Constella: first-in-class treatment option for IBS patients with constipation

Almirall has launched Constella (linaclotide) for the symptomatic treatment of moderate to severe irritable bowel syndrome with constipation.

Constella (linaclotide) is a once-daily oral capsule that should be taken at least 30 minutes before a meal to reduce gastrointestinal adverse effects.
Constella (linaclotide) is a once-daily oral capsule that should be taken at least 30 minutes before a meal to reduce gastrointestinal adverse effects.

PHARMACOLOGY

Linaclotide binds to the guanylate cyclase-C receptor on the luminal surface of the intestinal epithelium resulting in increased concentrations of both extra- and intra-cellular cyclic guanosine monophosphate (c-GMP).1 

Extracellular c-GMP decreases pain fibre activity thereby reducing visceral pain in animal models, while intracellular c-GMP causes secretion of chloride and bicarbonate into the intestinal lumen leading to increased intestinal fluid and accelerated transit.1

CLINICAL STUDIES

The efficacy and safety of linaclotide for the treatment of IBS-C was investigated in two randomised, double-blind, placebo-controlled phase III studies of similar design: study 1 (n=804) assessed patients over 26 weeks and study 2 (n=800) evaluated patients over 12 weeks before re-randomisation for an additional 4-week treatment period. In both studies, patients received linaclotide 290 microgram or placebo.1-3

Patients met Rome II criteria for IBS-C and were required to report a mean abdominal pain score of 3 or more on a 0–10 point numeric rating scale (criteria that correspond to a moderate to severe IBS population), <3 complete spontaneous bowel movements (SBMs and ≤5 SBMs per week during a 2-week baseline period.1

Investigators used IBS degree of relief response rate (considerably or completely relieved for ≥50% of treatment period) and abdominal pain/discomfort response rate (improvement of ≥30% for at least 50% of the treatment period) at 12 weeks as the co-primary endpoints.1

Pre-treatment, patients had a mean abdominal pain score of 5.6 and bloating score of 6.6 (0-10 scale) with 2.2% of days free of abdominal pain and an average of 1.8 SBMs per week.1

Reduction in IBS relief and abdominal pain/discomfort

In study 1, the IBS degree of relief response rate at 12 weeks was 33.7% in patients treated with linaclotide compared with 13.9% in patients on placebo (p<0.0001), and a further 48.9% of patients showed response to abdominal pain/discomfort comapred with 34.5% in the placebo arm.2

In study 2, patients treated with linaclotide had a IBS degree of relief response rate at week 12 of 33.6% versus 21% for patients on placebo (p<0.0001), and a greater percentage of patients given linaclotide showed a response in terms of abdominal pain/discomfort (50.1% vs 37.5% for placebo, p=0.0003).3

At 26 weeks in study 1, significantly higher percentages of linaclotide-treated patients showed a response in terms of IBS relief and abdominal pain/discomfort compared with patients on placebo: 37% and 54% for linaclotide and 17% and 36% for placebo, respectively (p<0.0001 for both comparisons).4

Other signs and symptoms of IBS-C including bloating, frequency of complete SBMs, straining and stool consistency were improved in linaclotide treated patients compared with those on placebo (p<0.0001). These effects were seen at 1 week and sustained over the entire treatment period.1

Safety profile

 

The most commonly reported adverse effect in both trials was diarrhoea. This resulted in discontinuation of linaclotide in 4.5% of linaclotide-treated patients compared with 0.2% of patients treated with placebo in study 1. Similar rates of discontinuation were observed in study 2: 5.7% for linaclotide versus 0.3% for placebo.2,3

Prescribers should advise patients to seek medical attention if diarrhoea is severe or prolonged (lasting over 1 week) and temporary discontinuation should be considered in this event.1

References

  1. Constella Summary of Product Characteristics, November 2012.
  2. Chey WD et al. Am J Gastroenterol 2012; 101: 1702–12.
  3. Rao S et al. Am J Gastroenterol 2012; 107: 1714–1724.
  4. Quigley EM et al. Aliment Pharmacol Ther 2013; 37: 49–61.

View Constella drug record

Further information:  Almirall

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