhea (majority [90.5% in RCTs] mild/moderate). Linaclotide patients experienced 1.1 diarrhea TEAE per patient-year in the RCTs (0.2 in placebo), and 0.3 in the LTS studies. In RCTs, 6.9% Linaclotide and 3.0% placebo patients discontinued due to any adverse event (AE); 4.0% Linaclotide and 0.3% placebo patients disco...

  • Safety and tolerability of Linaclotide for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation: pooled Phase 3 analysis
    2019
    Co-Authors: Judy W. Nee, S J Shiff, Jeffrey M Johnston, Elizabeth P Shea, Courtney E Walls, Kenneth Tripp, Susan M Fox, Wieslaw Bochenek, Darren Weissman, Mark G Currie
    Abstract:

    Background: Linaclotide is approved for treating irritable bowel syndrome with constipation (IBS-C; 290 µg QD) and chronic idiopathic constipation (CIC; 145 µg or 72 µg QD). These analyses aimed to assess Linaclotide safety in a large, pooled Phase 3 population. Methods: In six randomized controlled trials (RCTs), patients received Linaclotide (72 µg, 145 µg, 290 µg) or placebo daily for 12–26 weeks; in two long-term safety (LTS) studies, patients received open-label Linaclotide for ≤78 additional weeks. Laboratory values, vital signs, and treatment-emergent adverse events (TEAEs) were assessed. Results: Overall, 3853 patients received ≥1 dose of Linaclotide. The most common TEAE was diarrhea (majority [90.5% in RCTs] mild/moderate). Linaclotide patients experienced 1.1 diarrhea TEAE per patient-year in the RCTs (0.2 in placebo), and 0.3 in the LTS studies. In RCTs, 6.9% Linaclotide and 3.0% placebo patients discontinued due to any adverse event (AE); 4.0% Linaclotide and 0.3% placebo patients discontinued due to diarrhea. In LTS studies, 9.4% patients discontinued due to any AE, and 3.8% due to diarrhea. Serious AEs (SAEs) were rare and similar across treatment groups; there were no SAEs of diarrhea. Conclusion: These pooled analyses of patients treated for ≤104 weeks confirm Linaclotide’s overall safety.

  • high dose Linaclotide is effective and safe in patients with chronic constipation a phase iii randomized double blind placebo controlled study with a long term open label extension study in japan
    Neurogastroenterology and Motility, 2019
    Co-Authors: Shin Fukudo, Jeffrey M Johnston, Hiroto Miwa, Atsushi Nakajima, Yoshikazu Kinoshita, Masanori Kosako, Kenta Hayashi, Hiraku Akiho, Kentaro Kuroishi, Mark G Currie
    Abstract:

    BACKGROUND A previous phase II dose-ranging study of Linaclotide in a Japanese chronic constipation (CC) population showed that 0.5 mg was the most effective dose. This study aimed to verify the hypothesis that 0.5 mg of Linaclotide is effective and safe in Japanese CC patients. METHODS This was a Japanese phase III randomized, double-blind, placebo-controlled (part 1), and long-term, open-label extension (part 2) study of Linaclotide. CC patients (n = 186) diagnosed using the Rome III criteria were randomly assigned to Linaclotide 0.5 mg (n = 95) or placebo (n = 91) for a 4-week double-blind treatment period in part 1, followed by an additional 52 weeks of open-label treatment with Linaclotide in part 2. The primary efficacy endpoint was the change from baseline in weekly spontaneous bowel movement (SBM) frequency at the first week. Secondary endpoints included responder rate for complete SBM (CSBM), changes in stool consistency, and severity of straining. KEY RESULTS Part 1: Change in weekly mean SBM frequency in the first week of treatment with Linaclotide (4.02) was significantly greater than that with placebo (1.48, P < 0.001). Linaclotide produced a higher CSBM responder rate (52.7%) compared to placebo (26.1%, P < 0.001). Part 2: Patients continued to show improved SBM frequency with Linaclotide. Through parts 1 and 2, the most common drug-related adverse event was mild and occasionally moderate diarrhea. CONCLUSIONS AND INFERENCES The results of this study indicate that a Linaclotide dose of 0.5 mg/day is effective and safe in Japanese CC patients.

