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Felicia Avella has suffered from irritable bowel syndrome (IBS) all her life. Over the years, she has tried numerous drugs to deal with the painful constipation that goes along with her gastrointestinal disorder, but nothing has seemed to provide relief. Then, three-and-a-half years ago, at the age of 61, Avella signed up for a clinical trial testing a new agent called linaclotide, an experimental peptide designed to increase bowel movements in people with chronic constipation. “It just changed my life,” she says. “I didn’t know what normal was until I started on the drug.”
Since the trial ended and the drug was taken away from her, Avella, a retired accountant from Englewood, Florida, has had to rely on an over-the-counter laxative. This drug has helped with her constipation issues, but it hasn’t provided any reprieve from her abdominal discomfort or bloating.
Fortunately for Avella, the US Food and Drug Administration (FDA) today approved linaclotide, which will be marketed as Linzess by Ironwood Pharmaceuticals of Cambridge, Massachusetts, in collaboration with New York’s Forest Laboratories. Avella says she plans to be the first person lined up at her gastroenterologist’s office to discuss switching back to the more targeted agent.
Long-term constipation is a commonly occurring ailment that affects approximately 15% of the US population, resulting in 2.7 million physician visits and 38,000 hospitalizations each year. The first drug ever approved by the FDA for the treatment of chronic idiopathic constipation (CIC) and IBS with constipation was a serotonin receptor activator called tegaserod, which Novartis began selling as Zelnorm in 2002. The Swiss pharma giant pulled the anticonstipation agent five years later, however, after studies linked the drug with an increased risk of heart disease. That has left only lupiprostone, a chloride channel activator marketed as Amitiza by Japan’s Sucampo Pharma and Takeda Pharmaceuticals, for the treatment of lasting bowel problems. Amitiza gained US approval in 2006 and earned $226 million last year in domestic sales alone.
Like lupiprostone, linaclotide works to increase fluid secretion into the gut by stimulating chloride channels in the inner lining of the intestines—which is why both drugs are known as ‘intestinal chloride secretagogues’. Yet, whereas lupiprostone is thought to act primarily on the chloride channel protein 2, linaclotide triggers intestinal chloride secretion through activation of guanylate cyclase type-C (GC-C). This receptor—the same one as that activated by the bacterial toxins responsible for ‘traveler’s diarrhea’—stimulates the release of chloride and bicarbonate, along with water, into the intestinal lumen through the trafficking of messenger molecules that open another chloride channel known as the cystic fibrosis transmembrane conductance regulator. This same pathway has also been shown in rodent models to give the drug distinct pain-relieving properties (Neurogastroenterol. Motil. 22, 312–e84, 2010).
In two phase 3 trials involving a total of 1,276 people with CIC, around 20% of participants who received linaclotide once daily for close to three months showed significant improvements in the frequency of bowel movements, compared to only around 5% of those who received placebo pills (N. Engl. J. Med. 365, 527–536, 2011). Notably, around half the linaclotide-treated patients reported some degree of constipation relief, and a third experienced improvements in bloating and abdominal pain. (Similar response rates were seen in two phase 3 trials involving a combined 1,602 people with IBS with constipation, according to data presented in May at the Digestive Disease Week meeting in San Diego.) The only worrying adverse event found in the published CIC trials was diarrhea, which occurred in around 15% of linaclotide-treated patients compared to only 5% of those on placebo.
“It seems to be very safe, and the side effects are minimal,” says Brian Lacey, a gastroenterologist at the Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire, and a member of the scientific advisory boards for both Ironwood and Takeda. “I’m also impressed by the response rates, keeping in mind that many of these patients who entered the linaclotide studies had likely failed other agents and now responded to something else, which is quite exciting.”
