Digestive Health Matters, 2014 Vol. 23, No. 3
Here are summaries of some recent news about research and treatments for digestive health.
Relistor FDA Approved for Expanded Use in Treatment of Opioid-Induced Constipation
In September 2014 the U.S. Food and Drug Administration (FDA) approved an expanded use of the drug, Relistor, for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain. The European Medicines Agency is also reviewing the drug for this treatment application. The European Union already allows for use of Relistor in patients with advanced illness.
Linaclotide (Constella) Available in Europe for Treatment of IBS-C
Linaclotide is the first medicine approved by the European Commission for the symptomatic treatment of moderate to severe irritable bowel syndrome with constipation (IBS-C) in adult patients. It is currently available in several European countries with the EU brand name Constella.
Linaclotide, a guanylate cyclase type-C (GC-C) agonist, is a prescription drug used to relieve symptoms of abdominal pain, discomfort, bloating, and bowel symptoms in people who have IBS-C or chronic idiopathic constipation (CIC). It has been shown to be safe and effective in trials. It works by increasing the amount of fluid that flows into the bowel, allowing stool to pass more easily, and reducing visceral pain.
Linaclotide (Linzess) has been available in the U.S. to treat IBS-C and CIC in adults aged 18 and older since 2012. The safety and effectiveness of Linzess for the management of IBS-C were established in two, double-blind studies in which a total of 1,604 patients were randomly assigned to take Linzess or a placebo for at least 12 weeks. Results showed Linzess was more effective in reducing the amount of abdominal pain and increasing the number of complete spontaneous bowel movements compared with placebo.
Linzess should not be used in patients 17 years of age or younger. Linzess should not be used in patients with known or suspected mechanical gastrointestinal obstruction. The most common side effect reported during clinical studies was diarrhea.
Linaclotide is being co-produced in the U.S. by Ironwood Pharmaceuticals and Forest Laboratories. Ironwood has out-licensed linaclotide to Almirall, S.A. for development in Europe; to Astellas Pharma for development in Japan, Indonesia, Korea, the Philippines, Taiwan, and Thailand; and to AstraZeneca in China.
Medical Food in the Management of Diarrhea
EnteraGamTM is a new prescription medical food product to help people manage ongoing problems with chronic loose and frequent stools (diarrhea). Medical foods are required to be used under physician supervision as part of ongoing medical care for a specific condition or disease.
EnteraGam is manufactured and distributed by Entera Health, Inc. EnteraGam is indicated for the clinical dietary management of intestinal disease (enteropathy) in patients who, because of therapeutic or chronic medical needs, have limited or impaired capacity to ingest, digest, absorb, or metabolize ordinary foodstuffs or certain nutrients. The main ingredient in EnteraGam is a specially formulated protein preparation that consists of more than 50 percent of immunoglobulin (molecules involved with immune function). This ingredient, SBI (serum-derived bovine immunoglobulin/ protein isolate), is made up of beef serum proteins. The proteins in SBI remain in the intestine and are not absorbed whole.
A research review summarizing accumulated data from prior studies, reported that specially formulated immunoglobulin sources like SBI, the main ingredient in the prescription medical food EnteraGam, have multiple effects which collectively serve to improve and maintain nutrient utilization, including water balance. This review demonstrates that other protein sources, besides immunoglobulins, do not effect in the management of intestinal disorders (enteropathy) in patients with chronic loose and frequent stools in conditions like irritable bowel syndrome with diarrhea (IBS-D). The mode of action appears to be combined effects on binding microbial components, maintaining immune balance, and managing gut barrier function, which has the result of improving nutrient utilization, including water.
The reviewers concluded that, taken together, results from studies with SBI reveal a distinctive nutritional requirement for immunoglobulins for the purpose of restoring functional homeostasis to aid in the management of enteropathy. This meets a critical requirement that the FDA has for medical foods.
The review study, by Petschow et al, was published in August 2014 in the journal, Digestive Diseases and Sciences. The authors are employed by Entera Health.
Study Evaluates Impact of SBI in People with Diarrhea-Predominant IBS
Results from a randomized, double-blind, placebo-controlled pilot study enrolling 66 subjects suggest that nutritional therapy with SBI, the ingredient found in EnteraGam – used in addition to traditional medical care – can help manage various symptoms associated with irritable bowel syndrome with diarrhea (IBS-D). The study, by Wilson et al., was published in 2013 in the journal, Clinical Medicine Insights: Gastroenterology.