  • a randomized controlled and long term Linaclotide study of irritable bowel syndrome with constipation patients in japan
    Neurogastroenterology and Motility, 2018
    Co-Authors: Shin Fukudo, Jeffrey M Johnston, Hiroto Miwa, Atsushi Nakajima, Masanori Kosako, Hiraku Akiho, Ken Haruma, Ayako Nakagawa, Yusuke Yamaguchi, Mark G Currie
    Abstract:

    BACKGROUND Clinical testing was required to verify the effect of Linaclotide 0.5 mg/d in patients with irritable bowel syndrome with constipation (IBS-C) in Japan. METHODS This was a randomized, double-blind, placebo-controlled (Part 1) and long-term, open-label extension (Part 2) study of Linaclotide at 60 hospitals and clinics in Japan. Patients with IBS-C diagnosed using Rome III criteria (n = 500) were randomly assigned to Linaclotide 0.5 mg (n = 249) or placebo (n = 251) for a 12-week treatment period followed by open-label treatment with Linaclotide (n = 324) for an additional 40 weeks. The primary endpoints were the responder rate of global improvement of IBS symptoms and complete spontaneous bowel movement (CSBM) during 12 weeks. The secondary endpoints included responder rates of SBM and abdominal pain/discomfort relief. KEY RESULTS Part 1: The responder rates for global improvement and for CSBM frequency were significantly higher for Linaclotide compared to placebo (P < 0.001). Secondary endpoints including responder rates for SBM and abdominal pain/discomfort relief in the Linaclotide group were also significantly greater than those in the placebo group. Part 2: Patients switched from placebo to Linaclotide showed similar responder rates for global improvement and CSBM frequency to those in patients who continued to receive Linaclotide, supporting sustained efficacy. Diarrhea was seen in 14.5% of patients; all cases were mild or moderate. CONCLUSIONS AND INFERENCES This study suggests that a Linaclotide dose of 0.5 mg is effective and safe for IBS-C patients in Japan.

  • dose finding study of Linaclotide in japanese patients with chronic constipation a phase ii randomized double blind and placebo controlled study
    Neurogastroenterology and Motility, 2018
    Co-Authors: Shin Fukudo, Jeffrey M Johnston, Hiroto Miwa, Atsushi Nakajima, Yoshikazu Kinoshita, Masanori Kosako, Hiraku Akiho, Kentaro Kuroishi, Ayako Nakagawa, Mark G Currie
    Abstract:

    BACKGROUND Based on the previous phase II/III studies of irritable bowel syndrome with constipation (IBS-C) in Japan that demonstrated the efficacy and safety of Linaclotide 0.5 mg/d, we evaluated Linaclotide at doses of 0.5 mg/d and lower in the treatment of Japanese patients with chronic constipation (CC). METHODS This was a phase II randomized, double-blind, placebo-controlled, dose-finding study of Linaclotide for Japanese patients with CC (n = 382, 64 men, 318 women, age 20-75). After a baseline period of two weeks, patients were randomized to receive placebo (n = 80), or 0.0625 mg (n = 82), 0.125 mg (n = 71), 0.25 mg (n = 73) or 0.5 mg (n = 76) of Linaclotide during a two-week treatment period. The primary efficacy endpoint was change from baseline in weekly spontaneous bowel movement (SBM) frequency during the first week. Secondary endpoints included complete SBM (CSBM) responder rates and IBS-QOL. Safety and adverse events were also evaluated. KEY RESULTS The change in SBM frequency during the first week (mean) was 3.89, 3.11, 3.87, and 3.85 for 0.0625 mg, 0.125 mg, 0.25 mg, and 0.5 mg for Linaclotide, significantly higher than for placebo (1.91, P < 0.05). The CSBM responder, which is an important parameter, showed the greatest improvement at the 0.5 mg during the 2 week. The most frequent adverse event in the Linaclotide groups was diarrhea. CONCLUSIONS & INFERENCES Our results suggest that 0.0625, 0.125, 0.25, and 0.5 mg/d are effective doses of Linaclotide for treating CC in Japanese patients. ClinicalTrials.gov: NCT02425722, supported by Astellas Pharma, Inc.

Caroline B Kurtz - One of the best experts on this subject based on the ideXlab platform.

  • low dose Linaclotide 72 μg for chronic idiopathic constipation a 12 week randomized double blind placebo controlled trial
    The American Journal of Gastroenterology, 2018
    Co-Authors: Philip Schoenfeld, William D Chey, Mark G Currie, Caroline B Kurtz, Kenneth Tripp, Wieslaw Bochenek, David S Reasner, Anthony Lembo, Brian E Lacy, Susan M Fox
    Abstract:

    Low-Dose Linaclotide (72 μg) for Chronic Idiopathic Constipation: A 12-Week, Randomized, Double-Blind, Placebo-Controlled Trial

  • pwe 166 is response to Linaclotide after 4 weeks of treatment predictive of 12 week improvement
    Gut, 2014
    Co-Authors: William D Chey, Caroline B Kurtz, Bernard J Lavins, James E Macdougall, M Currie, S J Shiff, Jeffrey M Johnston
    Abstract:

