Linzess (linaclotide) is a guanylate cyclase-C (GC-C) agonist indicated for the treatment of irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) in adult men and women. It is jointly developed by Forest Laboratories and Ironwood Pharmaceuticals.
In August 2012, Forest Laboratories and Ironwood Pharmaceuticals received approval for Linzess from the US Food and Drug Administration (FDA) for the treatment of IBS-C and CIC.
Irritable bowel syndrome with constipation
Irritable Bowel Syndrome with constipation is a functional gastrointestinal disorder that leads to abdominal pain or discomfort along with constipation symptoms. Constipation may be caused by the slow movement of stools through the colon. It is estimated that about 13 million people in the US are affected by IBS-C.
Chronic idiopathic constipation
Chronic idiopathic constipation, or functional constipation, is also a gastrointestinal disorder. The term “idiopathic” means the cause of the constipation is unknown and not due to an underlying illness or medication. The symptoms of the disease include infrequent stools, hard stools and incomplete evacuation. It is estimated that around 35 million people in the US are affected by CIC.
Linzess’ mechanism of action
Linzess contains an active ingredient called linaclotide, which reduces intestinal pain and accelerates gastrointestinal transit, according to nonclinical studies. The drug increases the cyclic guanosine monophosphate (cGMP) levels to decrease the pain. The drug is available in 145mcg and 290mcg capsules.
Forest Laboratories and Ironwood Pharmaceuticals’ clinical trials
Forest Laboratories, in collaboration with Ironwood Pharmaceuticals, initiated two IBS-C phase III clinical trials on Linzess in July 2009. The studies were intended to evaluate the safety and efficacy of Linzess. The randomised, double-blind and placebo-controlled multicentre studies were conducted on 1,605 IBS-C patients aged between 18 and 87 years. Around 805 patients were administered with 290mcg capsules of the drug.
The results of the trials, announced in September and November 2010, showed that the patients treated with Linzess showed statistically significant improvement over placebo-administered patients. The studies met four primary endpoints, which included reducing abdominal pain and increasing complete spontaneous bowel movements (CSBMs) as well as composite endpoints combining the two measures. The secondary endpoints of the study included abdominal pain, discomfort, bloating and bowel symptoms.
Forest Laboratories and Ironwood Pharmaceuticals also conducted two phase III clinical studies on Linzess to evaluate the safety and efficacy of the drug in treating Chronic Idiopathic Constipation (CIC). The randomised, double-blind and placebo-controlled clinical studies enrolled about 1,275 CIC patients aged between 18 and 85 years. About 430 patients were administered with Linzess 145mcg, while 422 received Linzess 290mcg dose.
The results of the studies were announced in November 2009. The studies met their intended primary endpoints. The results demonstrated that significantly more patients treated with Linzess 145mcg dose versus placebo experienced at least three CSBMs and an increase of at least one CSBM from baseline in the same week for at least nine of the 12 weeks. It was also observed that the patients administered with Linzess experienced significant improvement in stool frequency and hardness of stool compared to placebo.
The most common adverse reactions encountered during IBS-C and CIC clinical studies included diarrhoea, abdominal pain and flatulence. Linzess is contraindicated in paediatric patients up to six years of age. The use of Linzess in paediatric patients from six to 17 years of age should be avoided.
Marketing Linzess in the US, Europe and Asia
Cilansetron – New Treatment for IBS
Developed by Solvay Pharmaceuticals, cilansetron is a 5-HT3 antagonist indicated for the treatment of diarrhoea-predominant irritable bowel syndrome (IBS).
Ironwood and Forest expect to introduce Linzess into the US market in the fourth quarter of 2012. Almirall filed for the marketing approval of Linzess in Europe. Astellas Pharma holds the marketing rights of Linzess in Japan and certain other Asian countries. The drug’s sales are expected to cross $2bn a year in the US, according to some analysts.
Linzess will compete with lubiprostone (Amitiza) developed by Sucampo Pharmaceuticals and Takeda Pharmaceutical Company. Tegaserod (Zelnorm), manufactured by Novartis, was also approved for similar indications but withdrawn from the market in 2007 due to FDA concerns about possible adverse cardiovascular effects.