A Healthy Pipeline Drugs for Irritable Bowel Syndrome Have So Far Been Limited, but a Promising Stream of Options Could Soon Enter the Market

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DRUG DEVELOPMENT A healthy pipeline Drugs for irritable bowel syndrome have so far been limited, but a promising stream of options could soon enter the market.

BY BRANWEN MORGAN issues, but do nothing to target the underlying mechanisms. In the 1970s, physicians began fter decades without any specific drugs reporting that certain serotonin-targeting for irritable bowel syndrome (IBS), antidepressants were effective at slowing down

the first few years of the millennium bowel movement, even at low doses. And, as SARAH J. COLEMAN Abrought hope in the form of two approvals. But the evidence mounted, drug developers started this new era turned out to be a false dawn. to look to the serotonin system for ideas. In February 2000, alosetron became the first The gastrointestinal tract produces about drug to be approved by the US Food and Drug 95% of the body’s serotonin; this neurotrans- Administration (FDA) for use in women who mitter is involved in gut motility, intestinal had IBS with diarrhoea (IBS-D). But within secretion and visceral sensitivity — all cru- a few months there were reports of serious cial elements of IBS symptoms. “Selective complications among people who were tak- serotonin re-uptake inhibitors and tricyclic ing the drug and several deaths. Alosetron was antidepressants have been effective in treat- withdrawn that November. ing global IBS symptoms,” says Baharak In 2002, the FDA approved tegaserod for Moshiree, a gastroenterologist at the Univer- IBS with constipation (IBS-C). But this drug sity of Miami in Florida. also encountered problems. By 2007, it too had There are seven main classes of serotonin been withdrawn, this time over concerns of an receptors, some of which also have subtypes increase in risk of cardiovascular problems. IBS or variants, making for a complicated pic- drug development was not going well. “There ture. The two classes most relevant to the was a general waning of enthusiasm on the part gastrointestinal tract are 5-HT3 and 5-HT4. of pharma,” says Alex Ford, a gastroenterologist Alosetron is an antagonist of 5-HT3 — it at the University of Leeds, UK, “because of the blocks the receptor’s action and so slows the bad experience with alosetron and tegaserod”. passage of stool through the gut. But in many Enthusiasm was also dampened by an incom- ways it works too well. “Alosetron was a case plete understanding of the multiple mecha- of classical receptor pharmacology where you nisms that drive IBS. It is not one disease, but make a drug that binds to the one receptor rather a condition comprised of a constellation you want to target — and it binds really tightly of symptoms, and its diagnosis depends on the and really well,” says neuroscientist Paul exclusion of other possible causes (see page Bertrand at RMIT University in Melbourne, S110). Localized gut problems include altered Australia. It binds so tightly that long-term bowel function, bloating and abdominal use will block the receptor indefinitely. “This pain, and for many people, anxiety and was obviously its downfall because it stayed stress can cause these symptoms to wax and there and many people became overly con- wane. It is difficult to stratify patients for clin- stipated,” Bertrand says. Alosetron was made ical trials, to develop appropriate animal models available again in 2002, but only for women or to identify genuine drug targets. with severe, uncontrollable IBS-D, and with But hundreds of millions of people — around tight restrictions — which were eased earlier 11% of the global population (see ‘Global vari- this year. ety’) — have IBS, so there is a considerable need Tegaserod is a 5-HT4 receptor agonist — for treatments. And slowly the hurdles are fall- rather than blocking the receptor, the drug ing. The FDA has approved three drugs for IBS activates it and increases the signals sent to within the past four years, and there is a bulg- the circular muscles that wrap around the ing drug pipeline ahead with numerous com- colon, speeding transit. Bertrand says that pounds — some of which are already approved tegaserod was meant to be safer than alose- for other conditions — that target all manner tron because it is a partial agonist, so it doesn’t of mechanisms from gut neurotransmission to elicit a full response from the receptor. “Its faecal composition. effect on the heart was unexpected,” he says. “We now know it has some affinity to other THE SEROTONIN STORY serotonin receptors.” Because people often have either IBS-D Serotonin receptors are found throughout or IBS-C, the treatment mainstays have his- the central and peripheral nervous system, torically been antidiarrhoeal agents and laxa- and so there is a risk of adverse events from tives, which can ease some of the functional systemic exposure to serotonergic drugs.

IRRITABLE BOWEL SYNDROME OUTLOOK

Women seem to have more of some types of down bowel contractions, which allows the serotonin receptor than men, so men may GLOBAL VARIETY intestines more time to absorb fluid, but it can have a different clinical response. Despite The global prevalence of irritable bowel syndrome also cause constipation. Eluxadoline, the sec-

71–80 (2014). varies hugely, which may re ect access to health

6, the early setbacks, serotonin remains one ond drug approved by the FDA for IBS-D last

. care or stigma surrounding the condition. The of the most attractive targets for IBS drug highest estimated rates are shown, but within year, also stimulates the μ-opioid receptor, development. “The overactivity or underac- countries the reported rates vary dramatically. but at the same time dampens activity of the tivity of the enteric nervous system is really Nigeria δ-opioid receptor. Pamela Hornby, lead sci-