    Introduction Linaclotide is a minimally absorbed guanylate cyclase C agonist approved in the US and EU for irritable bowel syndrome with constipation (IBS-C). A question for prescribing physicians is whether to continue Linaclotide in patients who do not improve during the early weeks of therapy. This post-hoc analysis assessed if response to Linaclotide at Week 4 predicts Week 12 improvement, and if Linaclotide should be continued in IBS-C patients not responding by Week 4. Methods Pooled data from 2 Phase 3 IBS-C trials of Linaclotide were analysed. For Degree of Relief of IBS Symptoms, Degree of Relief of Abdominal Pain, and Spontaneous Bowel Movement [SBM] frequency, a patient’s Week-4 clinical response was used to predict improvement at Week 12. For the purposes of determining a patient’s Week-4 response, the 7-point balanced Degree of Relief scale was collapsed into 3 categories: Improved (completely, considerably, or somewhat relieved), Unchanged, and Worse (somewhat worse, considerably worse, or as bad as I can imagine) compared with baseline. For SBM frequency, a dichotomous end point was used: SBMs increased by ≥2/week or not increased by ≥2/week from baseline. Results The proportion of patients who had response at Week 4 was significantly greater for Linaclotide- vs placebo-treated patients: 72 vs. 47% for Degree of Relief of IBS Symptoms, 70 vs. 47% for Degree of Relief of Abdominal Pain, and 59% vs 33% for SBM frequency (all comparisons: p Conclusion Patients whose IBS symptoms improved after 4 weeks with Linaclotide were likely to maintain improvement. At least 30% of Linaclotide patients who were unchanged at Week 4 experienced symptom improvement by Week 12. The significant differences between Linaclotide and placebo in the percentage of patients improved at Week 12 who were unchanged at Week 4 indicates that in some patients ≥1 month of Linaclotide therapy may be required for improvement. Hence, an initial course of Linaclotide therapy in patients with IBS-C shou.ld be >4 weeks. Study funded by Forest Laboratories, Inc., and Ironwood Pharmaceuticals, Inc. Disclosure of Interest W. Chey Consultant for: Ironwood Pharmaceuticals, Forest Research Institute, B. Lavins Shareholder of: Ironwood Pharmaceuticals, Employee of: Ironwood Pharmaceuticals, S. Shiff Shareholder of: Forest Research Institute, Employee of: Forest Research Institute, J. MacDougall 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, J. Johnston Shareholder of: Ironwood Pharmaceuticals, Employee of: Ironwood Pharmaceuticals.

  • effect of Linaclotide on severe abdominal symptoms in patients with irritable bowel syndrome with constipation
    Clinical Gastroenterology and Hepatology, 2014
    Co-Authors: Satish S C Rao, Eamonn Martin Quigley, Mark G Currie, Caroline B Kurtz, Bernard J Lavins, James E Macdougall, S J Shiff, Jeffrey M Johnston
    Abstract:

    BACKGROUND & AIMS: Patients with irritable bowel syndrome with constipation (IBS-C) have abdominal symptoms that vary in severity. Linaclotide, a guanylate cyclase-C agonist, improves abdominal and bowel symptoms in these patients. We examined the prevalence of severe abdominal symptoms in patients with IBS-C and assessed the effects of Linaclotide on abdominal symptoms, global measures, and quality of life (QOL). METHODS: In two phase 3 trials, patients who met modified Rome II criteria for IBS-C were randomly assigned to groups given oral, once-daily Linaclotide (290 mg) or placebo for 12 weeks. During the baseline (2 weeks prior to treatment) and treatment periods, patients rated abdominal pain, discomfort, bloating, fullness, and cramping daily (from 0 [ none to 10 [ very severe). Linaclotide’s effects on abdominal symptoms, global measures, and IBS-related QOL were assessed in subpopulations of patients who rated specific individual abdominal symptoms as severe (‡7.0) at baseline. RESULTS: In the intent-to-treat population (1602 patients; 797 receiving placebo and 805 receiving Linaclotide), baseline prevalence values for severe abdominal symptoms were 44% for bloating, 44% for fullness, 32% for discomfort, 23% for pain, and 22% for cramping, with considerable overlap among symptoms. In patients with severe symptoms, Linaclotide reduced all abdominal symptoms; mean changes from baseline severity scores ranged from –2.7 to –3.4 for Linaclotide vs –1.4 to –1.9 for placebo (P < .0001). Linaclotide improved global measures (P < .0001) and IBS-QOL scores (P < .01) compared with placebo. Diarrhea was the most common adverse event of Linaclotide in patients with severe abdominal symptoms (18.8%–21.0%). CONCLUSIONS: Of 5 severe abdominal symptoms assessed, bloating and fullness were most prevalent in patients with IBS-C. Linaclotide significantly improved all abdominal symptoms, global measures, and IBS-QOL in subpopulations of IBS-C patients with severe abdominal symptoms. Clinicaltrials.gov Numbers: NCT00938717, NCT00948818.

