Linaclotide: new mechanisms and new promise for treatment in constipation and irritable bowel syndrome

Phase IIa study

In a randomized, double-blind, placebo-controlled phase IIa pilot study to evaluate the effects of linaclotide in CIC, 42 patients were randomized to linaclotide (100, 300 or 1000 µg) or placebo once daily for 2 weeks [Johnston et al. 2009]. The mean age of patients was 45 years and 88% were women. Eligible individuals had to report less than three spontaneous bowel movements (SBMs) per week, along with one or more of lumpy or hard stools, straining and a sense of incomplete evacuation on at least 25% of bowel movements.

After 2 weeks of therapy there were numerically greater increases in SBMs, complete spontaneous bowel movements (CSBMs), and also improvements in stool consistency and straining, measured by the ease of passage score. CSBM frequency, stool consistency and straining scores improved in a dose-dependent manner. Improvements were also demonstrated in abdominal discomfort, severity of constipation and overall symptom relief. Compared with placebo, linaclotide 100 µg significantly increased the frequency of SBMs (p = 0.047), and linaclotide 1000 µg significantly improved stool consistency (p = 0.014). No dichotomous data concerning response to therapy were reported in this phase IIa study. The commonest adverse events with active therapy reported in this study were diarrhoea and abdominal pain, but all of these were judged as mild or moderate in severity by the investigators.

Phase IIb study

Following the previous study, a phase IIb multicentre, randomized, double-blind, placebo-controlled trial was conducted in 310 patients with CIC [Lembo et al. 2010]. The study was conducted at 57 clinical centres in the USA. The mean age of patients was 47 years and 92% were women. Eligibility criteria were similar to those for the phase IIa trial, and patients were randomized in approximately equal numbers to receive 75, 150, 300 or 600 µg of linaclotide, or placebo, once daily for 4 weeks. The primary endpoint was the change in mean weekly SBM frequency from baseline during the 4-week treatment period. Other endpoints included CSBM frequency, stool consistency, straining, SBM response rates (defined as at least three SBMs per week with an increase of at least one from baseline for 3 out of 4 weeks of therapy), CSBM response rates (defined similarly to SBM response rates), treatment satisfaction and effect on quality of life [using the Patient Assessment of Constipation Quality of Life (PAC-QOL) questionnaire].

There was a dose-dependent increase in weekly SBM frequency (2.6, 3.3, 3.6 and 4.3 for 75, 150, 300 and 600 µg of linaclotide respectively, linear-trend p < 0.001), compared with 1.5 for placebo. The mean number of CSBMs per week was also increased in a dose-dependent manner. Stool consistency and straining improved significantly and with a dose–response effect. SBM responder rates ranged between 55% and 68% with linaclotide compared with 32% for placebo (p ≤ 0.01 for all doses), and CSBM responder rates from 19% to 32% compared with 7% for placebo (p ≤ 0.05 for all doses except 75 µg). Following cessation of therapy, bowel habits returned towards baseline levels. Patient satisfaction with therapy was significantly greater in all four of the linaclotide arms, and quality-of-life scores were significantly higher with 75, 150 and 600 µg of linaclotide. Total numbers of adverse events were similar with linaclotide and placebo, although the number of patients reporting diarrhoea with active therapy was numerically higher.

Phase III studies

The results of two phase III, multicentre, randomized, double-blind, placebo-controlled trials involving 1276 patients with CIC (trial 303 and trial 01) were published in 2011 [Lembo et al. 2011]. The studies were conducted in the USA and Canada. The mean age of patients in each arm of the two trials ranged from 47 to 49 years and 87–90.5% were women. Eligibility criteria were identical to those for the phase IIb trial. Patients who met the inclusion criteria were entered into a 12-week treatment period and randomized to receive linaclotide 145 or 190 µg, or placebo. The adjustment in total dose of the drug from the phase IIa and IIb studies does not reflect a change in the amount of linaclotide used in these clinical trials, but resulted from improved methods used to measure linaclotide content.

After completing the 12 weeks of treatment, subjects in trial 303 were then entered into a 4-week, double-blind period of randomized withdrawal. Patients who had received linaclotide in the previous 12 weeks were randomized to receive either the dose of linaclotide that they had received previously or placebo, and those who had received placebo previously were assigned to linaclotide 290 µg. The primary endpoint of the trials was achieving at least three CSBMs per week, with an increase of at least one CSBM per week from baseline for 9 or more weeks during the 12-week treatment period. Secondary endpoints included the effect of linaclotide on stool frequency, stool consistency, straining, satisfaction with treatment, and health-related quality of life, again using the PAC-QOL questionnaire.

In trials 303 and 01, 21% and 16% who received linaclotide 145 µg and 19% and 21% who received 290 µg met the primary endpoint for response respectively compared with 3% and 6% who received placebo (p < 0.01). Differences in the overall response rates between the two linaclotide arms were not significant in either trial. There were significant improvements from baseline to week 12 in all secondary endpoints with linaclotide compared with placebo. Treatment satisfaction scores were significantly higher with active therapy and the proportion of patients with an improvement in PAC-QOL score of at least 1 from baseline was also significantly higher with linaclotide.

