Abstract
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).
We read with great interest the recent article published by Roque and Camilleri in Expert Review of Gastroenterology and Hepatology entitled ‘Linaclotide, a synthetic guanylate cyclase C agonist, for the treatment of functional gastrointestinal disorders associated with constipation’ Citation[1]. We thank the authors for the robust coverage of available data. However, we noticed a couple of inaccuracies and wanted to make sure that readers have correct information about the conduct of the clinical studies.
The authors mistakenly represented the primary end points for two recently completed Phase III clinical trials of the investigational product linaclotide in irritable bowel syndrome with constipation (IBS-C) patients. They indicated that one of the four primary end points was defined as a patient who had a ≥30% reduction from baseline in abdominal pain and had ≥3 complete spontaneous bowel movements (CSBMs) per week for at least 6 of 12 weeks of treatment (in their Table 1, they added “…and increase ≥1 from baseline [CSBMs per week] for ≥6 of 12 weeks.” Citation[1]). The correct end point is shown below. In addition, we would like to clarify that both of the Phase III IBS-C randomized, placebo-controlled trials featured the same four primary end points:
• The ‘coprimary’ end point based on recommendations in the FDA’s draft guidance on IBS trials Citation[2]: a responder was defined as a patient who had a ≥30% reduction from baseline in abdominal pain at its worst (abdominal pain) and an increase in CSBMs of ≥1 per week in the same week, for at least 6 of 12 weeks of treatment;
• A similar, more stringent end point: a responder was defined as a patient who had a ≥30% reduction from baseline in abdominal pain and had ≥3 CSBMs per week, with an increase in CSBMs of ≥1 per week in the same week for at least 9 of 12 weeks of treatment;
• Abdominal pain responder end point: a responder had a ≥30% reduction from baseline in abdominal pain for at least 9 of 12 weeks of treatment; and
• Complete spontaneous bowel movement responder end point: a responder had ≥3 CSBMs per week with an increase in CSBMs of ≥1 per week for at least 9 of 12 weeks of treatment.
Results of treatment with linaclotide compared with placebo on each of these four end points met statistical significance, controlling for multiplicity, in both trials. (The results of these IBS-C trials were presented at the Digestive Disease Week Annual Meeting in May 2011).
We would also like to clarify the description of the Phase I studies that were conducted for linaclotide in healthy volunteers. There were two initial Phase I studies conducted in healthy volunteers prior to initiation of clinical trials in chronic constipation and IBS-C patients. A single ascending dose, pharmacokinetics and pharmacodynamics Phase I study was conducted that compared nominal linaclotide doses of 29, 97, 290, 966 and 2897 µg to placebo. This study included 30 healthy volunteers. A multiple ascending dose pharmacokinetics and pharmacodynamics Phase I study was conducted that compared once-daily nominal linaclotide doses of 29, 97, 290 and 966 µg to placebo over 7 days in 48 healthy volunteers. (Note: these Phase I doses differ slightly from the equivalent Phase I linaclotide doses previously presented in the literature, as they reflect improved methods used to measure linaclotide content. This adjustment does not reflect a change in the actual amount of linaclotide used in these clinical studies).
Disclaimer
This work is the opinion of the authors and does not represent the views of Expert Reviews Ltd or its employees.
Financial & competing interests disclosure
JM Johnston is an employee of Ironwood Pharmaceuticals, Inc. and owns stock/stock options in that company. HA Schneier is an employee of Forest Laboratories, Inc. and owns stock/stock options in that company. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Chris O’Dea (Ironwood Pharmaceuticals) provided writing assistance in the development of this manuscript.
References
- 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).
- FDA Center for Drug Evaluation and Research. Guidance for Industry: Irritable Bowel Syndrome: Clinical Evaluation of Products for Treatment (Draft IBS Guidance). US FDA, Center for Drug Evaluation and Research, MD, USA (2010).