  • responders vs clinical response a critical analysis of data from Linaclotide phase 3 clinical trials in ibs c
    Neurogastroenterology and Motility, 2014
    Co-Authors: Brian E Lacy, S J Shiff, Caroline B Kurtz, James E Macdougall, Anthony Lembo, M Currie, Jeffrey M Johnston
    Abstract:

    Background US Food and Drug Administration (FDA) set a rigorous standard for defining patient responders in irritable bowel syndrome-C (IBS-C; i.e., FDA's Responder Endpoint) for regulatory approval. However, this endpoint's utility for health-care practitioners to assess clinical response has not been determined. We analyzed pooled IBS-C Linaclotide trial data to evaluate clinically significant responses in Linaclotide-treated patients who did not meet the FDA responder definition. Methods Percentages of FDA non-responders reporting improvement in abdominal pain, bowel function and/or global relief measures were determined using pooled data from two Linaclotide Phase 3 IBS-C trials. Key Results 1602 IBS-C patients enrolled; 34% of Linaclotide-treated and 17% of placebo-treated patients met the FDA Responder Endpoint (p < 0.0001). Among FDA non-responders at week 12, 63% of Linaclotide-treated patients reported their abdominal pain was at least somewhat relieved, compared with 48% of placebo-treated patients. For stool frequency, 62% of Linaclotide-treated patients reported that they were at least somewhat improved at week 12, compared with 46% of placebo-treated patients. For global IBS symptoms, 65% of Linaclotide-treated patients reported at least some IBS-symptom relief, 43% reported adequate relief of IBS symptoms, and 57% reported being satisfied with Linaclotide treatment, vs placebo rates of 48%, 34%, and 41% respectively. Conclusions & Inferences Most Linaclotide-treated IBS-C patients who were FDA non-responders reported some improvement in abdominal pain and stool frequency, and global relief/satisfaction. In addition to the FDA Responder Endpoint, differing response thresholds and symptom-specific change from baseline should be considered by clinicians for a complete understanding of clinical response to Linaclotide and other IBS-C therapies.

  • Guanylate cyclase-C/cGMP: an emerging pathway in the regulation of visceral pain
    Frontiers Media S.A., 2014
    Co-Authors: Gerhard Ehannig, Alexander P Bryant, Mark G Currie, Boris Etchernychev, Caroline B Kurtz, Inmaculada Esilos-santiago
    Abstract:

    Activation of guanylate cyclase-C (GC-C) expressed predominantly on intestinal epithelial cells by guanylin, uroguanylin or the closely related GC-C agonist peptide, Linaclotide, stimulates generation and release of cyclic guanosine-3’,5’-monophosphate (cGMP). Evidence that the visceral analgesic effects of Linaclotide are mediated by a novel, GC-C-dependent peripheral sensory mechanism was first demonstrated in animal models of visceral pain. Subsequent studies with uroguanylin or Linaclotide have confirmed the activation of a GC-C/cGMP pathway leading to increased submucosal cGMP mediated by cGMP efflux pumps, which modulates intestinal nociceptor function resulting in peripheral analgesia. These effects can be reproduced by the addition of exogenous cGMP and support a role for GC-C/cGMP signaling in the regulation of visceral sensation, a physiological function that has not previously been linked to the GC-C/cGMP pathway. Notably, targeting the GC-C/cGMP pathway for treatment of gastrointestinal pain and abdominal sensory symptoms has now been validated in the clinic. In 2012, Linaclotide was approved in the United States and European Union for the treatment of adult patients with irritable bowel syndrome with constipation

Susan M Fox - One of the best experts on this subject based on the ideXlab platform.

