The U.S. market for prescription pharmaceuticals to treat inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) was $4.26 billion in 2011 and is expected to reach $7.70 billion by 2017, according to Frost & Sullivan. The growth is driven by the introduction of biologicals and new, more effective therapies. Development of new approaches, however, is limited by incomplete knowledge of the underlying pathology of these diseases.
“The IBD market of about 4 million has 50% penetration, while IBS’ market of about 400 million has only 0.6% penetration,” says Debbie Toscano, senior industry analyst, Frost & Sullivan. Of the two, IBD is a more serious disease. “It may require surgery to remove the bowel, so it is prudent to manage it,” she adds.
According to the Frost & Sullivan report, “Analysis of the Expanding U.S. Market for Gastrointestinal Disorders Prescription Pharmaceuticals,” the greatest need for IBD is more efficacious disease-modifying therapeutics to slow progression and maintain remission. Evidence supports the first line use of biologics, offering “tremendous growth opportunity if payers and clinicians are willing to adopt a new treatment paradigm,” Toscano says.
In the early stages of IBD, physicians often prescribe generic, low-cost therapies like aminosalicylates, she explains. At that stage, several virtually interchangeable therapeutics are available—more so for ulcerative colitis than for Crohn’s disease, the two most common forms of IBD. Therapy then steps up to antibiotics, and then to steroids. “Steroids also are inexpensive, but have bad side effects,” Toscano points out.
“Growth opportunities exist for biologicals and other novel agents, particularly for those that justify initiation of therapy earlier in the course of IBD, as well as for first line therapies that incorporate important improvements such as enhanced delivery or administration,” she explains. “There are unmet needs for drugs that induce and maintain remission. Better efficacy is needed,” along with a better understanding of IBD and IBS to enable genomic-based therapeutics.
“Some biomarkers are emerging” for IBD, Toscano continues, “but the list is not extensive. A recent finding at the University of Cambridge resulted in a gene expression profile to enable detection of nonresponders with severe disease versus mild cases that will respond to treatment. One of the main goals is to keep patients off steroids as long as possible.”
Toscano predicts opportunities for IBD therapeutics that could fill the gap between aminosalicylates and steroids, and between steroids and biologics. Some companies are developing drugs similar to aminosalicylates that target the gut rather than being absorbed throughout the body. This reduces side effects and cuts costs because the molecule itself is not new. “Gut selective formulations are the new thing,” Toscano says.
Takeda, for example, is developing vedolizumab (similar to Tysabri®) for ulcerative colitis. The company filed a marketing authorization application with the EMA in March and the FDA in June for the gut-selective humanized monoclonal antibody as a treatment for adults with moderate to severe ulcerative colitis and Crohn’s disease.
Lialda®, by Shire, is another gut-selective reformulation. The drug was reintroduced two years ago in a delayed-release formulation to maintain remission in patients with mild to moderate ulcerative colitis. In May 2013, Shire gained an injunction against Watson Pharmaceuticals Group and its related companies, preventing them from proceeding to an abbreviated NDA for a generic version of Lialda. Shire’s Lialda remains the only once-daily mesalamine product indicated for both the induction and maintenance of remission of mild to moderate ulcerative colitis.
Janssen’s infliximab (Remicade®), the first FDA-approved biologic for IBD, is currently being evaluated in a Phase III trial to determine safety and efficacy in Chinese patients with active ulcerative colitis. A study also is being planned to evaluate the immunogenicity of influenza vaccines in relationship to maintenance infliximab dosing.
Janssen also is recruiting patients for a Phase IV multicenter, prospective, long-term, observational registry of pediatric patients with IBD. The study will evaluate the long-term safety and clinical status of patients in relation to infliximab and other therapies. Particular focus is on anti-TNF therapies. Study completion is set for December 2035. Meanwhile, Janssen is recruiting participants to bank biological samples that will be used to identify biomarkers predisposing IBD patients to develop hepatosplenic T-cell lymphoma.
Merck has several trials in various stages for IBD therapeutics. The firm is now recruiting patients for a study of biomarkers of intestinal mucosal healing in Crohn’s disease. Completion is anticipated in 2014. Another trial will determine whether HPV vaccination and/or anal dysplasia screening is needed in patients with IBD. Working with Ferring Pharmaceuticals, Merck is completing a seven-year follow-up of 562 adult and pediatric IBD patients to determine the consequences of biological treatment of IBD.
