Clinical Trials

Date: 2016-12-22

Type of information: Results

phase: 2b

Announcement: results

Company: Ironwood Pharmaceuticals (USA - MA) Allergan (Ireland)

Product: linaclotide colonic release-2 (CR2) formulation

Action mechanism:

• peptide. Linaclotide is a guanylate cyclase-C receptor agonist (GCCA) with visceral analgesic and secretory activities. This 14-amino acid synthetic peptide is structurally related to the endogenous guanylin peptide family. Both linaclotide and its active metabolite bind to the guanylate cyclase-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.
• Linaclotide was discovered by scientists at Ironwood. This company has then out-licensed the compound to Almirall for European development and commercialisation and to Astellas Pharma for development and commercialisation in Japan, Indonesia, Korea, the Philippines, Taiwan and Thailand.  In October 2015, Allergan acquired rights to Constella® (linaclotide) in the European Union , Switzerland , Turkey and the Commonwealth of Independent States from Almirall,  and has also reacquired rights to Linzess® (linaclotide) in Mexico from Almirall.
• Constella/Linzess® is approved by the European Commission for the symptomatic treatment of moderate-to-severe IBS-C in adults.

Disease: irritable bowel syndrome with constipation (IBS-C)

Therapeutic area: Inflammatory diseases - Gastrointestinal diseases

Country:

Trial details:

• Patients in the double-blind, placebo-controlled, dose-ranging Phase IIb clinical trial were randomized to one of eight groups: one group received placebo, one group received linaclotide 290 mcg (approved formulation), three groups received various doses of linaclotide CR1 (30 mcg, 100 mcg or 300 mcg), and three groups received various doses of linaclotide CR2 (30 mcg, 100 mcg or 300 mcg). The 290 mcg approved formulation was included as a reference group for this study. The trial was designed to evaluate the safety and efficacy of each linaclotide colonic release dose and formulation relative to placebo; the statistical power was based on a linear dose response. Additional objectives included assessing how the two colonic release formulations compared to each other and to the approved 290 mcg formulation of linaclotide. All doses were administered orally, once daily for 12 weeks.

Latest news:

• • On December 22, 2016, Ironwood Pharmaceuticals and Allergan announced topline data from a Phase IIb clinical trial evaluating an investigational linaclotide colonic release-2 (CR2) formulation in adult patients with irritable bowel syndrome with constipation (IBS-C). The data showed that CR2, as intended, numerically improved abdominal pain and other abdominal symptoms, such as bloating and discomfort, relative to placebo, with no apparent effect on bowel movement function. These findings support further investigation of CR2 in specific gastrointestinal indications where patients experience abdominal pain but are not necessarily constipated, such as IBS-Mixed, IBS with diarrhea, ulcerative colitis and diverticulitis. The companies plan to engage with the FDA to discuss next steps for advancing CR2 into a Phase IIb dose-ranging clinical trial in patients with non-constipation subtypes of IBS.
• "There is increasing research into the mechanisms underlying pain and other abdominal symptoms in GI disorders, including IBS, as well as research highlighting the hypersensitivity of pain-sensing nerves in the lower GI tract in many patients suffering from these conditions," said Brennan Spiegel , director of Health Services Research at Cedars-Sinai Health System . "We currently have a limited number of treatment options for these patients, and a medicine that could address abdominal pain without impacting bowel function could represent a real advancement in care."
• Linaclotide is thought to work in two ways, based on non-clinical studies: by decreasing the activity of pain-sensing nerves and by increasing fluid secretion into the intestine. Linaclotide CR2 is designed to provide targeted delivery of linaclotide to the colon, where the majority of the abdominal pain associated with IBS-C is believed to originate. This clinical trial was designed to evaluate whether CR2 could further decrease the activity of key pain-sensing nerves in the colon with a minimal effect on fluid secretion. Ironwood and Allergan also announced topline results from the same Phase IIb trial with a second formulation, linaclotide colonic release-1 (CR1). The double-blind, placebo-controlled, dose-ranging Phase IIb trial randomized 532 adult patients with IBS-C into one of eight possible treatment arms. This trial was exploratory in nature and comparisons to placebo were evaluated using nominal p-values. In the trial, the average weekly change in Bristol Stool Form Scale (BSFS) scores and frequency of complete spontaneous bowel movements (CSBM) from baseline to week 12 were comparable for CR2 and placebo (BSFS: 1.0 - 1.15 for CR2 compared to 0.94 for placebo on a 7-point scale; CSBM: 0.87 - 1.28 for CR2 compared to 1.11 for placebo), indicating no apparent effect on bowel movement function in this study. In contrast, the average weekly change in abdominal pain from baseline to week 12 ranged from -1.63 to -1.83 across the CR2 dose range studied versus -1.37 for placebo, using an 11-point scale. Reduction from baseline at week 12 in abdominal pain was -33.8% to -36.6% for the CR2 doses compared to -26.2% for placebo. Together these data suggest the potential for CR2 to reduce abdominal pain in GI indications not associated with constipation. The most common adverse event in CR2 patients in this trial was upper respiratory tract infection/nasopharyngitis, which was reported in 3% of CR2-treated patients and 4.5% of placebo-treated patients. The rate of diarrhea reported in the trial ranged from 0%-3% for CR2-treated patients compared to 1.5% for placebo. Additional data from the Phase IIb trial are expected to be shared at upcoming scientific meetings and via peer-reviewed publications.

Is general: Yes