Digestive Health Matters, 2012 Vol 21 No 4
Here are summaries of some recent news about research and treatments for digestive health.
The U.S. FDA has Approved the Drug Linaclotide (Linzess) for the Treatment of Irritable Bowel Syndrome with Constipation and Chronic Constipation
On August 30, 2012, Ironwood Pharmaceuticals, Inc. and Forest Laboratories, Inc. announced that the U.S. Food and Drug Administration approved the New Drug Application (NDA) for linaclotide (Linzess®), a guanylate cyclase type-C (GC-C) agonist, to treat irritable bowel syndrome with constipation (IBS-C) and chronic constipation (CC) in adults aged 17 and older. Linaclotide is a drug used to relieve symptoms of abdominal pain, discomfort, bloating, and bowel symptoms in people who have IBS-C or CC. It has been shown to be safe and effective in trials. Linaclotide works by increasing the amount of fluid that flows into the bowel, allowing stool to pass more easily, and reducing visceral pain.
The safety and effectiveness of Linzess for the management of IBS-C were established in two, double-blind studies. A total of 1,604 patients were randomly assigned to take 290 micrograms of 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.
The safety and effectiveness of Linzess for the management of chronic idiopathic constipation also were established in two, double-blind studies. A total of 1,272 patients were randomly assigned to take Linzess at doses of 145 mcg or 290 mcg or a placebo for 12 weeks. Results from these studies showed patients taking Linzess experienced more complete spontaneous bowel movements than those taking the placebo. The 290 mcg dose is not approved for chronic constipation because studies indicated it was no more effective than the 145 mcg dose.
Linzess is approved with a Boxed Warning to alert patients and health care professionals that the drug should not be used in patients 16 years of age and younger. Linzess should not be used in patients with known or suspected mechanical gastrointestinal obstruction. The most common side effect reported in during the clinical studies was diarrhea.
Ironwood and Forest are co-producing linaclotide in the United States. Ironwood has out-licensed linaclotide to Almirall, S.A. for development in Europe; and to Astellas Pharma, Inc. for development in Japan, Indonesia, Korea, the Philippines, Taiwan, and Thailand.
The European Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion recommending the marketing approval for linaclotide for the treatment of moderate to severe irritable bowel syndrome with constipation (IBS-C) in adults. The CHMP positive opinion is a recommendation to the European Commission (EC) and one of the final steps in the review of a marketing authorization application. It would be marketed under the brand name Constella, once approved.
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 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 statistically significant weekly findings in the primary endpoint and key secondary endpoint noted above were supported by daily findings in the secondary endpoints of global IBS symptoms, bloating, stool consistency and abdominal pain and discomfort. Additionally, the NEJM publication includes results of an analysis of a composite endpoint of abdominal pain or discomfort and loose or watery stools as outlined in the March 2010 draft FDA Guidance for Industry relating to the clinical evaluation of products for treatment of IBS.
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 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.
FDA Approves new Clinical Trial Looking at Repeat Treatment with Rifaximin
On November 16, 2011 Salix Pharmaceuticals announced that the U.S. Food and Drug Administration (FDA) Gastrointestinal Drugs Advisory Committee supported the Salix/FDA developed proposed design of a clinical trial to evaluate the safety, efficacy and durability of response with repeat treatment cycles of Xifaxan (rifaximin) for irritable bowel syndrome with diarrhea (IBS). A multi-center, randomized, double-blind, placebocontrolled trial with IBS patients will look at the efficacy and safety of rifaximin on repeat treatment.
Patient enrollment is planned during the first quarter of 2012. About 24 months could be required for the company to complete the trial and secure an FDA decision regarding approval.
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.
The U.K. Medicines and Healthcare Products Regulatory Agency has approved lubiprostone (Amitiza) for the treatment of chronic idiopathic constipation (CIC) and associated symptoms in adults, when response to diet and other non-pharmacological measures are inappropriate.
The U.S. Food and Drug Administration (FDA) has given priority review to an additional indication for lubiprostone for the treatment of opioid-induced constipation (OIC) in patients with chronic, non-cancer pain. FDA’s decision is expected by late January 2013.
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, placebocontrolled, 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.
Lubiprostone currently is available under the name Amitiza to treat chronic idiopathic (functional) constipation and irritable bowel syndrome with constipation.
The New Drug Application for Gattex to Treat Short Bowel Syndrome is under Review by the U.S. Food and Drug Administration (FDA)
Gattex (teduglutide) is a drug currently under investigation by NPS Pharmaceuticals, Inc. 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 October 16, 2012, the FDA’s Gastrointestinal Drugs Advisory Committee voted unanimously to recommend approval of Gattex for adults with SBS. The drug is currently under review by the FDA, which is expected to make a final decision on the drug by the end of this year.
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. Of the 566 Gattex-treated subjects, 97 SBS subjects had at least 12 months of exposure to Gattex. Across the company’s Phase 3 studies, a total of 15 patients were able to achieve independence from PN/IV. Side effects include abdominal pain, upper respiratory tract infections, nausea, injection site reactions, headaches, 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
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.
If you’re interested in taking part in this clinical trial, you will find participation and contact information in the shaded box that follows.
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.