Linaclotide Found Safe for Long-Term Use in Intestinal Disorders

Linaclotide is a guanylate cyclase C (GC - C) agonist, which acts locally in the gastrointestinal tract by binding and activating GC-C located on the luminal surface of the intestinal epithelium.

Its activation causes an increase in the intracellular and extracellular concentrations of cyclic guanosine monophosphate (cGMP), which stimulates the secretion of chloride and bicarbonate in the intestinal lumen and the subsequent acceleration in intestinal transit and an increase in fluid. intestinal.

It is approved in North America and Japan for the treatment of adults with IBS-C and CIC, and in China, Europe, Hong Kong and Macau for IBS-C. This agent demonstrated its effectiveness in various intestinal symptoms of both functional intestinal disorders, such as frequency and consistency of stool, complete evacuation and straining, and abdominal symptoms – such as abdominal pain and discomfort – and abdominal distension.

In animal models, it was shown that the improvement in abdominal pain is due to the increase in extracellular cGMP, which reduces painful nerve activity.

In 2 large, phase III, double-blind, randomized, controlled trials, the efficacy and safety of linaclotide at a dose of 290 µg in IBS-C was demonstrated, leading to the approval of the drug by the Food and Drug Administration  . US Administration  (FDA).

In 2 other large phase III randomized controlled trials, linaclotide at doses of 145 to 290 µg demonstrated efficacy and safety in CIC, but only the 145 µg dose was approved.

In 2 other randomized controlled phase III studies, the efficacy and safety of the linaclotide dose of 145 µg in CIC and a lower dose of 72 µg were demonstrated.

The authors performed an analysis of pooled data from these 6 randomized controlled phase III studies and 2 open-label phase III trials conducted in the US and Canada on linaclotide.

Patients and methods

The analysis pooled safety data from 6 phase III and two phase III open-label long-term randomized controlled trials of linaclotide, conducted in the US and Canada.

These trials comprised patients 18 years of age or older who met modified Rome II criteria for IBS-C or CIC and received study medication once daily for 12 or 26 weeks.

In the long-term trials, all patients received open-label linaclotide at a dose of 290 µg and, in case of intolerance, the dose was reduced to 145 µg and follow-up was extended for a further 78 weeks. In the phase III trials, participants met the Rome II or Rome III criteria for IBS-C or CIC, respectively.

Information about adverse events was collected at each follow-up visit and the researchers rated them according to their severity (mild, moderate, or severe) and their relationship to treatment (unrelated, unlikely, possible, probable, definite; the last 3 were considered in the current analysis).

At baseline and at predetermined intervals, blood and urine samples were collected for laboratory determinations. In addition, vital signs and weight were evaluated, and electrocardiograms (ECG) were performed.

The population analysis included all patients who received more than one dose of the study medication. The pooled results of the included trials were presented by treatment, by indication and overall. The data were also analyzed to identify potential differences in age, sex, or race.

Results

In total, 4584 patients were included in the randomized controlled trials (1792 assigned to placebo and 2792 to linaclotide).

In the randomized controlled phase III and long-term studies combined, 3853 participants received one dose or more of linaclotide, 3321 (86.2%) received linaclotide for 60 days or more, 1853 (48.1%) for 180 days or more and 1506 (39.1%) for more than 360 days.

The overall exposure to linaclotide in both the randomized controlled and long-term trials was 3018.2 patient-years in the pooled analysis, while the exposure to placebo in the pooled placebo-controlled studies was 468.4 patient-years.

The age of the participants ranged from 18 to 90 years, with a median of 44 to 48 years; 8.6% were 65 years old or older. There was a predominance of women (87.3%), white people (75.6%) and non-Hispanics (82.3%).

The average body mass index ranged between 27.7 and 28.9 kg/m 2 , and demographic characteristics were similar between the groups, with the exception of a single study that presented a lower number of women and a higher percentage of Hispanics in the linaclotide group at higher doses. of 72 µg.

In randomized controlled trials, 51.1% of patients treated with linaclotide and 46.4% of those assigned to placebo experienced a treatment-emergent adverse event and the rates were higher in patients with IBS-C (linaclotide 60.8%, placebo 54.9%), compared to those with CIC (47.1% vs. 39.5%, respectively).

In people with IBS-C, the 3 most common treatment-emergent adverse effects in those treated with linaclotide were diarrhea (19.8%), abdominal pain (6.6%), and flatulence (4.3%), while in those with CIC the The 3 most common adverse reactions due to linaclotide treatment were diarrhea (16.9%), abdominal pain (4.3%), and upper respiratory tract infection (3.1%).

With the exception of diarrhea, the percentages of patients with adverse events arising from linaclotide treatment were similar to those receiving placebo.

In long-term studies, with linaclotide exposures of up to 78 weeks, 73.4% of participants (72.1% of those with IBS-C and 74.8% of those with CIC) had an adverse effect due to treatment, the most frequent of which were diarrhea (28.7%), abdominal pain (8.3%) and sinusitis (6.9%), in the grouped analysis.

Patients treated with linaclotide had 1.1 treatment-emergent adverse events (diarrhoea) per patient/year in the randomized controlled trials (0.2 per patient/year with placebo) and 0.3 per patient/year in the long-term studies.

In randomized controlled trials, 6.9% of participants assigned to linaclotide and 3% of those receiving placebo had to withdraw from the studies due to an adverse effect, with diarrhea occurring in 4% and 0.3%, respectively.

In randomized controlled trials, 9.4% of patients receiving linaclotide had to discontinue the studies due to an adverse effect, 4% due to diarrhea, while the respective figures with placebo were 2.9% and 0.3%. . The onset of diarrhea occurred most frequently within the first 2 weeks .

Serious adverse reactions were rare and similar between therapeutic groups and none were due to diarrhea.

In the randomized and controlled trials and in the long-term trials, no clinically significant changes were recorded in vital signs, weight and ECG, nor in laboratory determinations.

There were minimal differences related to age, sex, and race, except that rates of diarrhea with treatment were higher in people 65 years or older, in those who were white, compared to those who were black. and non-Hispanics compared to Hispanics.

Discussion and conclusion

The present analysis supports the safety and tolerability of linaclotide for long-term use in patients with IBS-C and CIC.

According to the authors, their pooled analysis of safety data on linaclotide in patients with IBS-C and CIC is the largest to date, including 6 North American and 2 long-term phase III randomized controlled trials. term.

The pooled analysis confirmed the safety results of previously published phase III trials with linaclotide, while long-term investigations of up to 78 weeks provide additional information on the safety of this drug.

The adverse effect that occurred with the most frequent treatment with linaclotide was diarrhea, an expected adverse reaction given the mechanism of action of the drug, which is the activation of GC-C, which increases fluid secretion and accelerates gastrointestinal transit.

The percentage of research dropouts due to diarrhea was less than 4%. There were no clinically significant changes in vital signs, weight, or laboratory parameters.

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