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New Drugs and Diagnostics for IBS-D

An expanded treatment arsenal and the first validated biomarker.

According to a recent clinical review, irritable bowel syndrome is the most commonly diagnosed gastrointestinal condition affecting 7% to 21% of the general population, though it is likely not a single disease but rather a “symptom cluster resulting from diverse pathologies.” As such, diagnosing IBS has traditionally been made by identifying key symptoms and excluding other organic diseases, while treatments have targeted symptoms rather than an underlying cause.

According to experts interviewed by Healio Gastroenterology, however, a number of recent advances have been made in the diagnosis and treatment of diarrhea-predominant IBS (IBS-D), including the first validated biomarker for diagnosing IBS-D and a number of new drugs, one of which has a unique mechanism of action.

First Biomarker for IBS-D

Diagnosing IBS has historically been challenging due to its complexity and heterogeneity. According to a recent systematic review and meta-analysis evaluating different diagnostic methods for IBS, symptom-based criteria such as the current gold standard Rome III criteria, as well as biomarkers and psychological markers, “performed only moderately well,” while combinations of symptoms and markers appeared to be more effective.

Researchers at Cedars-Sinai Medical Center in Los Angeles have since identified anti-cytolethal distending toxin B (CdtB) and anti-vinculin antibodies as a mechanism-based biomarker that can accurately differentiate IBS from other causes of chronic diarrhea. The data from a large-scale validation of this biomarker was presented at Digestive Disease Week (DDW) 2015 by Mark Pimentel, MD, from Cedars-Sinai, to a standing-room only crowd.

Mark Pimentel

“We know postinfectious IBS now probably accounts for the majority of patients with IBS out there, based on math modeling that was published about 2 years ago,” Pimentel told Healio Gastroenterology. “Essentially, what we discovered is a particular toxin [involved in] food poisoning that, through animal models, appeared to be the toxin that is triggering the development of IBS. Through a series of studies, we were able to determine that this toxin creates autoimmunity to a protein called vinculin. So it’s two antibodies that we measure: anti-CdtB, which is the antibody in the bloodstream against the original toxin, and the auto-antibody to vinculin.”

By combining the two antibodies, he said, IBS-D can be positively diagnosed and differentiated from Crohn’s disease, ulcerative colitis, celiac disease and healthy controls.

To validate this biomarker, Pimentel and colleagues evaluated plasma levels of anti-CdtB and anti-vinculin antibodies in 2,375 patients with IBS-D who were recruited from a large multicenter clinical trial, and compared them with 142 patients with inflammatory bowel disease, 121 with celiac disease and 43 healthy controls.

Antibody titers were highest in patients with IBS compared with all other groups individually or collectively (P < .00001), and for differentiating IBS-D from IBD (the primary endpoint), the areas under the receiver operating curves were 0.81 for anti-CdtB and 0.62 for anti-vinculin. The respective optimal cutoff points for anti-CdtB and anti-vinculin to distinguish IBS and IBD were optical densities of at least 2.8 and 1.68, which performed with 91.6% and 83.8% specificity, 43.7% and 32.6% sensitivity and positive likelihood ratios of 5.2 and 2, respectively.

“Measurement of plasma anti-CdtB and anti-vinculin in humans discriminates IBS from other forms of chronic diarrhea,” Pimentel concluded in his presentation. “This is the first diagnostic test for IBS based on a possible pathophysiological mechanism in the development of IBS. A positive diagnosis based on a test such as this may ... suggest that IBS has an autoimmune origin and may be an organic disease.”

As IBS has traditionally been a “diagnosis of exclusion,” according to Pimentel, the benefit of a test like this is that it provides the patient with a definitive diagnosis and “stops the madness” of unnecessary testing. Furthermore, “for the 40 million people in the U.S. with IBS, this is the first time we can say you have a real disease, not just a syndrome,” he said.

According to study co-author Anthony J. Lembo, MD, from Beth Israel Deaconess Medical Center at Harvard Medical School, the lack of readily available biomarkers in IBS has limited understanding of its pathophysiology and hampered drug development.

“Without a well-defined biomarker, it’s been difficult to really characterize the patients well and measure outcomes. This biomarker has potential to open new doors and new areas of research into the pathophysiology of IBS, so it’s very exciting,” he said in an interview.