  • efficacy of Linaclotide in reducing abdominal symptoms of bloating discomfort and pain a phase 3b trial using a novel abdominal scoring system
    The American Journal of Gastroenterology, 2021
    Co-Authors: Lin Chang, Wilmin Bartolini, Wieslaw Bochenek, Brian E Lacy, Baha Moshiree, Amy Kassebaum, Jessica L Abel, Jennifer Hanlon, Ramesh Boinpally, Susan M Fox
    Abstract:

    INTRODUCTION Linaclotide improves abdominal pain and constipation in patients with constipation-predominant irritable bowel syndrome (IBS-C). Patients report additional bothersome abdominal symptoms of bloating and discomfort. The intention of this study was to evaluate Linaclotide's efficacy in relieving IBS-C-related abdominal symptoms (bloating, discomfort, and pain) using a novel multi-item Abdominal Score (AS). METHODS Patients with IBS-C with abdominal pain ≥3 (0-10 scale) were randomized to Linaclotide 290 μg or placebo daily for 12 weeks. The AS, derived from the Diary for IBS Symptoms-Constipation, is the average of abdominal bloating, discomfort, and pain at their worst (0 = none, 10 = worst possible). The primary end point was overall change from baseline (CFB) in AS. Secondary end points included CFB in 12-week AS evaluated using cumulative distribution function and 6-week/12-week AS responder (AS improvement ≥2 points for ≥6-week/12-week). RESULTS Overall, 614 patients (mean age 46.7 years; 81% female) were randomized. All prespecified end points showed significant benefit of Linaclotide vs placebo. The mean overall CFB AS reduction for Linaclotide was -1.9 vs -1.2 for placebo (P < 0.0001); the 6-week/12-week AS responder rate was 40.5% for Linaclotide vs 23.4% for placebo (odds ratio = 2.2 [95% confidence interval, 1.55-3.12; P < 0.0001]). Diarrhea was the most common treatment-emergent adverse event (Linaclotide = 4.6%, placebo = 1.6%). DISCUSSION Linaclotide significantly reduced multiple abdominal symptoms important to patients with IBS-C (bloating, discomfort, and pain) compared with placebo, as measured by a novel multi-item AS. The AS, derived from the Diary for IBS Symptoms-Constipation, should be considered for use in future IBS-C clinical studies to measure clinically meaningful improvements beyond traditional end points.

  • randomized trial of 2 delayed release formulations of Linaclotide in patients with irritable bowel syndrome with constipation
    The American Journal of Gastroenterology, 2021
    Co-Authors: William D Chey, Wilmin Bartolini, Elizabeth P Shea, Kenneth Tripp, Susan M Fox, Wieslaw Bochenek, David S Reasner, Ramesh Boinpally, Gregory S Sayuk, Niels Borgstein
    Abstract:

    Introduction Immediate-release (IR) formulation of Linaclotide 290 μg improves abdominal pain and constipation (APC) in patients with irritable bowel syndrome (IBS) with constipation. Delayed-release (DR) formulations were developed on the premise that targeting the ileum (delayed-release formulation 1 [DR1]) or ileocecal junction and cecum (MD-7246, formerly DR2) would modulate Linaclotide's secretory effects while preserving pain relief effects. Methods This phase 2b study randomized patients with IBS with constipation to placebo or 1 of 7 once-daily Linaclotide doses (DR1 30, 100, or 300 μg; MD-7246 30, 100, or 300 μg; or IR 290 μg) for 12 weeks. Key efficacy endpoints were change from baseline in abdominal pain and complete spontaneous bowel movement frequency, and 6/12-week combined APC+1 responder rate. Results Overall, 532 patients were randomized; mean age was 45.1 years, and most were women (83.3%) and White (64.7%). All Linaclotide DR1 and MD-7246 groups experienced greater improvements in abdominal pain from baseline and vs placebo throughout treatment. Linaclotide DR1 and IR led to numerically greater improvements from baseline in complete spontaneous bowel movement frequency and higher APC+1 responder rates compared with placebo; MD-7246 results were similar to placebo. Diarrhea was the most common adverse event with DR1 and IR; rates were similar between MD-7246 and placebo. Discussion Altering the site of drug delivery in the intestine might uncouple Linaclotide's pain relief from secretory effects. Persistent, modest abdominal pain improvement with limited impact on bowel symptom parameters, as seen across MD-7246 doses, warrants further study of MD-7246 as a novel treatment for abdominal pain, regardless of IBS subtype.

  • efficacy and safety of Linaclotide for opioid induced constipation in patients with chronic noncancer pain syndromes from a phase 2 randomized study
    Pain, 2020
    Co-Authors: Darren M Brenner, Susan M Fox, Wieslaw Bochenek, Charles Argoff, Patricia Dʼastoli, Rick E Blakesley, David S Reasner, Christopher R Oʼdea, Brooks D Cash
    Abstract:

