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.
AbbVie and Ironwood Pharmaceuticals, both based in the US, are responsible for the development and commercialisation of Linzess in the country. AbbVie markets linaclotide under the brand name Constella® for the treatment of moderate to severe IBS-C in adults in Europe.
In Japan, Ironwood’s partner Astellas commercialises Linzess for the treatment of adults with IBS-C or chronic constipation. Another partner, UK-based pharmaceutical company AstraZeneca commercialises Linzess for the treatment of adults with IBS-C in China, including Hong Kong and Macau.
AbbVie and Ironwood develop and commercialise linaclotide in all other global territories.
Linzess is available as white to off-white opaque hard gelatine capsules in three dosage strengths, 72mcg, 145mcg and 290mcg, for oral administration.
Regulatory approvals for Linzess
In August 2012, Forest Laboratories (now Allergan, which is part of AbbVie) and Ironwood Pharmaceuticals received approval for Linzess from the US Food and Drug Administration (FDA) for the treatment of IBS-C and CIC.
In December 2022, AbbVie submitted a supplemental new drug application (sNDA) for Linzess to the FDA for the treatment of functional constipation (FC) in children and adolescents aged six to 17 years. The application was accepted and granted priority review in February 2023.
The sNDA is based on the results of a Phase III clinical trial that met the primary and secondary endpoints. The study evaluated Linzess 72mcg for improvement in the frequency of spontaneous bowel movements (SBM) and stool consistency in people aged from six to 17 years.
Details of irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC)
IBS-C 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. An estimated 11.5 million people in the US suffer from IBS-C.
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. Symptoms include infrequent stools, hard stools, and incomplete evacuation. An estimated 28.5 million people in the US are affected by CIC.
Linzess’ mechanism of action
Linzess is a once-daily capsule that contains an active ingredient called linaclotide, which reduces intestinal pain and accelerates gastrointestinal transit, according to non-clinical studies. The drug increases the cyclic guanosine monophosphate (cGMP) levels to decrease the pain.
Linaclotide binds to the local receptor, GC-C, within the epithelium of the intestinal tract.
When GC-C is activated, intestinal fluid secretion increases, transit time increases, and pain-sensitive nerves in the intestine become less active.
Clinical trials on Linzess
In collaboration with Ironwood Pharmaceuticals, Allergan initiated two IBS-C phase III clinical trials on Linzess in July 2009. The studies were intended to evaluate the safety and efficacy of the medication. The randomised, double-blind, placebo-controlled multi-centre studies were conducted on 1,605 IBS-C patients aged between 18 and 87 years. A total of 805 patients were administered 290mcg capsules of the drug.
The results of the trials, announced in September and November 2010, showed that the patients treated with Linzess experienced 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. Secondary endpoints included abdominal pain, discomfort, bloating and bowel symptoms.
Allergan and Ironwood Pharmaceuticals also conducted two Phase III clinical studies on Linzess to evaluate its safety and efficacy in treating CIC. The randomised, double-blind and placebo-controlled clinical studies enrolled 1,275 CIC patients aged between 18 and 85 years. A total of 430 patients were administered with a 145mcg of Linzess while 422 received a 290mcg dose.
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 compared to a 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 aged up to six years. The use of Linzess in paediatric patients from six to 17 years of age should be avoided.