Also important, Lembo said, is the identification of a “plausible mechanism of action” by this study. “We know that a number of people develop postinfectious IBS, and this represents a possible link as to the mechanism of action — why people get IBS symptoms after an infection.” However, a limitation of the biomarker is it may represent a subset — rather than all — IBS patients. “A number of healthy controls also seemed to have this marker, so it may not be the only explanation for why people are getting IBS,” he said.

A number of studies evaluating anti-CdtB and anti-vinculin for mixed IBS and constipation-predominant IBS (IBS-C), as well as predictions of severity and improvement are currently ongoing, Pimentel said. The test is commercially available and physicians globally are already ordering it, he added.

Findings from the TARGET 3 study, the clinical trial from which Pimentel and colleagues recruited their cohort, were also presented at DDW, which in part led to the recent FDA approval of Xifaxin (rifaximin, Salix) for IBS-D.

Rifaximin for IBS-D

Until recently, the only other FDA-approved treatment for IBS-D has been Lotronex (alosetron hydrochloride, Prometheus), which is approved for women with severe IBS-D who have not responded to traditional therapies. It’s “biggest limitation,” Lembo said, “is its association with ischemic colitis,” which in part has limited its overall use.

Anthony J. Lembo

The major challenge in drug development for IBS over the past 20 years has been an exclusive focus on treating symptoms, Pimentel said. For patients with IBS-C, laxatives like Amitiza (lubiprostone, Sucampo Pharma/Takeda) and Linzess (linaclotide, Actavis/Ironwood) are typically prescribed, and patients with IBS-D are prescribed tricyclics or alosetron, “which just slow the gut down; they’re not really treating the cause of IBS,” he said. “I think that’s why we need new therapies, and rifaximin comes in at a different angle than everything else. Everything else is either a laxative or an antidiarrheal, and rifaximin comes in as a possible mechanistic treatment.”

According to a news release from the FDA announcing the drug’s approval in May, rifaximin is an antibiotic derived from rifampin, previously approved for travelers’ diarrhea caused by E. coli and for reducing risk of recurring overt hepatic encephalopathy in adults. It may be taken orally three times a day for 2 weeks, and patients who have symptom recurrence can be retreated for 2 additional weeks, but no more than twice. Its treatment mechanism for IBS-D is thought to be related to changes in gut bacteria, and its approval followed results from the TARGET 3 trial, which were recently presented at DDW 2015 by William D. Chey, MD, from University of Michigan Health System.

“TARGET 1 and 2 were large, randomized placebo-controlled trials that were intended to assess the efficacy of a single course of rifaximin in patients with diarrhea-predominant IBS, and those very methodologically rigorous studies showed that a single course of rifaximin did indeed improve symptoms in a greater proportion of patients with IBS-D compared to placebo,” Chey told Healio Gastroenterology. “And that’s just two of the five randomized, controlled trials that showed the same thing; so the publication of TARGET 1 and 2 in the New England Journal of Medicine really bolstered the evidence supporting the efficacy of a single course of rifaximin for IBS-D.”

The identically designed TARGET 1 and 2 trials collectively evaluated 1,260 patients with IBS-D who were randomly assigned to receive 550-mg rifaximin or placebo three times a day for 2 weeks and then followed for an additional 10 weeks. The primary endpoint was the proportion of patients who reported adequate improvement in global IBS symptoms for at least 2 of the first 4 weeks after treatment.

Significantly more patients who received rifaximin achieved the primary endpoint compared with those who received placebo: 40.8% vs. 31.2% (P = .01) in TARGET 1; 40.6% vs. 32.2% (P = .03) in TARGET 2; and 40.7% vs. 31.7% (P < .001) in both trials combined. More patients who received rifaximin also reported adequate improvement in bloating: 39.5% vs. 28.7% (P = .005) in TARGET 1; 41% vs. 31.9% (P = .02) in TARGET 2; and 40.2% vs. 30.3% (P < .001) in both trials combined. Finally, more patients who received rifaximin responded to treatment based on daily assessments of symptoms, bloating, abdominal pain and stool consistency, and adverse events were comparable between groups.

“The antibiotic effect of rifaximin is the presumed mechanism for its sustained beneficial effects in patients with IBS,” the study authors wrote. “However, there is debate about which antibiotic-related effect is most important. On the basis of existing data, there are three reasonable explanations: rifaximin affects gut bacteria and reduces bacterial products that negatively affect the host, the effect on gut flora reduces local mucosal engagement of bacteria such as the immune responses of the host, or the antibiotic alters both the bacteria and the host response. Whatever the final pathway, the durable effects suggest that rifaximin is affecting an underlying cause of IBS that is linked to an alteration in the intestinal microbiota.”