A total of 45 persons completed the study per the protocol, with 31 in the SBI group and 14 in a placebo group. The symptom profile of each participant was determined during the first week, followed by a six-week treatment period. Of the subjects who did not complete the study, five were lost to follow-up, three did not comply with the study requirements, one discontinued due to lack of efficacy, and two were removed at the Principal Investigator’s discretion. The safety profile of SBI in the study was similar to that of placebo. A total of four people withdrew, from both the placebo and the SBI groups, due to nausea. No serious adverse events were reported. The proportion of subjects who withdrew was not significantly different between treatment groups.
The study showed that nutritional therapy with either 10 g/day or 5 g/day of SBI in patients was well tolerated and resulted in statistically significant improvements in days with symptoms and a trend for improvement in symptom severity scores in participants with IBS-D. In particular, the 15 participants who received 10 g/day of SBI showed significant reductions in abdominal pain, loose stools, bloating, flatulence, and urgency. The product has been extremely well tolerated for up to a year in HIV patients and up to eight months in infants. The major side effects in clinical trials (2–5%) included mild nausea, constipation, stomach cramps, headache, and increased urination. EnteraGam is contraindicated for patients with a hypersensitivity (allergy) to beef, or any components in EnteraGam. Therefore, patients who have an allergy to beef or any component of EnteraGam should not take this product. The effect of EnteraGam on nursing mothers and the infant is unknown. The choice to administer EnteraGam in pregnant or nursing mothers is up to the clinical decision of the physician.
Medical foods like EnteraGam are required by the U.S. Food and Drug Administration (FDA) regulations to be dosed and monitored by physicians as part of ongoing care for patients with chronic conditions or diseases.
A phase 2 study is underway on a new drug to treat gastroesophageal reflux disease (GERD) in patients not adequately helped by proton pump inhibitors (PPIs). The study will assess the effect of the drug (IW-3718) compared to placebo as an added treatment in GERD patients who will continue to also take a once-daily PPI. Ironwood Pharmaceuticals is developing the drug.
Review Article Concludes that Bile Acid Transport Inhibitor Elobixibat is Effective in Treating Chronic Idiopathic Constipation
Elobixibat is a first-in-class compound under investigation by Ferring Pharmaceuticals for treatment of chronic idiopathic constipation (CIC), and for irritable bowel syndrome with constipation (IBS-C).
An article recently published in the journal Therapeutic Advances in Gastroenterology reviewed data that examined the mechanisms by which bile acids can affect symptoms in CIC and the role of the drug elobixibat in managing these symptoms. Bile acids are digestive juices that have a stimulating effect in the colon. Elobixibat reduces bile absorption in the small intestine. This stimulates bowel movements by increasing fluid secretions and motility in the colon. The authors concluded that published research shows that elobixibat significantly affects the symptoms of CIC, with minimal and tolerable side effects.
In June 2014 the U.S. Food and Drug Administration (FDA) approved updated labeling for Gattex (teduglutide) for injection to include long-term data from adult patients with Short Bowel Syndrome (SBS). The revised labeling provides important information for healthcare professionals and patients about long-term use of Gattex.
The data, published in 2013, demonstrated that there was an increased response to treatment over time in all groups receiving Gattex. The open-label extension study included 88 adult patients with SBS. Investigators reported that the long-term use of Gattex in patients with SBS resulted in additional, clinically meaningful reductions in the volume and days per week of parenteral support requirements in this extension study. Thirteen patients in the study achieved complete independence from parenteral support with long-term Gattex therapy. No new unexpected safety concerns were observed with longterm Gattex treatment and the product’s safety profile remains consistent with the product’s label.
The drug works by regeneration of cells in the intestinal lining, slowing down transit through the gut and increasing blood flow, allowing for increased nutrient absorption. In studies, the drug was associated with achieving and maintaining clinically meaningful reductions in parenteral nutrition (PN) and intravenous (IV) fluid volume in adult subjects with SBS. Gattex was approved by the U.S. Food and Drug Administration (FDA) in 2012 for treatment of adult patients with SBS who are dependent on parenteral support. To help ensure that the benefits of Gattex outweigh the risks for causing other serious conditions, the drug is approved with a Risk Evaluation and Mitigation Strategy, which patients need to discuss with their doctors. While the researchers found the safety profile to be acceptable, they advise that physicians closely monitor patients beginning the drug for side effects and possible need to adjust dosage. SBS is a rare condition related to poor absorption of nutrients. It typically occurs in people who have a significant portion of their small intestine removed due to disease or injury. They cannot absorb enough water, vitamins, and other nutrients from food and may then need to use parenteral nutrition and intravenous fluids.