    Constipation is the most common adverse event (AE) of opioid therapy. This multicenter, phase 2 study evaluated the efficacy and safety of Linaclotide in treating opioid-induced constipation (OIC) in patients with chronic noncancer pain syndromes (NCT02270983). Adults with OIC (<3 spontaneous bowel movements [SBMs]/week) related to chronic noncancer pain were randomized 1:1:1 to receive Linaclotide 145 µg, Linaclotide 290 µg, or placebo once daily for 8 weeks. The primary endpoint was change from baseline in 8-week SBM frequency rate (SBMs/week). Secondary efficacy endpoints included 6/8-week SBM 3 + 1 responders, time to first SBM, and changes from baseline in 8-week stool consistency, abdominal bloating, and straining. Additional endpoints included treatment satisfaction and adequate relief responders. In total, 254 patients were randomized: 87, 88, and 79 received Linaclotide 145 µg, Linaclotide 290 µg, and placebo, respectively. The mean changes from baseline in SBMs/week during the treatment period were 2.9 and 3.5 in the Linaclotide 145 and 290 µg groups (P < 0.01 for both doses), respectively, vs 1.6 in the placebo group. Diarrhea, the most common AE, was generally mild, resulting in 1.1%, 5.7%, and 1.3% of patients discontinuing in the Linaclotide 145 μg, Linaclotide 290 μg, and placebo groups, respectively. No serious AEs related to diarrhea were reported in any treatment group. Compared with placebo, Linaclotide-treated patients had significant improvements in stool consistency, straining, abdominal bloating, and treatment satisfaction scores (P < 0.05). Linaclotide significantly improved OIC symptoms and was well tolerated in patients with chronic noncancer pain.

  • safety and tolerability of Linaclotide for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation pooled phase 3 analysis
    Expert Review of Gastroenterology & Hepatology, 2019
    Co-Authors: Judy Nee, S J Shiff, Jeffrey M Johnston, Elizabeth P Shea, Courtney E Walls, Kenneth Tripp, Susan M Fox, Wieslaw Bochenek, Darren Weissman, Mark G Currie
    Abstract:

    ABSTRACTBackground: Linaclotide is approved for treating irritable bowel syndrome with constipation (IBS-C; 290 µg QD) and chronic idiopathic constipation (CIC; 145 µg or 72 µg QD). These analyses aimed to assess Linaclotide safety in a large, pooled Phase 3 population.Methods: In six randomized controlled trials (RCTs), patients received Linaclotide (72 µg, 145 µg, 290 µg) or placebo daily for 12–26 weeks; in two long-term safety (LTS) studies, patients received open-label Linaclotide for ≤78 additional weeks. Laboratory values, vital signs, and treatment-emergent adverse events (TEAEs) were assessed.Results: Overall, 3853 patients received ≥1 dose of Linaclotide. The most common TEAE was diarrhea (majority [90.5% in RCTs] mild/moderate). Linaclotide patients experienced 1.1 diarrhea TEAE per patient-year in the RCTs (0.2 in placebo), and 0.3 in the LTS studies. In RCTs, 6.9% Linaclotide and 3.0% placebo patients discontinued due to any adverse event (AE); 4.0% Linaclotide and 0.3% placebo patients disco...

  • Safety and tolerability of Linaclotide for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation: pooled Phase 3 analysis
    2019
    Co-Authors: Judy W. Nee, S J Shiff, Jeffrey M Johnston, Elizabeth P Shea, Courtney E Walls, Kenneth Tripp, Susan M Fox, Wieslaw Bochenek, Darren Weissman, Mark G Currie
    Abstract:

    Background: Linaclotide is approved for treating irritable bowel syndrome with constipation (IBS-C; 290 µg QD) and chronic idiopathic constipation (CIC; 145 µg or 72 µg QD). These analyses aimed to assess Linaclotide safety in a large, pooled Phase 3 population. Methods: In six randomized controlled trials (RCTs), patients received Linaclotide (72 µg, 145 µg, 290 µg) or placebo daily for 12–26 weeks; in two long-term safety (LTS) studies, patients received open-label Linaclotide for ≤78 additional weeks. Laboratory values, vital signs, and treatment-emergent adverse events (TEAEs) were assessed. Results: Overall, 3853 patients received ≥1 dose of Linaclotide. The most common TEAE was diarrhea (majority [90.5% in RCTs] mild/moderate). Linaclotide patients experienced 1.1 diarrhea TEAE per patient-year in the RCTs (0.2 in placebo), and 0.3 in the LTS studies. In RCTs, 6.9% Linaclotide and 3.0% placebo patients discontinued due to any adverse event (AE); 4.0% Linaclotide and 0.3% placebo patients discontinued due to diarrhea. In LTS studies, 9.4% patients discontinued due to any AE, and 3.8% due to diarrhea. Serious AEs (SAEs) were rare and similar across treatment groups; there were no SAEs of diarrhea. Conclusion: These pooled analyses of patients treated for ≤104 weeks confirm Linaclotide’s overall safety.