The FDA did not approve rifaximin for IBS-D following the publication of TARGET 1 and 2, Chey said. “One of the main concerns of the advisory committee that convened to discuss the approval of rifaximin was not fully understanding the proportion of patients who develop recurrent symptoms after a single course of rifaximin, and whether a repeat course of rifaximin would offer any benefits to patients who had suffered with recurrent symptoms. So that led to TARGET 3 ... a very large methodologically rigorous randomized controlled trial that was intended to assess the efficacy of repeat courses of rifaximin in patients with IBS-D who had responded to an initial course of rifaximin,” Chey said.

William D. Chey

The first phase of the study involved 2,579 patients with IBS-D who received an open-label, 2-week course of 550-mg rifaximin taken three times daily. Those who responded and subsequently experienced a recurrence of symptoms within 18 weeks (n = 636 after exclusion) were then randomly assigned to receive a second, 2-week, double-blind, repeat treatments of rifaximin or placebo. All patients who completed the first retreatment received a second retreatment with rifaximin or placebo separated by 10 weeks.

“We found that 64% of the patients who responded to the initial open-label course of rifaximin developed a relapse of their symptoms over the course of the 18-week follow-up period,” Chey said. “Interestingly, more than a third [36%] developed no symptoms during 18 weeks of follow-up after the initial course of rifaximin. So some of these patients get a more durable response ... and the two-thirds of patients who developed recurrence ... were then entered into the randomized placebo-controlled retreatment phase of the trial.”

The primary endpoint was the proportion of patients who responded during at least 2 of 4 weeks for abdominal pain and stool consistency, which was assessed after the first repeat treatment and achieved by 33% of the rifaximin group compared with 25% of the placebo group (P = .02). After the second repeat treatment, 35% of the rifaximin group had improved abdominal pain and stool consistency compared with 27% of the placebo group (P = .03). Individual symptoms, including urgency, bloating, abdominal pain and stool consistency also improved after the first repeat treatment, with treatment gains of 8.1% to 9.2% compared with placebo (all P < .05). Treatment gains after the second repeat treatment were 7.6% to 12.1% compared with placebo (P < .05 for urgency and bloating), and the most common adverse events were nausea (4%), upper respiratory tract infection (4%) and urinary tract infection (3%).

“Repeat treatment with rifaximin 550 mg taken three times daily for 14 days in patients with recurrent IBS-D symptoms confers significant improvement during treatment-free follow-up periods,” Chey concluded in his presentation. “Repeat treatment with rifaximin led to significantly greater likelihood of improvement in IBS-related symptoms than placebo, including abdominal pain and stool consistency, bloating as well as urgency, and from a safety standpoint, repeated courses of rifaximin were generally well tolerated.”

Eluxadoline for IBS-D

In the same May 27 FDA announcement of the approval of rifaximin for IBS-D, the approval of Viberzi (eluxadoline, Patheon Pharmaceuticals), a locally active, mixed mu-opioid receptor agonist and delta-opioid receptor antagonist was also announced.

Eluxadoline is taken orally twice daily with food, contains a new active ingredient and activates mu while inhibiting delta opioid receptors that may reduce bowel contractions, the FDA news release said.

According to Chey, this new drug’s mechanism of action has some similarities to Imodium [loperamide, Janssen], another mu-opioid agonist, “but it is also a delta-opioid antagonist, so this drug also affects a different type of opioid receptor.”

“Eluxadoline is essentially an antidiarrheal,” Pimentel said. “It’s almost like Lomotil [diphenoxylate/atropine, Pfizer], a scheduled narcotic-like drug that slows the gut down if you have diarrhea. The difference between Lomotil and eluxadoline is that Lomotil never went through phase 3 clinical trials for IBS. But essentially, eluxadoline went that distance and so has been shown to be efficacious in IBS in terms of diarrhea.”

Chey also presented data from two large phase 3, double-blind, placebo-controlled clinical trials of eluxadoline at DDW, which aimed to evaluate the sustained efficacy of twice-daily treatment. “One was a 26-week randomized controlled trial, the other was a 12-month trial,” he said. “The efficacy endpoint was also a composite endpoint consisting of an improvement in abdominal pain and stool consistency. For the FDA, the primary efficacy endpoint was assessed at 12 weeks, and for the European Medicines Agency, there was also an assessment at 26 weeks.”