In trial 303 among patients continuing to take linaclotide and those who were rerandomized from placebo to linaclotide, the increase in CSBMs remained similar to those during the initial 12 weeks of therapy, while among those who were rerandomized from linaclotide to placebo, CSBMs returned to a similar level to that of the patients originally assigned to placebo. However, there was no evidence of rebound worsening of symptoms. Serious adverse events were no more common with linaclotide, but again absolute numbers of patients reporting diarrhoea were higher with active therapy.

Systematic review and meta-analysis of randomized controlled trials

In a systematic review and meta-analysis of the three trials that reported dichotomous outcome data [Lembo et al. 2010, 2011], 860 of 1089 patients (79%) receiving linaclotide failed to respond to therapy, compared with 468 of 493 (95%) placebo patients [Ford and Suares, 2011]. The relative risk of failure to respond to therapy was significantly lower with linaclotide [0.84; 95% confidence interval (CI) 0.80–0.87], with no significant heterogeneity between studies. The number needed to treat with linaclotide was 6 (95% CI 5–8). Analyses according to the dose of linaclotide used demonstrated similar efficacy for 145 µg and 290 µg. All three trials reported the number of patients experiencing diarrhoea, which was more common with linaclotide (relative risk 3.08; 95% CI 1.27–7.48).

Phase IIa study

The results of the first phase IIa double-blind placebo-controlled dose-ranging study to investigate the effects of linaclotide in patients with IBS-C were published in 2007 [Andresen et al. 2007]. In this trial 36 women who met the ROME II criteria for IBS were randomized in a 1:1:1 ratio to receive linaclotide 100 µg, linaclotide 1000 µg or placebo once daily for 5 days. Trial medication was administered as an oral solution, which was thawed each morning. In order to be enrolled in the study, participants had to demonstrate slow colonic transit at baseline, as measured by scintigraphy. Primary endpoints were the ascending colon emptying half time and overall colonic transit time at 24 h, again measured using scintigraphy. The authors also collected data concerning stool frequency and consistency, ease of stool passage, sense of complete emptying of bowels and time to first bowel movement after drug intake. No dichotomous data concerning response to therapy were reported in this phase IIa study.

Linaclotide led to a significant effect on ascending colon emptying half time but only for the 1000 µg dose compared with placebo (p = 0.004). Overall colonic transit time at 48 h was also accelerated significantly with 1000 µg compared with placebo (p = 0.01), although the effect at 24 h was not statistically significant. Time to first bowel movement was significantly lower with linaclotide 1000 µg and 100 µg (512 and 487 min respectively versus 750 min with placebo, p = 0.013), and there were significant increases in stool frequency (p = 0.037), improvements in stool consistency (p < 0.001) and ease of stool passage (p < 0.001) in a dose-dependent manner.

No serious adverse events were reported and no patients discontinued therapy due to adverse events. The most commonly reported adverse events were headache, abdominal bloating, and borborygmi, which were numerically higher among those assigned to active therapy.

Phase IIb study

In 2010 the results of a randomized phase IIb, double-blind, parallel group, placebo-controlled trial were published [Johnston et al. 2010]. This was a multicentre study conducted in the United States and Canada, recruiting 420 patients with IBS-C as defined by the ROME II criteria. To be eligible, recruited patients also had to report less than three SBMs per week in addition to one or more of lumpy or hard stools, straining or a sensation of incomplete evacuation for at least 25% of bowel movements. The mean age of patients was 44 years and 92% were women. Patients were randomized to receive linaclotide 75, 150, 300 or 600 µg, or placebo, once daily for 12 weeks. The primary endpoint was the change in the number of CSBMs per week from baseline. Secondary endpoints included effect on individual symptoms and quality of life, as well as the proportion of patients who were CSBM responders, defined as a patient with a weekly CSBM rate of at least three and an increase of at least one from baseline for 9 of the 12 weeks of therapy, the proportion who were adequate relief responders, defined as reporting adequate relief of symptoms for 9 of 12 weeks, and the proportion who were global relief responders, defined as symptoms being somewhat, considerably or completely relieved for all 12 weeks, or completely relieved for 6 of 12 weeks.

The mean change in the number of CSBMs per week for placebo was 1.01. For 75, 150, 300 and 600 µg the mean change in CSBMs per week was 2.90, 2.49, 3.61 and 2.68 respectively (p < 0.01 for all linaclotide doses compared with placebo). Stool consistency, straining and abdominal pain scores were significantly improved with all doses of linaclotide compared with placebo. Differences in quality of life scores, however, were not significantly different. The proportion of patients who were CSBM responders with placebo was 12% compared with 25%, 19.5%, 32% and 24% with 75, 150, 300 and 600 µg linaclotide. These differences were statistically significant for all linaclotide doses, except the 150 µg dose. Significantly higher proportions of patients receiving linaclotide (33–51%) were adequate relief responders compared with placebo (22%). Response rates for global relief were 44–58% with linaclotide versus 29% with placebo.

