Microbia, Inc. and Forest Laboratories, Inc. posted positive top-line results from two phase IIb randomised, double-blind, placebo-controlled studies assessing the safety, therapeutic effect, and dose response of four different once-daily doses of linaclotide: 75 mcg, 150 mcg, 300 mcg, and 600 mcg.
The first study examined the effects of linaclotide in patients with chronic constipation (CC), while the second study examined its effects in patients with irritable bowel syndrome with constipation (IBS-C). Preliminary analysis of the CC study data and an interim analysis of the IBS-C study data indicate that each study met its primary endpoint.
In the four-week CC study, the primary efficacy endpoint was the change from pre-treatment in weekly spontaneous bowel movement (SBM) frequency rate. During the two-week pre-treatment period, the mean baseline weekly SBM frequency rate across all treatment groups was 2.31. Patients who received once-daily dosing of linaclotide demonstrated a dose-responsive increase in weekly SBM frequency rate ranging from 0.98 (75 mcg, p = 0.09) to 2.99 (600 mcg, p < 0.0001) compared to patients receiving placebo. The response was significant at all doses above 75 mcg.
Linaclotide-treated patients also experienced improvements in all other top-line efficacy endpoints-complete spontaneous bowel movement (CSBM) frequency, stool consistency, straining, abdominal pain, bloating, and abdominal discomfort-that were statistically significant for at least two of the four linaclotide dose groups for each endpoint. Linaclotide was well tolerated at all doses with no serious adverse events in any patient during the treatment period. The most common adverse event was diarrhoea, which was dose-related and ranged from 4.8 per cent to 14.3 per cent in the linaclotide-treated patients compared to 2.9 per cent of placebo-treated patients. Diarrhea resulted in discontinuation of 2.5 per cent of linaclotide-treated patients and no placebo-treated patients. At this time the companies have reviewed only top-line results and further analyses will be conducted in the coming weeks.
An interim analysis of the recently completed 12-week IBS-C study was carried out to enable timely dose selection for phase III trials. The interim analysis was performed on the unlocked database for this study, following the last patient's last visit. Patients with IBS-C who received once-daily treatment with linaclotide experienced a significant increase in weekly CSBM frequency rate-the primary endpoint for this study-at all doses except for 150 mcg. Linaclotide-treated patients also experienced improvements in all other top-line efficacy endpoints-SBM frequency, stool consistency, abdominal pain, bloating, abdominal discomfort, adequate relief, and IBS-C symptom severity-that were statistically significant for at least two of the four linaclotide dose groups for each endpoint.
Linaclotide was well tolerated at all doses; there was one serious adverse event in a linaclotide-treated patient which was considered unrelated to treatment by the investigator. The most common adverse event was diarrhea, and diarrhea was the most common adverse event resulting in discontinuation. Once the full analysis of the data is completed, Microbia and Forest Laboratories plan to present the results of these trials at an appropriate scientific conference.
Based on these data and subject to a complete review of the full results for both completed studies, the companies intend to initiate phase III trials in both CC and IBS-C patients in the second half of 2008.
The US-based phase IIb study was designed to assess the safety, efficacy, and dose-response of linaclotide in patients with CC. The primary efficacy endpoint was the change in the overall mean weekly frequency of SBMs from the pre-treatment baseline through the four-week treatment period. Following a no-drug washout period of 14-17 days, patients (N=310, with equal randomization across treatment groups) were randomized to receive placebo or linaclotide once-daily in the morning at doses of 75 mcg, 150 mcg, 300 mcg or 600 mcg for 28 days.
Following completion of the four weeks of double-blind treatment, patients were followed up for safety assessments for an additional two weeks. Bowel function measurements included the number of spontaneous and complete spontaneous bowel movements (CSBM) compared to baseline, stool consistency using the Bristol Stool Form Scale (BSFS), and straining. Patient-reported outcomes included measures of abdominal pain, abdominal discomfort, and bloating on a daily basis, and constipation severity and overall relief of constipation on a weekly basis. In addition, the use of rescue medication, end-of-treatment satisfaction, and disease-specific quality of life were assessed.
The US and Canadian based phase IIb study was designed to assess the safety, efficacy, and dose-response of linaclotide in patients with IBS-C. The primary efficacy endpoint was the change in the overall mean weekly frequency of CSBMs from the pre-treatment baseline through the 12-week treatment period. Following a no-drug washout period of 14-17 days patients (N=420, with equal randomization across treatment groups) were randomized to receive placebo or linaclotide once-daily in the morning at doses of 75 mcg, 150 mcg, 300 mcg or 600 mcg for 12 weeks. Following completion of the double-blind treatment period, patients were followed up for safety assessments for an additional two weeks.
Bowel function measurements included the number of SBMs and CSBMs compared to baseline, stool consistency using the BSFS, and straining. Patient-reported outcomes included measures of abdominal pain, abdominal discomfort, and bloating on a daily basis, and constipation severity and overall assessment of IBS symptoms on a weekly basis. In addition, the use of rescue medication, end-of-treatment satisfaction, and disease-specific quality of life were assessed.
Linaclotide is a first-in-class compound currently being tested for the treatment of IBS-C, CC, and other gastrointestinal disorders. Linaclotide is an agonist of guanylate cyclase type-C, a receptor found on the lining of the intestine. In preclinical testing linaclotide was shown to increase fluid secretion into the intestine, accelerate intestinal transit, and decrease visceral pain. Linaclotide was designed to exert its effect on the intestine with minimal systemic exposure. In phase IIa trials, linaclotide improved bowel function as measured by both CSBMs and SBMs in patients with CC and IBS- C. An issued composition of matter patent for linaclotide provides protection to 2025. In September 2007, Microbia, an entrepreneurial pharmaceutical company dedicated to the science and art of great drug making, and Forest entered into a 50/50 collaboration to co-develop and co-promote linaclotide in United States.