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WALL STREET BIOBEAT Biobusiness Big Need in IBD: Drugs to Slow Progression Innovators Are Working to Develop New Treatments for Infammatory Bowel Disease Gail Dutton The U.S. market for prescription pharmaceuticals to treat infammatory 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 effcacious disease-modifying therapeutics to slow progression and maintain remission. Evidence supports the frst 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 frst 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 effcacy 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 fnding at the University of Cambridge resulted in a gene expression profle 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 fll the gap between aminosalicylates and steroids, and between steroids and biologics. Some companies are 14 | cruiting 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 developing drugs similar to aminosalicylates vaccination and/or anal dysplasia screening that target the gut rather than being absorbed is needed in patients with IBD. Working with throughout the body. This reduces side effects Ferring Pharmaceuticals, Merck is completand cuts costs because the molecule itself is ing a seven-year follow-up of 562 adult and not new. "Gut selective formulations are the pediatric IBD patients to determine the connew thing," Toscano says. sequences of biological treatment of IBD. Takeda, for example, is repurposing the NPS Pharmaceuticals is marketing tedumultiple sclerosis therapeutic vedolizumab glutide as Gattex® for adult short bowel syn(similar to Tysabri®) for ulcerative colitis. drome (SBS) patients on parenteral support, The company fled a marketing authoriza- and has completed Phase II studies using tedution application with the EMA in March and glutide for Crohn's disease. Teduglutide also is the FDA in June for the gut-selective human- in preclinical studies for pediatric SBS. ized monoclonal antibody as a treatment for "There is also a tremendous need for adults with moderate safe and effective to severe ulcerative treatments for severe colitis and Crohn's forms of IBS, which disease. affects a very sizeable Lialda®, by Shire, patient population," is another gut-selecToscano says. tive reformulation. IBS is a largely unThe drug was reintrotapped pharmaceuduced two years ago tical market, yet afin a delayed-release fects about 100 times formulation to mainmore people than tain remission in paIBD. "It affects about tients with mild to 10% of the general moderate ulcerative population, mainly colitis. In May 2013, women," says DougShire gained an inlas Drossman, M.D., junction against Watpresident, Drossman son Pharmaceuticals Center for the EduGroup and its related cation and Practice companies, preventof Biopsychosocial ing them from pro- The two most common forms of irritable bowel Care, and member ceeding to an abbrevi- disease are ulcerative colitis and Crohn's disease. of the International The greatest need for IBD suferers is more ated NDA for a gener- efcacious disease-modifying therapeutics to Foundation for Funcic version of Lialda. slow progression and maintain remission. tional GastrointestiShire's Lialda remains Sebastian Kaulitzki/Fotolia nal Disorders advithe only once-daily sory board. mesalamine product indicated for both the inThe lack of attention is attributed to an duction and maintenance of remission of mild inadequate understanding of the basic pato moderate ulcerative colitis. thology of the condition and because sympJanssen's infiximab (Remicade®), the frst toms often are mild or moderate and can be FDA-approved biologic for IBD, is currently managed with diet and lifestyle changes. being evaluated in a Phase III trial to deterIBS is also a heterogeneous condition. mine safety and effcacy in Chinese patients "It is diagnosed by symptoms, and there are with active ulcerative colitis. A study also is many determinants of those symptoms," Dr. being planned to evaluate the immunogenic- Drossman emphasizes. For example, IBS can ity of infuenza vaccines in relationship to occur post-infection or be caused by psychomaintenance infiximab dosing. logical conditions. The mucosa from these Janssen also is recruiting patients for a conditions may show features that promote Phase IV multicenter, prospective, long-term, infammation. Additionally, "Those who get observational registry of pediatric patients with bowel infections may have IBS symptoms IBD. The study will evaluate the long-term even though the disease is cleared. Even the safety and clinical status of patients in relation nerves may be altered." to infiximab and other therapies. Particular foDr. Drossman says most current therapies cus is on anti-TNF therapies. Study completion address the symptoms of a particular subset is set for December 2035. Meanwhile, Janssen of the disease, though not the severe pain is recruiting participants to bank biological sometimes associated with those symptoms, samples that will be used to identify biomark- nor the underlying cause of the condition. ers predisposing IBD patients to develop hepa- Rather, pain is often addressed with antidetosplenic T-cell lymphoma. pressants, "because they are better at blocking Merck has several trials in various stages more severe pain. for IBD therapeutics. The frm is now reWhat is needed is a therapy to address the August 2013 | GENengnews.com | Genetic Engineering & Biotechnology News underlying pathophysiology—particularly something to block the brain's regulation of bowel disturbance and pain." Innovators Emerge Dr. Drossman points to Entera Health as one frm 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 signifcant 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 infammation 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 frst-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 frst FDA-approved guanylate cyclase-C agonist. Salix Pharmaceuticals is recruiting patients to assess the repeat treatment effcacy 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.