Date: 2017-01-26
Type of information: Granting of a Market Authorisation in the US
Product name: Constella® (EU)/Linzess® (USA)
Compound: linaclotide
Therapeutic area: Inflammatory diseases - Gastrointestinal diseases
Action mechanism:
- peptide. Linaclotide, a first-in-class investigational drug, is an agonist of the guanylate cyclase type-C (GC-C) receptor located on the luminal surface of the intestine. In preclinical models, linaclotide reduced visceral hypersensitivity, increased fluid secretion, and accelerated intestinal transit. The effects on secretion and transit are mediated through cyclic guanosine monophosphate (cGMP), which is also believed to modulate the activity of local nerves to reduce pain. Linaclotide is an orally delivered peptide that acts locally in the gut with no measurable systemic exposure at therapeutic doses and is intended for once-daily administration.
Ironwood Pharmaceuticals and Forest Laboratories are co-developing and, if approved, will co-promote linaclotide in the United States. Ironwood has out-licensed linaclotide to Almirall for European development and commercialisation and to Astellas for development and commercialisation in Japan, Indonesia, Korea, the Philippines, Taiwan and Thailand.
Company: Almirall (Spain) Allergan (Ireland)
Disease:
- Irritable Bowel Syndrome with Constipation (IBS-C)
- chronic idiopathic constipation (CIC)
Latest news:
- • On November 28, 2012, Almirall and Ironwood Pharmaceuticals have announced that the European Commission has granted marketing authorization to Constella® (linaclotide 290mcg) for the symptomatic treatment of moderate to severe Irritable Bowel Syndrome with Constipation (IBS-C) in adults. This approval follows the positive recommendation received from the European Committee for Medicinal Products for Human Use (CHMP) in September.
- • On September 20, 2012, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended the authorisation of the first medicine specifically for the symptomatic treatment of irritable bowel syndrome (IBS) in the European Union (EU). The Agency is recommending that Constella® (linaclotide) be authorised for adults with moderate to severe IBS with constipation (IBS-C), a common subtype of the disease.
The Committee based its recommendation on the results of two main clinical studies showing superiority of linaclotide over placebo in terms of improving symptoms after 12 weeks. These effects were sustained for at least six months. However, it noted that around half of the patients in the main studies did not respond to linaclotide sufficiently, leading to the recommendation that prescribers should assess patients regularly and reconsider treatment if there is no improvement in symptoms after four weeks.
The most common side effect in clinical trials was diarrhoea, which was reported in a fifth of the patients taking the medicine. The Agency is recommending that patients with severe or prolonged diarrhoea should be monitored closely when taking linaclotide and that it should be used with caution in patients prone to water or electrolyte-balance disturbances.
- • On August 30, 2012, the FDA has approved Linzess® to treat chronic idiopathic constipation and to treat irritable bowel syndrome with constipation (IBS-C) in adults. Linzess® is a capsule taken once daily on an empty stomach, at least 30 minutes before the first meal of the day. Linzess® helps relieve constipation by helping bowel movements occur more often. In IBS-C, it may also help ease abdominal pain.
The safety and effectiveness of Linzess® for the management of IBS-C were established in two, double-blind studies. A total of 1,604 patients were randomly assigned to take 290 micrograms of Linzess® or a placebo for at least 12 weeks. Results showed Linzess was more effective in reducing the amount of abdominal pain and increasing the number of complete spontaneous bowel movements compared with placebo.
The safety and effectiveness of Linzess® for the management of chronic idiopathic constipation also were established in two, double-blind studies. A total of 1,272 patients were randomly assigned to take Linzess at doses of 145 mcg or 290 mcg or a placebo for 12 weeks. Results from these studies showed patients taking Linzess experienced more complete spontaneous bowel movements than those taking the placebo. The 290 mcg dose is not approved for chronic constipation because studies indicated it was no more effective than the 145 mcg dose. Linzess® is approved with a Boxed Warning to alert patients and health care professionals that the drug should not be used in patients 17 years of age and younger. The most common side effect reported in during the clinical studies was diarrhea.
- • On September 29,2011, Amirall anounced hat it has submitted a Marketing Authorisation Application (MAA) to the European Medicines Agency (EMA) for linaclotide for the treatment of irritable bowel syndrome with constipation (IBS-C). Once approved, linaclotide will be marketed in Europe under the trademark Constella®.
The submission includes efficacy and safety data from a Phase III program comprising two double-blind placebo-controlled trials1 and two open-label long term safety studies. A total of more than 1,600 subjects received an once?daily dose of either linaclotide or placebo across the two placebo-controlled studies in patients with IBS-C. Full results of these two studies will be presented at the European Gastroenterology Week (UEGW) congress in Stockholm in October 23rd-26th, 2011. This MAA follows the submission of an NDA for linaclotide (Linzess®) to the FDA in August 2011 by Ironwood Pharmaceuticals and its US partner, Forest Laboratories
Patents:
Submission of marketing authorization application USA : 2011-08
Submission of marketing authorization application UE: 2011-09-29
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
US authorization: 2012-08-30
UE authorization: 2012-11-28
Favourable opinion UE: 2012-09-20
Favourable opinion USA:
Orphan status USA:
Orphan status UE:
Pediatric exclusivit _USA:
Pediatric exclusivity UE:
OTC status:
Other news:
- • On January 26, 2017, Ironwood Pharmaceuticals, and Allergan announced that the FDA has approved a 72 mcg dose of Linzess® (linaclotide) for the treatment of chronic idiopathic constipation in adult patients. The new dose is expected to be available in the first quarter of 2017. Linzess® is now FDA -approved in three dosage strengths: 290 mcg for adult patients with irritable bowel syndrome with constipation and 145 mcg and a new 72 mcg for the treatment of adults with chronic idiopathic constipation.
The approval of Linzess® 72 mcg is based on results from a Phase III clinical trial of 1,223 adults with chronic idiopathic constipation. As previously reported, this trial met its primary endpoint; the 72mcg dose demonstrated statistically significant improvement in Complete Spontaneous Bowel Movements compared to placebo over 12 weeks. The most common adverse event was diarrhea; the rates of diarrhea and of discontinuations due to diarrhea were numerically lower for the 72 mcg dose than the 145 mcg dose in this trial.
Is general: Yes