CLIN. EPIDEMIOL the basis of IBS as far as we understand it,” Iceland entist on the gastrointestinal discovery team . explains Bertrand. Croatia at the pharmaceutical company Janssen near ET AL ET The current IBS drug pipeline includes Peru Philadelphia, Pennsylvania, which developed several 5-HT4 agonists for use in patients Greece eluxadoline, explains that this contrasting with IBS-C, but with one crucial difference United Kingdom action helps to “normalize gastrointestinal from tegaserod. “The greater specificity of the United States transit without causing rebound constipa- newer drugs suggest they’ll be much safer,” Russia tion”. Adding, “it helps with pain, too”. SOURCE: C. CANAVAN SOURCE: C. CANAVAN says gastroenterologist Michael Camilleri at New Zealand BETTER TOOLS the Mayo Clinic in Rochester, Minnesota, and Brazil president of the American Gastroenterologi- Finland One of the reasons that these locally acting cal Association. One such agent is prucalo- South Korea drugs are popular with drug developers is that pride, which is highly specific for the 5-HT4 Sweden their effects are easier to see in animals. “We receptor and has so far not been associated Spain have quite a good model for motility and mus- with any heart issues. It was first approved Japan cle physiology,” says Jakub Fichna, a biochem- in Europe in 2009 for chronic constipation Canada ist at the Medical University of Łódź, Poland. in women, and extended to use in men in The symptoms that lack robust IBS models, Pakistan 2015. It is available in Canada, but it is not yet however, are also those that have the greatest Australia approved in the United States. Clinical trials unmet medical need. For example, pain, which Germany to extend its use to IBS are ongoing. may or may not be associated with a change in Mainland China Alternatives to alosetron are also in the bowel function, is not easy to quantify — and Israel pipeline. The anti-nausea drug ramosetron, is even harder to target at a molecular level. Turkey which was originally approved in East Asia International In an effort to meet this need, Fichna’s group Bangladesh in the 1990s for use in people with cancer, average 11.2% has adapted a mouse model of colon sensitiv- Norway is also a 5-HT3 antagonist, but it is much ity to allow the team to replicate the sensation more potent than alosetron and so can be South Africa and pattern of visceral pain associated with given at lower doses. In 2008, its use in Japan Iran IBS. Fichna suspects that multiple signals are was extended to men with IBS-D, and so far Italy involved in these sensations, involving systems there have been no reports of severe side Thailand found throughout the body. “We were working effects. Although not currently approved for France mostly in opioids and cannabinoids, but now we women, ramosetron has been shown to also 0 5 10 15 20 25 30 35 are also looking at nociception and are slowly improve their IBS symptoms (S. Fukudo et al. Highest prevalence (%) entering into the serotonin area,” he says. “Prob- Gastroenterology 150, 358–366; 2016). ably all of these are involved in visceral pain.” The challenge will be to establish whether it is VARIED TARGETS (approved in 2015), may ease IBS symptoms. possible to isolate the actions of each of these Fundamentally, IBS involves a problem Problems also occur when too much bile acid systems in the gastrointestinal tract and, if they with how the bowel functions. Because of is produced, or if too little is absorbed in the can be, whether activation of particular recep- this, many drugs aim to treat symptoms small intestine. Three bile-acid modulators tors relieves or exacerbates IBS symptoms. by changing the local environment in the are in early-stage clinical trials for IBS-D — IBS drug development has come a long gut — mainly by modifying fluid levels to colesevelam and colestipol, which absorb way in the past few years. With so many treat- affect the speed of faecal transit. Lubipros- bile acid (and are already approved as choles- ments in the pipeline, now is an exciting time tone, which was approved by the FDA for terol-lowering agents), and obeticholic acid, to be an IBS researcher, says Ford. For clini- IBS-C in 2008, activates chloride channels which reduces produc- cians like Moshiree, it is a relief to finally have to increase fluid levels. Linaclotide, which tion of bile acid and is “The greater more treatment options available. “Patients was approved in the United States in 2012, set to launch later this specificity usually know within a few weeks if a drug is targets the enzyme guanylate cyclase, and year to treat an auto- of the newer going to work,” she says, “and if they don’t, you not only stimulates the release of ions and immune liver disease. drugs suggest need something else to put them on.” A better water, but also relieves pain. Diarrhoea is a Bile-acid levels can also they’ll be understanding of the multitude of mechanisms common side effect, however. Plecanatide, be increased to help much safer.” behind IBS will be pivotal, particularly in rela- which is still in phase III trials for IBS-C, with IBS-C. Elobixi- tion to how diet, anxiety and stress influence activates the same receptor as linaclotide, bat has completed phase II trials for IBS-C symptoms. Summing up the feeling within but is a weaker agonist — this should reduce in Europe and the United States; it partially the community, Fichna says that pharmacol- the chance of rebound diarrhoea. inhibits absorption of bile acid, allowing more ogy is not enough when you want to combat Around one-quarter of IBS-D cases are to pass into the colon. IBS because there are so many other factors caused by excess bile acid, which is produced Opioids have long been known to affect involved. “There is no single target, no single by the liver to help with the digestion of fats. stool composition; constipation is a rec- magic pill.” He relishes the challenges ahead. Bile-acid balance can be affected by changes ognized side effect of morphine use. The “This is part of the adventure.” ■ in the gut microbiota and by immune dys- μ-opioid receptor agonist loperamide is a regulation, which is why anti-inflammatory well-established over-the-counter medication Branwen Morgan is a freelance science writer drugs and antibiotics, such as rifaximin for general diarrhoea. It works by slowing based in Sydney, Australia.