Collectively, the two trials enrolled 2,428 patients with IBS-D who were randomly assigned to receive 75 mg or 100 mg eluxadoline or placebo twice daily. Significantly more patients in the 100 mg eluxadoline group were composite responders compared with the placebo group over every time interval (P < .017).

“For the 12-week assessment ... eluxadoline at a dose of 75 mg led to an improvement in 24% to 29% of patients vs. 16% to 17% with placebo, and for that higher dose of 100 mg twice a day the efficacy proportion that responded was 25% to 30% compared to 16% to 17% with placebo,” Chey said. “If you look at the pooled data, eluxadoline 75 mg led to improvements in 26%; for 100 mg, 27% vs. 17% with placebo; and if you look at the 1-to-26 week pooled data, [with] the 75-mg dosage of eluxadoline, 27% responded vs. 20% with placebo and 31% responded with the higher dose vs. around 20% with placebo. So it’s a therapeutic gain in that 10% to 12% range.

“The effect of this drug is pretty quick,” he added. “You start to see clear separation of the curves between the two doses of eluxadoline and placebo within a week.”

Adverse events and serious adverse events were comparable across the 75-mg (60.2%, 4.2%), 100-mg (58.2%, 4.8%) and placebo (55.7%, 3%) groups, the most common of which included constipation, nausea and abdominal pain.

“One issue that’s really important to be aware of is the fact that there were some cases of abdominal pain and elevated liver enzymes, which were eventually attributed to sphincter Oddi spasms with eluxadoline vs. placebo,” Chey said. “In fact, there were 10 cases out of 1,666 patients — an incidence rate of 0.6% — so it’s a pretty rare event, but it does happen, and all events went away with discontinuation of the drug. All of the events occurred in individuals with a history of prior cholecystectomy, so this drug would probably not be appropriate for someone who had a previous cholecystectomy. In addition, there were four other patients with abdominal pain and elevated pancreatic enzymes suggestive of acute pancreatitis. Three of those individuals had a history of alcohol abuse, and one had a history of biliary sludge. So, this drug would also not be appropriate for people consuming significant amounts of alcohol.”

Patients with a history of bile duct obstruction, pancreatitis, severe liver impairment or severe constipation, or patients who consume more than three alcoholic drinks per day should not take eluxadoline, the FDA news release said.

Addressing Subsets of IBS Patients

According to Chey, these newly approved drugs, like all drugs for IBS, are intended to treat the symptoms of different subsets of IBS patients.

“IBS being a symptom-based condition is heterogeneous both in terms of its symptom presentation and pathophysiology, and because of that ... it’s not surprising that virtually all of the drugs that have been evaluated in IBS offer an efficacy in the range between 7% to 15% — optimistically 20% — over placebo,” he said. “I think the reason for that is we’re designing drugs that address a specific mechanism or pathophysiological factor in this heterogeneous, symptom-based condition. So what we’re doing is developing drugs that are likely to improve symptoms in a subset of IBS sufferers, but as long as IBS remains a purely symptom-based condition, there really isn’t ever going to be a silver bullet that makes all IBS sufferers better.”

The bottom line, he said, is that these drugs are likely to be positioned as second-line therapies after patients have tried over-the-counter remedies, but where they ultimately fit in the treatment algorithm will depend on payers and clinical profiling.

“We’ve gotten a number of new drugs for IBS-C, including lubiprostone as well as linaclotide,” Chey said, “but we haven’t had a new drug approved for IBS-D since alosetron,” which was approved in June 2002. “So it’s been quite a long time since we’ve seen any new therapeutics that have received FDA approval for that group of patients. These recent events are exciting because they open a door to a number of new options for clinicians who are taking care of patients with IBS and diarrhea.” – by Adam Leitenberger

Disclosures: Chey reports he is a consultant for Ardelyx, AstraZeneca, Asubio, Forest, Furiex, Ironwood, Nestle, Prometheus, Salix, SK, Sucampo and Takeda, and has received research grants from Ironwood, Prometheus, Perrigo and Nestle. Lembo reports he is a consultant for AstraZeneca, Commonwealth Labs, GlaxoSmithKline, Forest, Ironwood, Prometheus and Salix, has received research grants from Prometheus, and is on the scientific advisory board for Prometheus and Ironwood/Forest. Pimentel reports he is a consultant for Commonwealth Labs, Naia Pharmaceuticals, Micropharma, Salix and Synthetic Biologics, and Cedars-Sinai has a licensing agreement with Commonwealth Labs, Naia Pharmaceuticals, Salix Pharmaceuticals and Synthetic Biologics.