NPS Pharmaceuticals is marketing teduglutide as Gattex® for adult short bowel syndrome (SBS) patients on parenteral support, and has completed Phase II studies using teduglutide for Crohn’s disease. Teduglutide also is in preclinical studies for pediatric SBS.
“There is also a tremendous need for safe and effective treatments for severe forms of IBS, which affects a very sizeable patient population,” Toscano says.
IBS is a largely untapped pharmaceutical market, yet affects about 100 times more people than IBD. “It affects about 10% of the general population, mainly women,” says Douglas Drossman, M.D., president, Drossman Center for the Education and Practice of Biopsychosocial Care, and member of the International Foundation for Functional Gastrointestinal Disorders advisory board.
The lack of attention is attributed to an inadequate understanding of the basic pathology of the condition and because symptoms often are mild or moderate and can be managed with diet and lifestyle changes.
IBS is also a heterogeneous condition. “It is diagnosed by symptoms, and there are many determinants of those symptoms,” Dr. Drossman emphasizes. For example, IBS can occur post-infection or be caused by psychological conditions. The mucosa from these conditions may show features that promote inflammation. Additionally, “Those who get bowel infections may have IBS symptoms even though the disease is cleared. Even the nerves may be altered.”
Dr. Drossman says most current therapies address the symptoms of a particular subset of the disease, though not the severe pain sometimes associated with those symptoms, nor the underlying cause of the condition. Rather, pain is often addressed with antidepressants, “because they are better at blocking more severe pain.
What is needed is a therapy to address the underlying pathophysiology—particularly something to block the brain’s regulation of bowel disturbance and pain.”
Dr. Drossman points to Entera Health as one firm developing a new type of treatment. In May, the company presented clinical data on the use of a prescription medical food. Patients taking EnteraGam™, a serum-derived bovine immunoglobulin/protein isolate for diarrhea-predominant IBS, showed a statistically significant improvement over the control group in the number of days in which symptoms occurred.
Gerald L. Klein, M.D., sharing data with the Rome Foundation, concluded that, “EnteraGam may provide distinct nutrition for a multifaceted therapeutic approach aimed at restoring mucosal membrane integrity and inhibiting decreasing intestinal inflammation in patients with IBS-D.” EnteraGam became available commercially in the U.S. July 2013.
Furiex Pharmaceuticals’ Eluxadoline (MuDelta) is currently in two Phase III trials for diarrhea-predominant IBS, with FDA fast-track status. Eluxadoline is a first-in-class, locally acting μ-opioid receptor agonist and μ-opioid receptor antagonist. By acting on these two opioid receptors, earlier trials indicated improved control of the GI function and decreased pain. The therapeutic also appears to “mitigate the constipating effect of unopposed mu agonism,” according to Furiex. Because it acts in the gut, its limited systemic bioavailability also limits side effects. The compound is licensed to Johnson & Johnson.
In June, Ironwood Pharmaceuticals and Almirall launched Constella® (linaclotide) in Europe for adults with moderate to severe IBS. Clinical trials have shown that it reduces abdominal pain and constipation-related symptoms. In December, Ironwood and Forest Laboratories launched linaclotide in the U.S. as Linzess®, making it the first FDA-approved guanylate cyclase-C agonist.
Salix Pharmaceuticals is recruiting patients to assess the repeat treatment efficacy and safety of Rifaximin for IBS-D. The FDA is seeking input from an advisory committee on Salix’ supplemental NDA for Relistor® (methylnaltrexone bromide), a subcutaneous injection for opioid-induced constipation in patients with chronic pain. The committee was formed to provide insights into the potential for cardiovascular risks, based upon concerns with a similar drug developed by a competing company.
Pharmacogenomics also has a role to play in IBS, in terms of identifying polymorphisms to determine why some patients respond to a particular drug while others do not. Alosetron hydrochloride, developed by Glaxo SmithKline and marketed by Prometheus Laboratories, is a good example. This is a selective 5-HT3 antagonist that has been approved only for the treatment of women with severe diarrhea-predominant IBS.