Constella(R) (linaclotide) Approved in Europe for the Treatment of Irritable Bowel Syndrome with Constipation (IBS-C) in Adults

In April 2009, Almirall signed a license agreement with Ironwood, under which Almirall holds exclusive marketing rights for linaclotide in all European Union member states, plus Russia, the CIS (Commonwealth of Independent States of the former USSR), Switzerland, Norway and Turkey, as well as other countries in Europe, including the countries of former Yugoslavia. In September 2012, Almirall also signed an agreement by which Forest Laboratories sublicensed its commercialization rights for linaclotide in Mexico to Almirall.

Linaclotide is a Guanylate Cyclase-C receptor agonist (GCCA) with visceral analgesic and secretory activities.

Linaclotide is a 14-amino acid synthetic peptide structurally related to the endogenous guanylin peptide family. Both linaclotide and its active metabolite bind to the GC-C receptor, on the luminal surface of the intestinal epithelium. Through its action at GC-C, linaclotide has been shown to reduce visceral pain and increase GI transit in animal models and increase colonic transit in humans. Activation of GC-C results in an increase in concentrations of cyclic guanosine monophosphate (cGMP), both extracellularly and intracellularly. Extracellular cGMP decreases pain-fiber activity, resulting in reduced visceral pain in animal models. Intracellular cGMP causes secretion of chloride and bicarbonate into the intestinal lumen, through activation of the cystic fibrosis transmembrane conductance regulator (CFTR), which results in increased intestinal fluid and accelerated transit.

The characteristics of the patient population included in Phase 3 clinical trials were as follows: mean age of 43.9 years [range 18 – 87 years with 5.3% ≥ 65 years of age], 90.1% female. All patients met Rome II criteria for IBS-C and were required to report a mean abdominal pain score of ≥ 3 on a 0-to-10-point numeric rating scale (criteria that correspond to a moderate to severe IBS population), < 3 complete spontaneous bowel movements and ≤ 5 SBMs per week during a 2-week baseline period.

The co-primary endpoints in both clinical studies were 12-week IBS degree of relief responder rate and 12 week abdominal pain/discomfort responder rate. An IBS degree of relief responder was a patient that was considerably or completely relieved for at least 50% of the treatment period; an abdominal pain/discomfort responder was a patient that had an improvement of 30% or more for at least 50% of the treatment period.

For the 12 weeks data, study 1 shows that 39% of the patients treated with linaclotide compared with 17% of the patients treated with placebo showed response to IBS degree of relief (p<0.0001) and 54% of the patients treated with linaclotide compared with 39% of the patients treated with placebo showed response to abdominal pain/discomfort (p<0.0001). Study 2 shows that 37% of the patients treated with linaclotide compared with 19% of the patients treated with placebo showed response to IBS degree of relief (p<0.0001) and 55% of the patients treated with linaclotide compared with 42% of the patients treated with placebo showed response to abdominal pain/discomfort (p=0.0002).

For the 26 weeks data, study 1 shows that 37% and 54% of the patients treated with linaclotide compared with 17% and 36% of the patients treated with placebo showed response to IBS degree of relief (p<0.0001) and abdominal pain/discomfort (p<0.0001) respectively.

In both studies, these improvements were seen by week 1 and sustained over the entire treatment periods. Linaclotide has been shown not to cause rebound effect when the treatment was stopped after 3 months continuous treatment.

Other signs and symptoms of IBS-C including bloating, complete spontaneous bowel movement (CSBM) frequency, straining, stool consistency, were improved in linaclotide treated patients vs. placebo (p<0.0001). These effects were reached at 1 week and sustained over the entire treatment periods.

Treatment with linaclotide also resulted in significant improvements in validated and disease-specific Quality of Life (QoL) measure (IBS-QoL; p<0.0001), and EuroQoL (p = 0.001). Clinically meaningful response in overall IBS-QoL (> 14 points difference) was achieved in 54% of linaclotide treated patients vs. 39% in placebo treated patients.

The most frequently reported adverse reaction associated with linaclotide therapy was diarrhoea, mainly mild to moderate in intensity, occurring in less than 20% of patients. Other common adverse reactions (>1%) were abdominal pain, abdominal distension and flatulence.

Almirall is an international pharmaceutical company based on innovation and committed to health. Headquartered in Barcelona, it researches, develops, manufactures and commercialises its own R&D and licensed drugs with the aim of improving people’s health and wellbeing. Almirall focuses its research resources on respiratory, gastrointestinal, dermatology and pain. Almirall’s products are currently present in over 70 countries in the five continents. With the opening of the Canadian affiliate, Almirall has now direct presence in Europe, Mexico and Canada through 13 affiliates.