Linaclotide is a 14-amino acid peptide that stimulates intestinal guanylate cyclase type-C (GC-C) receptors. Linaclotide is acid stable and protease resistant with low bioavailability; it is undetectable in the systemic circulation at therapeutic doses. Activation of GC-C stimulates the production of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP), which then increases the flow of electrolytes(HCO3- and Cl–) and water into the lumen of the GI tract. This is associated with faster GI transit. Stimulation of the GC-C receptor on intestinal epithelial cells and release of cGMP into the serosa leads to a reduction in visceral hyperalgesia.
Johnston and colleagues were the first to investigate the safety, tolerability, and efficacy of linaclotide in patients with CC who met modified Rome II criteria. This multicenter, placebo-controlled pilot study published in 2009, showed that there was a trend towards a dose-dependent increase in the frequency of weekly spontaneous bowel movements (SBMs) and complete spontaneous bowel movements (CSBMs). Stool consistency, straining, and patient reported outcomes also improved in all dosing groups.
Linaclotide – CAS 851199-59-2
These promising results led to a larger multicenter, placebo-controlled study involving 310 CC patients defined by modified Rome II criteria. Patients were randomized to one of four linaclotide dosages (75, 150, 300, or 600 μg) or placebo once daily for 4 weeks. The primary end point was the change in mean weekly SBM frequency from the 14-day pretreatment period to the 4-week treatment period. Patients were also analyzed using a responder definition of a weekly SBM > 3 and an increase of >1 relative to baseline, for 3 of the 4 treatment weeks. Secondary endpoints included changes in stool consistency, straining, abdominal discomfort, and bloating. Lembo and colleagues noted that the frequency of weekly SBMs increased significantly in a linear response to increasing dosages of linaclotide (2.6, 3.3, 3.6, and 4.3 for linaclotide doses of 75, 150, 300, and 600 μg, respectively), compared to 1.5 for placebo (p<0.05 for each linaclotide dosage group compared to placebo). The median time to first SBM, mean number of CSBMs, stool consistency, and severity of straining also demonstrated a significantly improved dose-dependent relationship compared to placebo. No rebound effect occurred during a 14-day post-treatment surveillance period. Adverse events were reported in 33.8 % of patients receiving the study drug and 31.9 % of placebo (n.s.). The most commonly reported AEs were GI related, of which diarrhea was the most frequent, 5.1 %–14.3 %, versus 2.9 % of placebo patients. Only two cases of diarrhea were graded as severe, both were in the 600 μg group and both resulted in cessation of treatment.
The most recent report on linaclotide describes data from two parallel, randomized, placebo-controlled, doubleblinded trials using either 145 μg or 290 μg linaclotide or placebo over 12-weeks in 1272 patients with CC. Trial 01 consisted of 630 patients while trial 303 consisted of 642 patients (median age 48; 89 % female). The primary endpoint of both trials was defined a priori as both three or more CSBMs/week and an increase of at least one CSBM/week from baseline for at least 9 out of the 12 weeks. Secondary endpoints included measurements of stool frequency, stool consistency, severity of straining, abdominal discomfort, bloating, and overall constipation severity. The authors reported that once daily linaclotide produced early and sustained improvement in bowel and abdominal symptoms, SBMs, and CSBMs within the first week of treatment. For the 12-week study period the primary end point (12-week CSBM overall responder for≥9 of 12 weeks) was met in both trial 01 (16.0 %, 21.3 % vs. 6.0 % for placebo, p=00.0012 and p<0.0001) and 303 (21.2 % and 19.4 % vs. 3.3 %, p<0.0001). These benefits remained when the data were pooled and analyzed for weeks 1 through week 12. Secondary endpoints including CSBMs/week, SBMs/week, stool consistency, straining, constipation severity, abdominal discomfort, and bloating were superior to placebo and statistically significant in both studies for each dose of linaclotide. Trial 303 included a randomized 4-week withdrawal study that included 538 of the 642 patients. A rebound effect was not found during the withdrawal period, and patients initially treated with placebo and then randomized to linaclotide noted results similar to those initially treated with linaclotide. Quality of life assessments, using the PAC-QOL instrument, showed an improvement in patients treated with linaclotide compared to those treated with placebo (p<0.01). The authors reported one death in this study—it occurred due to an overdose of fentanyl and was not thought related to the study drug. Discontinuation rates due to AEs were 4.2 % in placebo-treated patients, compared to 7.9 % in patients treated with 145 ug linaclotide and 7.3 % in those treated with 290 ug of linaclotide. Discontinuation of the study medication and AEs were primarily GI—related (e.g., diarrhea, flatulence, and abdominal pain). No clinically significant differences were found among the 3 groups
with regard to EKG results, vital signs, blood chemistries, urinalysis, or hematologic findings. Although the strict definition for entrance into these studies was chronic constipation, using modified Rome II criteria, it is reasonable to assume that many of these patients had difficult constipation, and thus these findings are relevant for that population.
Brian E. Lacy & John Levenick & Michael Crowell. Curr Gastroenterol Rep (2012) 14:306–312