Albireo today announced positive top-line results from a Phase IIb study in chronic idiopathic constipation (CIC) assessing efficacy and safety of three different dose levels (5, 10 and 15 mg orally once a day) of the investigational drug A3309 during an eight week trial.
Analyses of the data show clinically meaningful and statistically significant improvement for patients treated with A3309 compared to placebo-treated patients. A3309 is a first-in-class IBAT inhibitor with minimal systemic exposure which is developed for the treatment of CIC and constipation-predominant irritable bowel syndrome (IBS-C).
The primary efficacy endpoint, change from baseline in spontaneous bowel movements (SBMs), showed a dose-dependent increase and highly significant results were obtained for the two highest dose levels. In addition, the secondary endpoints of effects on SBM and complete SBM (CSBM) frequencies were also dose dependent and statistically significant. Bloating and straining, important constipation symptoms, also decreased significantly during A3309 treatment. The effect of A3309 was rapid and a significantly higher proportion of the A3309-treated patients had a CSBM within 24 hours of the first administration. The beneficial effects were maintained over the eight week trial period.
“A3309 has a unique and novel mode of action which utilizes the body's physiologic processes to induce an increase in bowel movements. The results of this Phase IIb study show that A3309 has the potential to be an important therapeutic addition for patients with chronic constipation. I am sure that scientists and clinicians alike look forward to seeing further results with this exciting new compound” said William D Chey, MD, Professor of Internal Medicine, University of Michigan, Ann Arbor.
“More than 30 million individuals suffer from CIC and IBS-C and the results of this Phase IIb trial further support the potential of A3309 to be an important treatment for these patients. The data in the trial presented today provide a solid base for moving forward into Phase III in 2011” said Hans Graffner, Chief Medical Officer of Albireo.
Albireo expects to present detailed results of the trial A3309-002 at upcoming scientific conferences.
A3309-002 was a multicentre, randomized, double-blind, placebo-controlled trial conducted in the US and included 190 patients with severe constipation treated for an eight-week period. The patients included into the study were mainly female (90%) and experienced severe constipation as judged by a low number of weekly CSBMs (0.4/week). The patients had severe straining and bloating problems.
A higher frequency of SBMs occurred in all three active dose groups with statistically significant increased levels for the 10 mg and the 15 mg groups (p=0.002 and p<0.001 respectively). The numerical magnitude of change was 4.0 and 5.4 SBMs/week respectively in the two highest dose groups.
A3309 treated patients demonstrated a significant increase in average weekly CSBMs from baseline (1.0 for placebo; 2.4, 2.5 and 4.1 for 5 mg, 10 mg and 15 mg respectively and with p values being 0.021, 0.017 and <0.001 respectively). The overall change for SBMs followed the same pattern.
A3309 has a fast onset; the percentage of patients having a CSBM within 24 hours of starting therapy was 20, 31 and 55% in the active groups ((p=0.027 and p<0.001 for the two highest dose levels) compared to 10% in the placebo group.
Other important symptoms of chronic constipation such as bloating, straining and hard stools were also relieved in higher proportions in the active dose groups.
No Serious Adverse events related to the treatment were reported.
Spontaneous Bowel Movement (SBM): An SBM is a bowel movement that occurs in the absence of laxative, enema, or suppository usage during the preceding 24 hours.
Complete spontaneous bowel movement (CSBM): A CSBM is an SBM that is accompanied by the patient self-reporting a feeling of complete emptying of the bowel.
A3309 is a therapeutic alternative with a novel mechanism of action developed for the treatment of CIC and IBS-C. A3309, which has minimal systemic exposure, modulates the re-uptake of bile acids by inhibiting the ileal bile acid transporter (IBAT or ASBT). This results in an increased concentration of bile acids in the colon which, in turn, increase fluid secretion and colonic motility. These physiological responses should provide benefits to patients with CIC and IBS-C without any effects on other parts of the gastrointestinal tract.
Chronic constipation is among the most common diseases, affecting approximately 15% of the general population particularly women and the elderly population. Patients with CIC often experience hard and lumpy stools, straining during defecation and a sensation of incomplete evacuation, as well as discomfort and bloating. CIC adversely affects a person´s quality of life and is associated with significant health care expenditure. Studies show that approximately 50% of individuals with CIC are not satisfied with available treatments underscoring the unmet medical need in this area.
IBS-C is a disease characterized by a combination of abdominal pain and constipation. Throughout the world, about 10%–20% of adults have symptoms consistent with IBS, and most studies find a female predominance. IBS symptoms come and go over time, often overlap with other functional disorders, impair quality of life, and result in high health care costs. There is a high rate of dissatisfaction with available therapies.
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