Rates of diarrhoea ranged between 11.4% of patients in the 75 µg arm and 18.0% in the 600 µg arm compared with 1.2% in the placebo group. Of those experiencing diarrhoea, 13 patients in the linaclotide arms discontinued therapy as a result. There were no cases of dehydration or electrolyte disturbance.

Phase III studies

Two phase III randomized, double-blind, placebo-controlled trials were published in 2012 [Chey et al. 2012; Rao et al. 2012]. The first of these was conducted in 102 centres in the USA and randomized 804 patients to receive linaclotide 290 µg or placebo for 26 weeks [Chey et al. 2012]. Inclusion criteria were similar to the aforementioned phase IIb trial. The mean age of included patients was 40 years and 90% were women.

Primary endpoints were based on US Food and Drug Agency (FDA) guidance for IBS trials developed in 2012. An FDA responder was defined as a patient who had an improvement of at least 30% from baseline in the average of the daily worst abdominal score, and an increase of at least one CSBM from baseline. Both needed to occur in the same week for at least 6 of the first 12 weeks of the treatment period. Other primary endpoints included an improvement of at least 30% from baseline in the weekly average of the daily worst abdominal pain scores, at least three CSBMs with an increase of at least one CSBM from baseline for at least 9 of the first 12 weeks of therapy, and finally a combination of the previous two points with a responder defined as a patient meeting both of the above in the same week. Key secondary endpoints included effect on abdominal pain, abdominal discomfort, bloating, stool frequency and consistency, and straining.

The European Medicines Agency (EMA) set slightly different primary endpoints [Quigley et al. 2013]. An abdominal pain or discomfort responder was required to experience a 30% reduction in mean abdominal pain or discomfort score on an 11-point scale, with neither condition worsening from baseline for at least 6 weeks, and a 12-week IBS degree of relief responder was required to report that symptoms were considerably or completely relieved for at least 6 weeks.

For all the primary endpoints, linaclotide 290 µg showed statistically significant improvements compared with placebo. For the first 12 weeks, 34% of patients receiving linaclotide met the FDA combined primary endpoint compared with 14% for placebo (p < 0.001). The number needed to treat for the primary endpoint was five. When symptom data over 9 of 12 weeks were examined, 18% of patients receiving linaclotide met criteria for response versus 5% of patients on placebo. When the combined endpoint was studied, 13% of patients receiving linaclotide were classified as responders compared with 3% of those assigned to placebo. Over the entire 26-week treatment period, 32% and 13% of patients receiving linaclotide and placebo respectively met the FDA endpoint for a minimum of 13 weeks out of the 26-week trial. Finally, improvements in abdominal pain, abdominal discomfort, bloating, stool frequency and consistency, and straining scores were all significantly greater with linaclotide over 12 and 26 weeks of therapy. The EMA responder endpoints were also met by significantly more patients receiving linaclotide [Quigley et al. 2013].

Total numbers of adverse events were significantly higher among linaclotide-treated patients, occurring in 65.4% compared with 56.6% (p < 0.05). However, most were mild or moderate in severity. Once again, the most common adverse event reported was diarrhoea, occurring in 19.7% of patients randomized to linaclotide, compared with only 2.5% of placebo patients. This resulted in cessation of linaclotide therapy in 4.5% of patients compared with 0.2% in patients receiving placebo.

The second phase III trial differed in terms of its design in that patients were randomized to receive linaclotide 290 µg or placebo for a total of 12 weeks, followed by a 4-week randomized withdrawal period [Rao et al. 2012]. However, inclusion criteria and endpoints were identical to the first trial. The mean age of the 800 participants was 43.5 and 90% were women. Among patients randomized to receive linaclotide, 34% met the FDA endpoint compared with 21% assigned to placebo (p < 0.001). The number needed to treat for the primary endpoint was 8. A statistically significantly higher number of patients also met criteria for the other primary endpoints and secondary endpoints. During the 4-week withdrawal period, patients originally randomized to linaclotide who remained on linaclotide showed a continued and sustained response whilst those rerandomized to placebo demonstrated an increase in symptoms of abdominal pain and a decrease in CSBM frequency to the level of those reported by the placebo arm of the trial during the first 12 weeks of therapy. Again, significantly more patients receiving linaclotide met the EMA responder endpoints [Quigley et al. 2013].

The total numbers of adverse events and serious adverse events were not significantly higher among patients receiving linaclotide in this trial (56.2% versus 53.0%). However, diarrhoea was again the predominant side effect experienced, with 19.5% of patients receiving linaclotide reporting diarrhoea compared with 3.5% of patients on placebo. Overall, 7.9% of patients taking linaclotide discontinued the drug as a result of any of the adverse events compared with 2.8% of patients on placebo.