According to a recent clinical review, irritable bowel syndrome is the most commonly diagnosed gastrointestinal condition affecting 7% to 21% of the general population, though it is likely not a single disease but rather a “symptom cluster resulting from diverse pathologies.” As such, diagnosing IBS has traditionally been made by identifying key symptoms and excluding other organic diseases, while treatments have targeted symptoms rather than an underlying cause.

According to experts interviewed by Healio Gastroenterology, however, a number of recent advances have been made in the diagnosis and treatment of diarrhea-predominant IBS (IBS-D), including the first validated biomarker for diagnosing IBS-D and a number of new drugs, one of which has a unique mechanism of action.

First Biomarker for IBS-D

Diagnosing IBS has historically been challenging due to its complexity and heterogeneity. According to a recent systematic review and meta-analysis evaluating different diagnostic methods for IBS, symptom-based criteria such as the current gold standard Rome III criteria, as well as biomarkers and psychological markers, “performed only moderately well,” while combinations of symptoms and markers appeared to be more effective.

Researchers at Cedars-Sinai Medical Center in Los Angeles have since identified anti-cytolethal distending toxin B (CdtB) and anti-vinculin antibodies as a mechanism-based biomarker that can accurately differentiate IBS from other causes of chronic diarrhea. The data from a large-scale validation of this biomarker was presented at Digestive Disease Week (DDW) 2015 by Mark Pimentel, MD, from Cedars-Sinai, to a standing-room only crowd.

Mark Pimentel

“We know postinfectious IBS now probably accounts for the majority of patients with IBS out there, based on math modeling that was published about 2 years ago,” Pimentel told Healio Gastroenterology. “Essentially, what we discovered is a particular toxin [involved in] food poisoning that, through animal models, appeared to be the toxin that is triggering the development of IBS. Through a series of studies, we were able to determine that this toxin creates autoimmunity to a protein called vinculin. So it’s two antibodies that we measure: anti-CdtB, which is the antibody in the bloodstream against the original toxin, and the auto-antibody to vinculin.”

By combining the two antibodies, he said, IBS-D can be positively diagnosed and differentiated from Crohn’s disease, ulcerative colitis, celiac disease and healthy controls.

To validate this biomarker, Pimentel and colleagues evaluated plasma levels of anti-CdtB and anti-vinculin antibodies in 2,375 patients with IBS-D who were recruited from a large multicenter clinical trial, and compared them with 142 patients with inflammatory bowel disease, 121 with celiac disease and 43 healthy controls.

Antibody titers were highest in patients with IBS compared with all other groups individually or collectively (P < .00001), and for differentiating IBS-D from IBD (the primary endpoint), the areas under the receiver operating curves were 0.81 for anti-CdtB and 0.62 for anti-vinculin. The respective optimal cutoff points for anti-CdtB and anti-vinculin to distinguish IBS and IBD were optical densities of at least 2.8 and 1.68, which performed with 91.6% and 83.8% specificity, 43.7% and 32.6% sensitivity and positive likelihood ratios of 5.2 and 2, respectively.

“Measurement of plasma anti-CdtB and anti-vinculin in humans discriminates IBS from other forms of chronic diarrhea,” Pimentel concluded in his presentation. “This is the first diagnostic test for IBS based on a possible pathophysiological mechanism in the development of IBS. A positive diagnosis based on a test such as this may ... suggest that IBS has an autoimmune origin and may be an organic disease.”

As IBS has traditionally been a “diagnosis of exclusion,” according to Pimentel, the benefit of a test like this is that it provides the patient with a definitive diagnosis and “stops the madness” of unnecessary testing. Furthermore, “for the 40 million people in the U.S. with IBS, this is the first time we can say you have a real disease, not just a syndrome,” he said.

PAGE BREAK

According to study co-author Anthony J. Lembo, MD, from Beth Israel Deaconess Medical Center at Harvard Medical School, the lack of readily available biomarkers in IBS has limited understanding of its pathophysiology and hampered drug development.

“Without a well-defined biomarker, it’s been difficult to really characterize the patients well and measure outcomes. This biomarker has potential to open new doors and new areas of research into the pathophysiology of IBS, so it’s very exciting,” he said in an interview.

Also important, Lembo said, is the identification of a “plausible mechanism of action” by this study. “We know that a number of people develop postinfectious IBS, and this represents a possible link as to the mechanism of action — why people get IBS symptoms after an infection.” However, a limitation of the biomarker is it may represent a subset — rather than all — IBS patients. “A number of healthy controls also seemed to have this marker, so it may not be the only explanation for why people are getting IBS,” he said.

