Digestive Health Matters Vol. 21 No. 2
- A report from IFFGD research award winner, Ronnie Fass, M.D., looks at the bi-directional relationship of sleep and GERD, and its link with more aggressive symptoms of GERD. Go »
- A newly updated overview reviews causes, symptoms, diagnosis, and treatments of gastroparesis, or delayed gastric emptying; from the NIH, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Go »
Research News You Can Use
The Human Microbiome in Health and Disease
(June 2012) The National Institutes of Health (NIH) reported that researchers have mapped the normal bacteria that live in and on the healthy human body. The accomplishment sets the stage for better understanding how bacterial communities affect human health and disease.
The human body is host to trillions of microbes. These microbes outnumber the body’s cells by 10 to 1. Most of the time they are beneficial to human health, but sometimes they can cause illness. Scientists are using new genomic techniques to study these microbial communities and their genes, which collectively are known as the microbiome.
The Human Microbiome Project (HMP) was launched by NIH in 2007 to characterize the microbes found in different regions of the body, including the digestive tract. The scientists studied the microbes of 242 healthy adult volunteers by collecting tissue from 15 body sites in men and 18 in women. The scientists found that more than 10,000 microbial species occupy the human body. They estimated that the microbiome provides more genes that contribute to human survival than the human genome itself provides (8 million vs. 22,000). Humans need bacterial genes to aid in basic processes such as digestion.
“Enabling disease-specific studies is the whole point of the Human Microbiome Project,” says Dr. Barbara Methé of the J. Craig Venter Institute. “Now that we understand what the normal human microbiome looks like, we should be able to understand how changes in the microbiome are associated with, or even cause, illnesses.”
Source: National Institutes of Health (NIH). NIH Research Matters web page: nih.gov/researchmatters/ june2012/06252012microbiome.htm (Accessed June 25, 2012)
Functional Dyspepsia and Sleep
A study by Lacy and colleagues found that functional dyspepsia (FD) is associated with sleep disturbances and lower sleep quality. Sleep disturbances, such as trouble falling asleep and early awakening, may have an effect on physical as well as emotional well-being.
This may be a bi-directional relationship. In other words, people with FD may suffer from disordered sleep due to their symptoms, and the sleep loss may worsen their symptoms. Functional dyspepsia is a chronic gastrointestinal disorder characterized by upper abdominal pain or discomfort.
Symptoms frequently include burning, pressure, or fullness, which often, but not necessarily, are related to meals. Other common symptoms include early feeling of fullness (satiety), nausea, belching, and bloating.
The researchers analyzed questionnaires from 131 people with FD. Fifty people without FD were also surveyed to serve as a control. The results show that people with FD spent more time than people without in getting to sleep. Forty-three percent of those with FD had trouble falling asleep while 64% reported trouble staying asleep (Compared to 28% and 36% respectively in the control group). Additionally, Lacy noted that the more severe the FD symptom, the more likely the person was to report a sleep disturbance.
In total, 70% of people with FD reported having problems falling or staying asleep. This lack of quality sleep reduces the ability of the body to cope with pain.
Source: Lacy BE, Everhart K, Crowell, MD. Functional dyspepsia is associated with sleep disorders. Clinical Gastroenterology and Hepatology 2011 May; 9(5):410-414.
August 30, 2012 - The U.S. Food and Drug Administration (FDA) approved Linzess (linaclotide) to treat chronic idiopathic constipation and to treat irritable bowel syndrome with constipation (IBS-C) in adults aged 17 and older. Learn more
Ironwood and Forest report the U.S. FDA has accepted for review the new drug application for linaclotide for the treatment of Irritable Bowel Syndrome with Constipation and Chronic Constipation
Linaclotide is a drug being studied to relieve symptoms of abdominal pain, discomfort, bloating, and bowel symptoms in people who have irritable bowel syndrome with constipation (IBS-C), or chronic constipation. It has proved safe and effective in trials, and has recently been submitted to the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for approval in the United States and in Europe. Linaclotide works by increasing the amount of fluid that flows into the bowel, allowing stool to pass more easily, and reducing visceral pain.
