Cambridge, Mass.-based Ironwood Pharmaceuticals has announced that the phase III clinical trial of its 72mcg dose of linaclotide in adults with chronic idiopathic constipation (CIC) met the primary endpoint. Ironwood and partner Allergan intend to submit a supplemental new drug application to the FDA in the first half of 2016.
Linaclotide currently is approved by the FDA as a 145mcg capsule to be taken once per day for the treatment of adults with CIC and as a 290mcg capsule to be taken once per day for the treatment of adults with irritable bowel syndrome with constipation (IBS-C).
Top-line data from the phase III trial indicate that the 72mcg dose of linaclotide demonstrated statistically significant improvement compared to placebo on the 12-week Complete Spontaneous Bowel Movements (CSBM) Overall Responder endpoint, the primary endpoint for the trial. Additionally, in a pre-specified sensitivity analysis, the 72mcg dose of linaclotide demonstrated statistically significant improvement compared to placebo on the Durable CSBM
Overall Responder endpoint, which currently is being requested by the FDA for phase III CIC trials. Both the 72mcg and 145mcg linaclotide doses were generally well-tolerated in the trial. Consistent with previous phase III trials of linaclotide, the most common adverse event reported in linaclotide-treated patients was diarrhea. The majority of diarrhea cases reported were characterized as mild in severity. The rates of diarrhea and of discontinuations due to diarrhea were lower for the 72 mcg dose than the 145mcg dose in the trial.
The randomized, double-blind, placebo-controlled, multi-site phase III clinical trial enrolled 1,223 adult patients with CIC. Patients with CIC were defined as having fewer than three spontaneous bowel movements per week, and they also may have experienced recurrent straining, lumpy or hard stools, and/or a sensation that they have not had a complete bowel movement.
Patients were randomized to receive 72mcg of linaclotide once per day, 145mcg of linaclotide once per day, or placebo once per day for 12 weeks. A 12-week CSBM Overall Responder was defined as a patient who experienced at least three CSBMs per week and an increase of at least one CSBM from baseline in the same week (Weekly Responder), and achieved both of these measures for nine out of 12 weeks. A Durable 12-week CSBM Overall Responder comprises patients that were 12-week CSBM Overall Responders and also met the Weekly Responder criteria for at least three of the last four weeks. The 145mcg dose was included as a positive control and supported the validity of the trial for evaluation of the 72mcg dose.