A number of studies evaluating anti-CdtB and anti-vinculin for mixed IBS and constipation-predominant IBS (IBS-C), as well as predictions of severity and improvement are currently ongoing, Pimentel said. The test is commercially available and physicians globally are already ordering it, he added.

Findings from the TARGET 3 study, the clinical trial from which Pimentel and colleagues recruited their cohort, were also presented at DDW, which in part led to the recent FDA approval of Xifaxin (rifaximin, Salix) for IBS-D.

Rifaximin for IBS-D

Until recently, the only other FDA-approved treatment for IBS-D has been Lotronex (alosetron hydrochloride, Prometheus), which is approved for women with severe IBS-D who have not responded to traditional therapies. It’s “biggest limitation,” Lembo said, “is its association with ischemic colitis,” which in part has limited its overall use.

Anthony J. Lembo

The major challenge in drug development for IBS over the past 20 years has been an exclusive focus on treating symptoms, Pimentel said. For patients with IBS-C, laxatives like Amitiza (lubiprostone, Sucampo Pharma/Takeda) and Linzess (linaclotide, Actavis/Ironwood) are typically prescribed, and patients with IBS-D are prescribed tricyclics or alosetron, “which just slow the gut down; they’re not really treating the cause of IBS,” he said. “I think that’s why we need new therapies, and rifaximin comes in at a different angle than everything else. Everything else is either a laxative or an antidiarrheal, and rifaximin comes in as a possible mechanistic treatment.”

According to a news release from the FDA announcing the drug’s approval in May, rifaximin is an antibiotic derived from rifampin, previously approved for travelers’ diarrhea caused by E. coli and for reducing risk of recurring overt hepatic encephalopathy in adults. It may be taken orally three times a day for 2 weeks, and patients who have symptom recurrence can be retreated for 2 additional weeks, but no more than twice. Its treatment mechanism for IBS-D is thought to be related to changes in gut bacteria, and its approval followed results from the TARGET 3 trial, which were recently presented at DDW 2015 by William D. Chey, MD, from University of Michigan Health System.

“TARGET 1 and 2 were large, randomized placebo-controlled trials that were intended to assess the efficacy of a single course of rifaximin in patients with diarrhea-predominant IBS, and those very methodologically rigorous studies showed that a single course of rifaximin did indeed improve symptoms in a greater proportion of patients with IBS-D compared to placebo,” Chey told Healio Gastroenterology. “And that’s just two of the five randomized, controlled trials that showed the same thing; so the publication of TARGET 1 and 2 in the New England Journal of Medicine really bolstered the evidence supporting the efficacy of a single course of rifaximin for IBS-D.”

PAGE BREAK

The identically designed TARGET 1 and 2 trials collectively evaluated 1,260 patients with IBS-D who were randomly assigned to receive 550-mg rifaximin or placebo three times a day for 2 weeks and then followed for an additional 10 weeks. The primary endpoint was the proportion of patients who reported adequate improvement in global IBS symptoms for at least 2 of the first 4 weeks after treatment.

Significantly more patients who received rifaximin achieved the primary endpoint compared with those who received placebo: 40.8% vs. 31.2% (P = .01) in TARGET 1; 40.6% vs. 32.2% (P = .03) in TARGET 2; and 40.7% vs. 31.7% (P < .001) in both trials combined. More patients who received rifaximin also reported adequate improvement in bloating: 39.5% vs. 28.7% (P = .005) in TARGET 1; 41% vs. 31.9% (P = .02) in TARGET 2; and 40.2% vs. 30.3% (P < .001) in both trials combined. Finally, more patients who received rifaximin responded to treatment based on daily assessments of symptoms, bloating, abdominal pain and stool consistency, and adverse events were comparable between groups.

“The antibiotic effect of rifaximin is the presumed mechanism for its sustained beneficial effects in patients with IBS,” the study authors wrote. “However, there is debate about which antibiotic-related effect is most important. On the basis of existing data, there are three reasonable explanations: rifaximin affects gut bacteria and reduces bacterial products that negatively affect the host, the effect on gut flora reduces local mucosal engagement of bacteria such as the immune responses of the host, or the antibiotic alters both the bacteria and the host response. Whatever the final pathway, the durable effects suggest that rifaximin is affecting an underlying cause of IBS that is linked to an alteration in the intestinal microbiota.”