On October 24, 2011 Ironwood Pharmaceuticals, Inc. and Forest Laboratories, Inc. announced that the FDA accepted for review the New Drug Application (NDA) for linaclotide, a guanylate cyclase type-C (GC-C) agonist, to treat irritable bowel syndrome with constipation (IBS-C) and chronic constipation (CC). The review, which will determine whether or not the FDA approves the drug, has a target date of September 2012.
The NDA includes efficacy and safety data from a Phase 3 program comprising four double-blind placebo-controlled trials and two open-label long term safety studies. A total of more than 2,800 patients received a once-daily dose of either linaclotide or placebo across the four placebo-controlled clinical trials: two trials in patients with IBS-C and two trials in patients with chronic constipation. In these trials, statistically significant improvements in abdominal and bowel symptoms were achieved for linaclotide-treated patients versus placebo-treated patients for all primary and secondary endpoints.
Safety data collected across the four placebo-controlled Phase 3 clinical trials demonstrated that diarrhea was the most commonly reported adverse event and led to study discontinuation in 4% to 5% of linaclotide-treated patients compared to fewer than 1% of patients receiving placebo. Additionally, over 3,200 patients have enrolled in ongoing open-label safety studies and more than 1,100 of those patients have received linaclotide for at least 12 months.
In September 2011, Ironwood announced that its European partner Almirall, S.A. submitted a Marketing Authorization Application (MAA) to the European Medicines Agency for linaclotide for the treatment of irritable bowel syndrome with constipation. Once approved, linaclotide will be marketed in Europe under the trademark Constella®.
Ironwood and Forest are co-developing linaclotide in the United States. Ironwood has out-licensed linaclotide to Almirall for development in Europe; and to Astellas Pharma, Inc. for development in Japan, Indonesia, Korea, the Philippines, Taiwan, and Thailand.
Solesta is now Available in the U.S. to treat Fecal Incontinence
In May 2011 the Food and Drug Administration (FDA) approved Solesta, a biocompatible tissue bulking agent, for the treatment of fecal incontinence in patients 18 years and older who have failed conservative therapy (e.g., diet, fiber therapy, anti-motility medications). Solesta is an injectable gel delivered into the anal canal in an outpatient procedure taking approximately 10 minutes without the need for surgery or anesthesia.
Fecal 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. The FDA based its approval on results from a clinical study of 206 patients. In the primary study, most patients received two treatments, consisting of four injections each, for a total of eight injections. After six months, more than half of the patients injected with Solesta experienced a 50 percent reduction in the number of fecal incontinence episodes. One-third of patients who received no Solesta in the study also experienced a similar reduction. Overall, a greater proportion of patients treated with Solesta experienced improvements, indicating the gel provides benefit.
Solesta is approved for use in patients ages 18 and up. 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 a registered trademark of Q-Med AB of Uppsala, Sweden; Oceana Therapeutics acquired exclusive worldwide sales and distribution rights to Solesta in June 2009. On December 20, 2011 Salix Pharmaceuticals, Ltd. acquired all of the outstanding stock of Oceana Therapeutics, Inc.
Rifaximin shows promise for treatment on non-constipated IBS
Rifaximin is an antibiotic currently under investigation for the treatment of nonconstipation irritable bowel syndrome (Non-C IBS) and IBS-related bloating. Rifaximin works by reducing or altering bacteria in the gut. In studies it has been found to improve IBS symptoms of bloating, belly pain, and diarrhea (watery or loose stools) after a 10–14 day course of treatment. It is only slightly absorbed in the gut and is generally tolerated well. Rifaximin is not yet approved by the FDA for the treatment of IBS.
Results from two Phase 3 clinical trials involving 1,260 non-constipated male and female patients with irritable bowel syndrome (Non-C IBS) were reported in the January 6, 2011 issue of the New England Journal of Medicine (NEJM) showing adequate relief of IBS symptoms, bloating, abdominal pain, and loose or watery stools.
