Linzess is a new drug that last week received FDA approval by Forrest laboratories for use in irritable bowel syndrome (IBS) with constipation and in chronic idiopathic constipation got my attention more because of its biochemistry than because I think it is going to be a drug I prescribe often. Learning about the mechanism of action of new drugs like Linzess reminds me how much more is understood about the molecular biological level of physiologic function of the human body than when I was in med school. Linzess is felt to act as a guanylate cyclase-C agonist. An agonist increases the activity of a process, the opposite of an antagonist. Linzess seems to act locally on the surface of the inside of the intestinal lining cells and by activation of guanylate cyclase-C increases levels of intracellular cGMP (cyclic guanosine monophosphate) which results in increased levels of chloride and bicarbonate in the intestinal lumen and speeds up gastrointestinal transit. Never having heard of guanylate cyclase-C before I looked and found out that it was initially discovered before I went to med school (just barely), in 1974-5, but as far as I know this is one of the first clinically important results of this study in medicine. If readers know of others please leave me a comment.
The FDA approved use of Linzess in IBS with constipation is 290 µg orally once daily and in chronic idiopathic constipation the approved dose of Linzess is 145 µg orally daily. In both conditions Linzess is best taken on anti-stomach at least 30 min. prior to first meal of the day. Linzess joins previously FDA approved and Amitiza (lubiprostone) as prescription medications specifically for IBS with constipation and gives us one more option for treatment of this difficult problem. IBS with constipation is among the more common and refractory conditions seen in gastroenterology and in primary care. Chronic laxative use is common in these patients and can lead to laxative dependence and poor colonic function and even toxic megacolon in severe cases. Osmotic laxatives like milk of magnesia and not observable sugars like lactulose are commonly used. MiraLax (polyethylene glycol) has become increasingly popular in recent years but all of these products have limited effectiveness and associated problems.
Linzess has also been shown to reduce intestinal type of nominal pain. Linzess also has an FDA approval for use in chronic idiopathic constipation at a dose of 145 µg daily.
The efficacy of Linzess in IBS with constipation and in chronic idiopathic constipation is expected to be at best modest. In the to placebo can trial IBS with constipation trials the incidence of an improvement in at least six of the 12 weeks trial duration for improvement in abdominal pain was only 33% for improvement both abdominal pain and constipation versus 21% with placebo or 12.6% benefit over placebo. For abdominal pain response 50% had improvement with Linzess versus 37% with placebo, a 12.7% difference, and in constipation improvement 48% improved with Linzess versus 29% on placebo, a 19% difference. In the two trials looking at improvement in at least nine out of the 12 weeks the numbers were considerably lower but did show significantly more patients improving on Linzess and with placebo. To look at the data more pacific we can look at the Forest Laboratories prescribing information.
As might be expected diarrhea is the most common side effect of Linzess occurring in up to 20% or patients, and often the diarrhea begins within the first 2 weeks of treatment. The diarrhea from Linzess can be severe and the manufacturer recommends that if a person using Linzess develops diarrhea that should immediately stop the medication and contact their doctor. Other GI symptoms are common also and include abdominal pain, gas and a feeling of fullness or swelling in the abdomen. In addition Linzess comes with a strict warning that it is not for use in children. In juvenile rats deaths were noted, and so Linzess is contraindicated for use in persons under age 18.
It is expected that Linzess will be another quite expensive medication, and although Forrest has not yet set a price they have intimated that the drug will be priced to be comparable to Amitiza, or in the $260. / month range. It remains to be seen if it will be more popular than Amitiza, or whether it will be just a niche drug for refractory cases of IBS with constipation and chronic idiopathic constipation.