Researchers haven’t tested linaclotide and lupiprostone head to head. Still, on the basis of existing placebo comparisons, analysts say that linaclotide could have a real market advantage. Linaclotide has demonstrated a superior analgesic profile and does not seem to cause nausea—a side effect seen around one in ten people treated with lupiprostone (Aliment. Pharmacol. Ther. 35, 587–599, 2012). With linaclotide, “the data are solid, and everything indicates that a great majority of the patients benefit,” says Juan Sanchez, a pharmaceutical analyst with Ladenburg Thalmann in New York. David Nierengarten of Wedbush Securities in San Francisco estimates that peak US sales of linaclotide will reach $2.4 billion by 2019. “It is eventually going to be a pretty large drug,” he says.
Testing the water
Linaclotide seemed to be the right drug for Felicia Avella. But a chloride channel activator that draws water into the intestines won’t be the solution for everybody. “There will be some patients for whom the problem of constipation is caused by this lack of sufficient fluid in the colon,” says Michael Camilleri, a gastroenterologist at the Mayo Clinic in Rochester, Minnesota, who has led trials investigating many experimental anticonstipation agents, including linaclotide. “On the other hand, there will be some other patients for whom the problem is one of the nerves and muscles not stimulating the propulsion of content through the colon, and there, flushing it from above with water, as it were, might not be sufficient.”
For this second group of patients, a drug called prucalopride could help. Like tegaserod, prucalopride stimulates serotonin 5-HT4 receptors in the gut to induce colonic contractions that help with defecation. But prucalopride’s increased selectivity for its target is thought to shield the drug from the problematic cardiac effects observed with tegaserod.
Prucalopride was developed by New Jersey’s Johnson & Johnson and has been marketed by Belgium’s Movetis (now part of Ireland’s Shire) in Europe as Resolor since 2009 for the treatment of long-term constipation. Shire acquired the US rights to the compound in January and is currently “working with the FDA to determine a regulatory path forward,” according to company spokesperson Gwen Fisher. Two similar serotonin receptor agonists—naronapride and velusetrag, both from small Northern California companies—have also completed phase 2 testing.
To determine the right course of therapy, Camilleri advocates using an imaging technique called ‘scintigraphic colonic transit’ in which patients swallow a radioactive marker that can be tracked to give an indication of the type of constipation they are suffering from (Clin. Pharmacol. Ther. 87, 748–753, 2010). “We actually measure how fast things move through the colon,” he says, “If they’re very slow then we’re more likely to use a secretagogue agent, and if they’re really, really slow we’re more likely to use something that stimulates the colon.”
But the therapeutic picture could be complicated by the arrival of another anticonstipation drug class. The Swedish company Albireo has a compound called elobixibat that modulates a transporter protein involved in delivering bile acids to the gut. Bile acids loosen stool consistency, allowing for easier defecation and reduced straining. In a phase 2 trial involving 190 people with CIC, elobixibat was found to increase the frequency of bowel movements two- to sixfold, depending on the dose, over the course of eight weeks (Am. J. Gastroenterol. 106, 1803–1812, 2011).
Meanwhile, Synergy Pharmaceuticals has its own GC-C agonist currently in phase 3 testing in 880 people with CIC. According to Gary Jacob, president and chief executive of the New York–based firm, Synergy’s compound, called plecanatide, doesn’t hang on to the GC-C receptor for as long as linaclotide does, suggesting that the drug might be less prone to causing diarrhea. Preliminary phase 2 data presented at this year’s Digestive Disease Week meeting seems to bear out that molecular inference: none of the 58 people who received a two-week course of plecanatide experienced diarrhea, the company reported.
Larger clinical studies will be needed to confirm whether plecanatide’s safety profile is indeed superior. In the meantime, Jacob is cheering for his competitor’s product to pave the way for other drugs in the same class. “We believe they’ve got a great drug in linaclotide,” Jacob says. “It’s going to change the whole landscape for treating gastrointestinal disorders.”
Editor’s note: A similar version of this story will appear in the September 2012 issue of Nature Medicine.