Results from the multiple center studies indicated that 550mg rifaximin, taken orally 3 times a day for 14 days, achieved adequate relief of global IBS symptoms (primary endpoint) and adequate relief of IBS-related bloating (key secondary endpoint) in a significantly greater proportion of patients, compared with placebo, during the primary evaluation period (first 4 weeks following treatment) as well as during the entire study period (10 weeks following treatment).
The safety profile of rifaximin was similar to that of placebo.
Rifaximin is a gut-selective antibiotic with negligible systemic absorption and broad-spectrum activity in vitro against both gram-positive and gram-negative pathogens. It is currently approved by the U.S. Food and Drug Administration (FDA) for treatment of travelers’ diarrhea (under the trade name of Xifaxan®), but at lower doses and shorter duration of therapy than being studied in IBS. It is not yet approved by the FDA for the treatment of IBS. The FDA has set a target date of March 7, 2011 to complete the Priority Review for expanding the uses of Xifaxan (rifaximin) to include treatment of non-constipation irritable bowel syndrome (Non-C IBS) and IBS-related bloating.
Amitiza study looks at long-term safety
Amitiza (lubiprostone) is a prescription drug used to relieve stomach pain, bloating, and straining and produce softer and more frequent bowel movements in men and women who have chronic idiopathic (functional) constipation, and 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.
A study of Amitiza published in the March 2012 issue of the journal Alimentary Pharmacology & Therapeutics looked at the long-term safety, tolerability, and patient outcomes in people with irritable bowel syndrome with constipation (IBS-C). The researchers concluded that in patients with IBS-C, lubiprostone 8 mcg twice daily was found to be safe and well tolerated over 9–13 months of treatment. The study provides preliminary evidence for the safety of lubiprostone in the long-term treatment of IBS-C.
The study was funded in part by Sucampo Pharma Americas, Inc., Bethesda, MD and in part by Takeda Pharmaceuticals USA, Deerfield, IL.
Lubiprostone results positive in treating Opioid-Induced Bowel Dysfunction
On July 26, 2012 Sucampo Pharmaceuticals, Inc. and Takeda Pharmaceuticals USA., Inc. announced that Sucampo Pharmaceuticals announced the filing of a supplemental new drug application (sNDA) with the U.S. Food and Drug Administration (FDA) seeking approval for a new indication for lubiprostone for the treatment of opioidinduced constipation (OIC) in patients with chronic, non-cancer pain.
Lubiprostone met the primary endpoint in a phase 3 clinical trial for the treatment of opioid-induced bowel dysfunction in patients with chronic, non-cancer pain, excluding those taking methadone.
Opioids are narcotics, such as morphine and codeine, used to treat pain. A number of gastrointestinal (GI) symptoms are potential side effects of using opioidbased medications. The most common symptom is constipation. Others symptoms may include decreased gastric emptying, abdominal cramping, spasm, bloating, and delayed GI transit.
The phase 3, randomized, placebo controlled, double-blinded trial looked at the efficacy and safety of lubiprostone in patients with opioid-induced bowel dysfunction. The primary endpoint was the overall spontaneous bowel movement response rate. Over a 12 week period, the response rate for 219 lubiprostone-treated patients was 26.9% versus 18.6% for 220 placebo-treated patients.
The trial included patients in the U.S. and Europe who continued opioid therapy throughout the study.
No drug-related serious adverse events were reported for patients taking lubiprostone. The most common treatment-related adverse events (experienced by 5–10% of patients) were diarrhea, nausea, and abdominal pain.
The U.S. Food and Drug Administration (FDA) will review the new drug application for Gattex to treat Short Bowel Syndrome
Gattex (teduglutide) is a drug currently under investigation for the treatment of short bowel syndrome (SBS). Short bowel syndrome 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, and cannot absorb enough water, vitamins, and other nutrients from food. They may then need to use parenteral nutrition (PN) and intravenous (IV) fluids, the slow infusion of a solution of nutrients and fluids into a vein.
Gattex 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 PN and IV fluid volume in adult subjects with short bowel syndrome.
On January 31, 2012 NPS Pharmaceuticals, Inc. announced that the FDA has accepted and filed for review the company’s New Drug Application (NDA) for Gattex for the treatment of adults with short bowel syndrome. The acceptance of the Gattex NDA is the FDA’s determination that the application is sufficiently complete to permit a substantive review.