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  • Linaclotide treatment reduces endometriosis associated vaginal hyperalgesia and mechanical allodynia through viscerovisceral cross talk
    Pain, 2019
    Co-Authors: Jingmei Ren, Joel Castro, Andrea M Harrington, Luke Grundy, Stuart M Brierley, Gerhard Hannig
    Abstract:

    AbstractEndometriosis, an estrogen-dependent chronic inflammatory disease, is the most common cause of chronic pelvic pain. Here, we investigated the effects of Linaclotide, a Food and Drug Administration–approved treatment for IBS-C, in a rat model of endometriosis. Eight weeks after endometrium tr

  • Linaclotide inhibits colonic and urinary bladder hypersensitivity in adult female rats following unpredictable neonatal stress
    Neurogastroenterology and Motility, 2018
    Co-Authors: Casey O Ligon, Gerhard Hannig, Carolyn S Higgins, Ehsan Mohammadi, Greenwoodvan B Meerveld
    Abstract:

    BACKGROUND Irritable bowel syndrome (IBS) and bladder pain syndrome (BPS) are female-predominant, chronic functional pain disorders that are associated with early life stress (ELS) and therapeutic options for such patients remain limited. Linaclotide, a guanylate cyclase-C (GC-C) agonist, relieves abdominal pain and bowel symptoms in adult patients suffering from IBS with constipation. Here, we test the hypothesis that Linaclotide will reverse colon and bladder hyperalgesia in a female-specific rodent model of adverse early life experience. METHODS Neonatal rats were exposed to an odor-attachment learning paradigm of early life stress (ELS). In adulthood, the effect of Linaclotide (3 μg kg-1  d-1 , p.o.) on colonic and bladder sensitivity was assessed via quantification of the visceromotor response to colorectal distension and the frequency of withdrawal responses to the application of von Frey hairs to the suprapubic region. In another cohort of rats, the effect of Linaclotide on ELS-induced colonic and bladder permeability was investigated via measurements of transepithelial electrical resistance (TEER). KEY RESULTS Rats exposed to unpredictable ELS exhibited colonic and bladder hypersensitivity that was significantly reduced by Linaclotide compared to vehicle-treated controls. Colonic and bladder tissue isolated from adult rats exposed to unpredictable ELS exhibited a decrease in colonic and bladder TEER that was reversed by Linaclotide. CONCLUSIONS AND INFERENCES Our results demonstrate that neonatal rats exposed to unpredictable ELS develop increased sensitivity and permeability of the colon and bladder in adulthood through a mechanism involving activation of peripheral GC-C signaling.

  • Linaclotide attenuates visceral organ crosstalk role of guanylate cyclase c activation in reversing bladder colon cross sensitization
    Journal of Pharmacology and Experimental Therapeutics, 2018
    Co-Authors: Ehsan Mohammadi, Gerhard Hannig, Casey O Ligon, Ada Silossantiago, Caroline Kurtz, Carolyn Higgins, Beverley Greenwoodvan Meerveld
    Abstract:

    Bladder pain syndrome (BPS) is poorly understood; however, there is a female predominance and comorbidity with irritable bowel syndrome (IBS). Here we test the hypothesis that Linaclotide, a guanylate cyclase-C (GC-C) agonist approved for the treatment of IBS with constipation (IBS-C), may represent a novel therapeutic for BPS acting through a mechanism involving an inhibition of visceral organ cross-sensitization. We showed previously that infusion of dilute protamine sulfate (PS) into the bladder increased sensitivity and permeability in the bladder and colon. PS was infused into the bladder of female rats; sensitivity was assessed via application of von Frey filaments applied to the suprapubic area and the frequency of withdrawal responses was recorded. Colonic sensitivity was measured via visceromotor behavioral response to graded pressures of colorectal distension (CRD). Permeability was measured in vitro via transepithelial electrical resistance (TEER) and conductance (G). Linaclotide (3 µg/kg, p.o.) or vehicle was administered daily for 7 days prior to experiments. Rats treated with PS bladder infusion exhibited visceral hyperalgesia, as shown by a significantly higher response frequency to individual von Frey filaments and increased behavioral responses to CRD. Linaclotide attenuated bladder and colonic hyperalgesia to control levels. PS infusion into the bladder increased bladder and colon permeability measured as a decrease in TEER and increased G. Linaclotide significantly inhibited PS-induced colonic hyperpermeability while having no effect on bladder hyperpermeability. Our findings suggest a novel treatment paradigm for GC-C agonism in IBS-C and BPS mediated through a mechanism involving visceral organ crosstalk.