The FDA did not approve rifaximin for IBS-D following the publication of TARGET 1 and 2, Chey said. “One of the main concerns of the advisory committee that convened to discuss the approval of rifaximin was not fully understanding the proportion of patients who develop recurrent symptoms after a single course of rifaximin, and whether a repeat course of rifaximin would offer any benefits to patients who had suffered with recurrent symptoms. So that led to TARGET 3 ... a very large methodologically rigorous randomized controlled trial that was intended to assess the efficacy of repeat courses of rifaximin in patients with IBS-D who had responded to an initial course of rifaximin,” Chey said.

William D. Chey

The first phase of the study involved 2,579 patients with IBS-D who received an open-label, 2-week course of 550-mg rifaximin taken three times daily. Those who responded and subsequently experienced a recurrence of symptoms within 18 weeks (n = 636 after exclusion) were then randomly assigned to receive a second, 2-week, double-blind, repeat treatments of rifaximin or placebo. All patients who completed the first retreatment received a second retreatment with rifaximin or placebo separated by 10 weeks.

“We found that 64% of the patients who responded to the initial open-label course of rifaximin developed a relapse of their symptoms over the course of the 18-week follow-up period,” Chey said. “Interestingly, more than a third [36%] developed no symptoms during 18 weeks of follow-up after the initial course of rifaximin. So some of these patients get a more durable response ... and the two-thirds of patients who developed recurrence ... were then entered into the randomized placebo-controlled retreatment phase of the trial.”

The primary endpoint was the proportion of patients who responded during at least 2 of 4 weeks for abdominal pain and stool consistency, which was assessed after the first repeat treatment and achieved by 33% of the rifaximin group compared with 25% of the placebo group (P = .02). After the second repeat treatment, 35% of the rifaximin group had improved abdominal pain and stool consistency compared with 27% of the placebo group (P = .03). Individual symptoms, including urgency, bloating, abdominal pain and stool consistency also improved after the first repeat treatment, with treatment gains of 8.1% to 9.2% compared with placebo (all P < .05). Treatment gains after the second repeat treatment were 7.6% to 12.1% compared with placebo (P < .05 for urgency and bloating), and the most common adverse events were nausea (4%), upper respiratory tract infection (4%) and urinary tract infection (3%).

PAGE BREAK

“Repeat treatment with rifaximin 550 mg taken three times daily for 14 days in patients with recurrent IBS-D symptoms confers significant improvement during treatment-free follow-up periods,” Chey concluded in his presentation. “Repeat treatment with rifaximin led to significantly greater likelihood of improvement in IBS-related symptoms than placebo, including abdominal pain and stool consistency, bloating as well as urgency, and from a safety standpoint, repeated courses of rifaximin were generally well tolerated.”

Eluxadoline for IBS-D

In the same May 27 FDA announcement of the approval of rifaximin for IBS-D, the approval of Viberzi (eluxadoline, Patheon Pharmaceuticals), a locally active, mixed mu-opioid receptor agonist and delta-opioid receptor antagonist was also announced.

Eluxadoline is taken orally twice daily with food, contains a new active ingredient and activates mu while inhibiting delta opioid receptors that may reduce bowel contractions, the FDA news release said.

According to Chey, this new drug’s mechanism of action has some similarities to Imodium [loperamide, Janssen], another mu-opioid agonist, “but it is also a delta-opioid antagonist, so this drug also affects a different type of opioid receptor.”

“Eluxadoline is essentially an antidiarrheal,” Pimentel said. “It’s almost like Lomotil [diphenoxylate/atropine, Pfizer], a scheduled narcotic-like drug that slows the gut down if you have diarrhea. The difference between Lomotil and eluxadoline is that Lomotil never went through phase 3 clinical trials for IBS. But essentially, eluxadoline went that distance and so has been shown to be efficacious in IBS in terms of diarrhea.”

Chey also presented data from two large phase 3, double-blind, placebo-controlled clinical trials of eluxadoline at DDW, which aimed to evaluate the sustained efficacy of twice-daily treatment. “One was a 26-week randomized controlled trial, the other was a 12-month trial,” he said. “The efficacy endpoint was also a composite endpoint consisting of an improvement in abdominal pain and stool consistency. For the FDA, the primary efficacy endpoint was assessed at 12 weeks, and for the European Medicines Agency, there was also an assessment at 26 weeks.”