Gattex is a novel peptide involved in gastrointestinal regeneration and repair (recombinant analog of human glucagonlike peptide 2). NPS Pharmaceuticals is a specialty pharmaceutical company developing orphan therapeutics for rare gastrointestinal and endocrine disorders.
The company’s SBS clinical development program represents the largest and most comprehensive to date. The information in the NDA is derived from fourteen completed and one ongoing clinical study. A total of 566 subjects have been treated with teduglutide. Of the 566 subjects treated with teduglutide, 299 subjects were treated in the clinical pharmacology studies, 94 subjects in Crohn’s Disease studies, and 173 subjects in the SBS efficacy and safety studies. The initial NDA included data from 75 SBS subjects who had at least 12 months of exposure to Gattex. Side effects include abdominal pain, nausea, gastrointestinal stoma complications, and abdominal distension.
People with SBS are highly prone to malnutrition, diarrhea, dehydration, and an inability to maintain weight due to the reduced intestinal capacity to absorb macronutrients, water, and electrolytes. As a result, many patients require the long-term use of parenteral nutrition (PN) and intravenous (IV) fluids to supplement their nutritional needs and stabilize their hydration. Although PN/IV can meet basic nutrition and fluid requirements, it does not improve the body’s ability to absorb nutrients.
The long-term use of PN/IV fluids is associated with serious and life-threatening complications. Patients on parenteral support often experience a poor quality of life with difficulty sleeping, frequent urination, and loss of independence.
Phase 3 Clinical trials Begin for new treatment of Diarrhea-Predominant Irritable Bowel Syndrome
MuDelta (JNJ-27018966) is a novel drug under development for the treatment of irritable bowel syndrome with diarrhea as the predominant bowel symptom (IBS-D). The drug was designed with the purpose of treating both the diarrheal and pain symptoms of IBS-D.
Phase 3 Clinical Trial
(June 15, 2012) Recruitment of male and female adult patients has started for the Phase 3 clinical study of this drug. The purpose of Phase 3 studies is to look at effectiveness, monitor side effects, and collect information that will allow the drug or treatment to be used safely.
A completed Phase 2 proof-of-concept clinical trial evaluated the safety and efficacy of MuDelta (JNJ-27018966). In the study, MuDelta was well-tolerated and had a favorable safety profile.
The drug met its primary objectives of establishing tolerability, safety, and efficacy in a 12-week randomized, doubleblind, placebo-controlled study. The study achieved statistically and clinically significant results for its primary as well as a number of key secondary endpoints. MuDelta also demonstrated durable efficacy through the 12-week treatment period.
A total of 807 patients with IBS-D were enrolled in the phase 2 trial. The primary endpoint was a composite analysis of stool consistency and abdominal pain at week four compared with baseline symptoms. The study demonstrated that treatment with MuDelta was statistically superior to placebo for this primary endpoint.
The compound now has an agreed-upon, clear regulatory path forward with the U.S. Food and Drug Administration (FDA). The drug has been granted fast-track status by the FDA in acknowledgement of the potential to address a significant unmet medical need for patients with IBS-D.
Phase 3 trials will accumulate data that further evaluates the drug’s safety and effectiveness. Furiex Pharmaceuticals, Inc. is developing the drug under a November 2009 development and license agreement with Janssen Pharmaceutica N.V.
- Save the Date – IFFGD Professional Symposium
- Investigators Sought for Phase 3 Trials
- Joint International Neurogastroenterology and Motility Meeting
- IFFGD Seeking Applications for 2013 Research Awards
- IFFGD appeared before the Senate Defense Appropriations Subcommittee to testify about the need to support research for Gulf War Illness. Go »
- Digestive Health Alliance advocates visited House and Senate offices in Washington, DC seeking support for federal programs that aim to improve care and find cures for people with functional GI and motility disorders. Go »
- Your action is needed to help continue federal budget support for biomedical research, and to make the Functional GI and Motility Disorders Research Enhancement Act law. Go »
- Digestive Health Advocates Raise Awareness and Funds for Research. Go »