  • Linaclotide activates guanylate cyclase c cgmp protein kinase ii dependent trafficking of cftr in the intestine
    Physiological Reports, 2017
    Co-Authors: Md Kaimul Ahsan, Gerhard Hannig, Marco Kessler, Robert Solinga, Boris Tchernychev, David Arthur, Cristina I Linde, Inmaculada Silossantiago, Nadia A Ameen
    Abstract:

    The transmembrane receptor guanylyl cyclase-C (GC-C), expressed on enterocytes along the intestine, is the molecular target of the GC-C agonist peptide Linaclotide, an FDA-approved drug for treatment of adult patients with Irritable Bowel Syndrome with Constipation and Chronic Idiopathic Constipation. Polarized human colonic intestinal cells (T84, CaCo-2BBe) rat and human intestinal tissues were employed to examine cellular signaling and cystic fibrosis transmembrane conductance regulator (CFTR)-trafficking pathways activated by Linaclotide using confocal microscopy, in vivo surface biotinylation, and protein kinase-II (PKG-II) activity assays. Expression and activity of GC-C/cGMP pathway components were determined by PCR, western blot, and cGMP assays. Fluid secretion as a marker of CFTR cell surface translocation was determined using in vivo rat intestinal loops. Linaclotide treatment (30 min) induced robust fluid secretion and translocation of CFTR from subapical compartments to the cell surface in rat intestinal loops. Similarly, Linaclotide treatment (30 min) of T84 and CaCo-2BBe cells increased cell surface CFTR levels. Linaclotide-induced activation of the GC-C/cGMP/PKGII signaling pathway resulted in elevated intracellular cGMP and pVASPser239 phosphorylation. Inhibition or silencing of PKGII significantly attenuated Linaclotide-induced CFTR trafficking to the apical membrane. Inhibition of protein kinase-A (PKA) also attenuated Linaclotide-induced CFTR cell surface trafficking, implying cGMP-dependent cross-activation of PKA pathway. Together, these findings support Linaclotide-induced activation of the GC-C/cGMP/PKG-II/CFTR pathway as the major pathway of Linaclotide-mediated intestinal fluid secretion, and that Linaclotide-dependent CFTR activation and recruitment/trafficking of CFTR from subapical vesicles to the cell surface is an important step in this process.

  • mrp4 modulation of the guanylate cyclase c cgmp pathway effects on Linaclotide induced electrolyte secretion and cgmp efflux
    Journal of Pharmacology and Experimental Therapeutics, 2015
    Co-Authors: Boris Tchernychev, Gerhard Hannig, Robert Solinga, Marco M Kessler, Derek Wachtel, Jenny V Tobin, Sara R Thomas, Craig E Lunte, Angelika Fretzen, Alexander P Bryant
    Abstract:

    MRP4 mediates the efflux of cGMP and cAMP and acts as an important regulator of these secondary messengers, thereby affecting signaling events mediated by cGMP and cAMP. Immunofluorescence staining showed high MRP4 expression localized predominantly in the apical membrane of rat colonic epithelium. In vitro studies were performed using a rat colonic mucosal layer mounted in an Ussing chamber. Linaclotide activation of the guanylate cyclase-C (GC-C)/cGMP pathway induced a concentration-dependent increase in transepithelial ion current [short-circuit current (Isc)] across rat colonic mucosa (EC50: 9.2 nM). Pretreatment of colonic mucosa with the specific MRP4 inhibitor MK571 potentiated Linaclotide-induced electrolyte secretion and augmented Linaclotide-stimulated intracellular cGMP accumulation. Notably, pretreatment with the phosphodiesterase 5 inhibitor sildenafil increased basal Isc, but had no amplifying effect on Linaclotide-induced Isc. MRP4 inhibition selectively affected the activation phase, but not the deactivation phase, of Linaclotide. In contrast, incubation with a GC-C/Fc chimera binding to Linaclotide abrogated Linaclotide-induced Isc, returning to baseline. Furthermore, Linaclotide activation of GC-C induced cGMP secretion from the apical and basolateral membranes of colonic epithelium. MRP4 inhibition blocked cGMP efflux from the apical membrane, but not the basolateral membrane. These data reveal a novel, previously unrecognized mechanism that functionally couples GC-C-induced luminal electrolyte transport and cGMP secretion to spatially restricted, compartmentalized regulation by MRP4 at the apical membrane of intestinal epithelium. These findings have important implications for gastrointestinal disorders with symptoms associated with dysregulated fluid homeostasis, such as irritable bowel syndrome with constipation, chronic idiopathic constipation, and secretory diarrhea.