Trade names Linzess Routes of
administration Oral Legal status US: ℞-only | License data US FDA: Linaclotide ATC code A06AX04 (WHO) Molar mass 1,526.74 g/mol | |
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Pregnancy
category US: C (Risk not ruled out) | ||
Video sindrome intestino irritabile terapia con linaclotide prof v stanghellini
Linaclotide (marketed under the trade name Linzess in the US and Mexico, and as Constella in Canada and many other countries) is an oligo-peptide agonist of guanylate cyclase 2C. It was approved by the FDA in August 2012 and by the European Medicines Agency for the treatment in adults of constipation-predominant irritable bowel syndrome and chronic idiopathic constipation.
Contents
Medical need
The National Institutes of Health (NIH) estimate that as many as 20% of Americans may experience irritable bowel syndrome (IBS); approximately one-third of those, as many as 10 million Americans, experience constipation-predominant IBS (IBS-C), that is, IBS with constipation often accompanied by abdominal pain. Laxatives can assist with constipation but do not treat pain, while opiates that are often prescribed to treat pain can aggravate constipation. While low-cost laxatives and pain killers would likely be tried first, linaclotide targets both associated conditions in a once-daily pill.
Structure
Linaclotide is a peptide mimic of endogenous guanylin and uroguanylin. It is a synthetic tetradecapeptide (14 amino acid peptide) with the sequence CCEYCCNPACTGCY by one-letter abbreviation, or by three-letter abbreviation:
H–Cys1–Cys2–Glu3–Tyr4–Cys5–Cys6–Asn7–Pro8–Ala9–Cys10–Thr11–Gly12–Cys13–Tyr14–OH
However, the actual structure of linaclotide is not full specified without the three disulfide (R-S-S-R) bonds it contains, which are between Cys1 and Cys6, between Cys2 and Cys10, and between Cys5 and Cys13; these are shown in exaggerated fashion in the line-angle graphic showing the chemical bonds within and between each amino acid (and their stereochemistries, see the infobox, above right), and are represented using a one-letter abbreviations in the following additional schematic:
Mechanism of action
Linaclotide, like the endogenous guanylin and uroguanylin it mimics, is an agonist that activates the cell surface receptor of guanylate cyclase 2C (GC-C). The medication binds to the surface of the intestinal epithelial cells. Linaclotide is minimally absorbed and it is undetectable in the systemic circulation at therapeutic doses. Activation of GC-C increases cyclic guanosine monophosphate (cGMP). Elevated cGMP stimulates secretion of chloride and bicarbonate and water into the intestinal lumen, mainly by way of cystic fibrosis transmembrane conductance regulator (CFTR) ion channel activation. This results in increased intestinal fluid and accelerated transit. By elevating cGMP, linaclotide is also considered to reduce activation of colonic sensory neurons, reducing pain; and activates colonic motor neurons, which increases smooth muscle contraction and thus promotes bowel movements.
Related therapeutics
Plecanatide, a drug marketed under the name Trulance, was approved by the FDA in January 2017 for the treatment of chronic idiopathic constipation (CIC), and is likewise an agonist of guanylate cyclase, except with hexadecapeptide structure.
Clinical trials
The FDA approval of linaclotide was based on four large randomized trials, two for each indication: IBS-C and CIC. The approved dose for constipation-predominant irritable bowel syndrome (IBS-C) is 290 micrograms daily. The approved dose for chronic idiopathic constipation (CIC) is 145 mcg daily; no benefit was seen in CIC by using 290 micrograms instead of 145 mcg daily. In both situations, the most common side effect was diarrhea.
In IBS-C, the phase III randomized double-blind clinical trials both showed some improvement in pain and constipation with the medication in comparison to placebo. Pain reduction started in the first week on the medication, with further improvement seen by weeks six to nine.
In CIC, some effect on bowel habits was seen during the first week of treatment, reaching its maximum within that interval. Similarly, the effect returned toward baseline within one week of discontinuing the medication. An open-label safety study in CIC using linaclotide for up to a year found diarrhea to be the most frequently reported adverse event.
Pharmacokinetics and pharmacodynamics
Systemic absorption of the globular tetradecapeptide is minimal.
Chemistry
A study in discovery synthesis reported that 2 of 14 strategies available to synthesize linaclotide were successful—the successful ones involving trityl protection of all cysteines, or trityl protection of all cysteines except Cys1 and Cys6, which were by tert-butyl group—a study which also reported that solution-phase oxidation (disulfide formation) was advisable over solid-supported synthesis for linaclotide, and that the Cys1–Cys6 disulfide bridge was the most favored, energetically.
Distribution and licensing
Under a partnership agreement announced in 2007 between Forest Laboratories and Microbia (as Ironwood Pharmaceuticals was then known), Forest would pay $70 million in licensing fees towards the development of linaclotide, with profits shared between the two companies. Distribution rights in the United States will be shared with Forest Laboratories, with Almirall distributing linaclotide in Europe and Astellas Pharma in Asia.