Collectively, the two trials enrolled 2,428 patients with IBS-D who were randomly assigned to receive 75 mg or 100 mg eluxadoline or placebo twice daily. Significantly more patients in the 100 mg eluxadoline group were composite responders compared with the placebo group over every time interval (P < .017).

“For the 12-week assessment ... eluxadoline at a dose of 75 mg led to an improvement in 24% to 29% of patients vs. 16% to 17% with placebo, and for that higher dose of 100 mg twice a day the efficacy proportion that responded was 25% to 30% compared to 16% to 17% with placebo,” Chey said. “If you look at the pooled data, eluxadoline 75 mg led to improvements in 26%; for 100 mg, 27% vs. 17% with placebo; and if you look at the 1-to-26 week pooled data, [with] the 75-mg dosage of eluxadoline, 27% responded vs. 20% with placebo and 31% responded with the higher dose vs. around 20% with placebo. So it’s a therapeutic gain in that 10% to 12% range.

“The effect of this drug is pretty quick,” he added. “You start to see clear separation of the curves between the two doses of eluxadoline and placebo within a week.”

Adverse events and serious adverse events were comparable across the 75-mg (60.2%, 4.2%), 100-mg (58.2%, 4.8%) and placebo (55.7%, 3%) groups, the most common of which included constipation, nausea and abdominal pain.

“One issue that’s really important to be aware of is the fact that there were some cases of abdominal pain and elevated liver enzymes, which were eventually attributed to sphincter Oddi spasms with eluxadoline vs. placebo,” Chey said. “In fact, there were 10 cases out of 1,666 patients — an incidence rate of 0.6% — so it’s a pretty rare event, but it does happen, and all events went away with discontinuation of the drug. All of the events occurred in individuals with a history of prior cholecystectomy, so this drug would probably not be appropriate for someone who had a previous cholecystectomy. In addition, there were four other patients with abdominal pain and elevated pancreatic enzymes suggestive of acute pancreatitis. Three of those individuals had a history of alcohol abuse, and one had a history of biliary sludge. So, this drug would also not be appropriate for people consuming significant amounts of alcohol.”

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Patients with a history of bile duct obstruction, pancreatitis, severe liver impairment or severe constipation, or patients who consume more than three alcoholic drinks per day should not take eluxadoline, the FDA news release said.

Addressing Subsets of IBS Patients

According to Chey, these newly approved drugs, like all drugs for IBS, are intended to treat the symptoms of different subsets of IBS patients.

“IBS being a symptom-based condition is heterogeneous both in terms of its symptom presentation and pathophysiology, and because of that ... it’s not surprising that virtually all of the drugs that have been evaluated in IBS offer an efficacy in the range between 7% to 15% — optimistically 20% — over placebo,” he said. “I think the reason for that is we’re designing drugs that address a specific mechanism or pathophysiological factor in this heterogeneous, symptom-based condition. So what we’re doing is developing drugs that are likely to improve symptoms in a subset of IBS sufferers, but as long as IBS remains a purely symptom-based condition, there really isn’t ever going to be a silver bullet that makes all IBS sufferers better.”

The bottom line, he said, is that these drugs are likely to be positioned as second-line therapies after patients have tried over-the-counter remedies, but where they ultimately fit in the treatment algorithm will depend on payers and clinical profiling.

“We’ve gotten a number of new drugs for IBS-C, including lubiprostone as well as linaclotide,” Chey said, “but we haven’t had a new drug approved for IBS-D since alosetron,” which was approved in June 2002. “So it’s been quite a long time since we’ve seen any new therapeutics that have received FDA approval for that group of patients. These recent events are exciting because they open a door to a number of new options for clinicians who are taking care of patients with IBS and diarrhea.” – by Adam Leitenberger

Disclosures: Chey reports he is a consultant for Ardelyx, AstraZeneca, Asubio, Forest, Furiex, Ironwood, Nestle, Prometheus, Salix, SK, Sucampo and Takeda, and has received research grants from Ironwood, Prometheus, Perrigo and Nestle. Lembo reports he is a consultant for AstraZeneca, Commonwealth Labs, GlaxoSmithKline, Forest, Ironwood, Prometheus and Salix, has received research grants from Prometheus, and is on the scientific advisory board for Prometheus and Ironwood/Forest. Pimentel reports he is a consultant for Commonwealth Labs, Naia Pharmaceuticals, Micropharma, Salix and Synthetic Biologics, and Cedars-Sinai has a licensing agreement with Commonwealth Labs, Naia Pharmaceuticals, Salix Pharmaceuticals and Synthetic Biologics.