The supplemental new drug application (sNDA) for the antibiotic rifaximin 550 mg has been accepted for review by the U.S. Food & Drug Administration (FDA). A decision regarding the approval status of the drug for the treatment of irritable bowel syndrome with diarrhea (IBS-D) is expected by February 28, 2015.
In July 2014 Salix Pharmaceuticals reported positive results from the TARGET 3 – Phase 3 study to evaluate the efficacy and safety of repeat 14-day treatment with rifaximin for the treatment of IBS-D in people who responded to an initial 14-day treatment course with rifaximin. Compared to placebo, subjects treated with rifaximin showed statistically significant improvement in IBS-related abdominal pain and stool consistency during the 4-week, treatmentfree follow-up period in the double blind repeat treatment phase.
Results from the two initial Phase 3 clinical trials had reported adequate relief of multiple symptoms in patients with IBS-D. Rifaximin works by reducing or altering bacteria in the gut. It is only slightly absorbed in the gut and is generally tolerated well.
Solesta Available in the U.S. to Treat Bowel Incontinence
Solesta, a biocompatible tissue bulking agent, is approved by the U.S. Food and Drug Administration (FDA) for the treatment of bowel incontinence in patients 18 years and older who have failed conservative therapy (e.g., diet, fiber therapy, anti-motility medications). The drug has been approved to treat bowel incontinence in the U.S. since 2011 and in Europe since 2006. Bowel incontinence is the involuntary loss of bowel control. While the exact mechanism of action has not been identified, it is thought that the Solesta injections may narrow the anal canal and allow for better control of those muscles.
Solesta is an injectable gel delivered into the anal canal. The medication is administered by physicians certified in its use in an outpatient procedure taking approximately 10 minutes without the need for surgery or anesthesia. It should not be used in patients who have active inflammatory bowel disease, immunodeficiency disorders, previous radiation treatment to the pelvic area, significant rectal prolapse, active infections, bleeding, tumors or malformations in the anorectal area, rectal distended veins, an existing implant in the anorectal region, or allergy to hyaluronic acid based products.
The most common side effects associated with Solesta include injection area pain and bleeding. Infection and inflammation of anal tissue are more serious risks, but are less common.
Solesta is under license from and manufactured by Q-Med AB for Salix Pharmaceuticals.
The National Institute for Health and Care Excellence (NICE) has issued guidance on the use of lubiprostone (Amitiza) for treating chronic idiopathic constipation in the United Kingdom (U.K.). The guidelines stipulate that the drug should only be considered in adults who have tried at least 2 laxatives at the highest tolerated recommended doses for at least 6 months, but who have not seen an improvement in their symptoms. NICE clinical guidelines are recommendations on the appropriate treatment and care of people with specific diseases and conditions within the National Health Service (NHS) in the U.K.
A study published in 2014 in the medical journal Pain Medicine examined the efficacy and safety of lubiprostone (Amitiza) for relieving symptoms of opioid-induced constipation (OIC) in chronic non-cancer pain. The study found that patients treated with lubiprostone showed significant overall improvement for abdominal discomfort, straining, constipation severity and stool consistency when compared to placebo. The authors concluded that lubiprostone was effective and well tolerated in OIC patients with chronic non-cancer pain.
Amitiza is a prescription drug first FDA approved in 2006 to relieve abdominal pain, bloating, and straining and produce softer and more frequent bowel movements in men and women who have chronic idiopathic constipation (CIC). It is also FDA approved to treat irritable bowel syndrome with constipation (IBS-C) in women who are at least 18 years of age. Amitiza works by increasing the amount of fluid that flows into the bowel and allowing the stool to pass more easily.
The drug was FDA approved in 2013 for the treatment of OIC in patients with chronic, non-cancer pain. Opioids (such as morphine and codeine) are narcotics used to treat pain. The effectiveness of Amitiza has not been established in those taking methadone. A number of gastrointestinal (GI) symptoms are potential side effects of using opioidbased medications. The most common symptom is constipation. Other symptoms may include decreased gastric emptying, abdominal cramping, spasm, bloating, and delayed-GI transit.