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Oral Biologics: A Boon to Inflammatory Bowel Disease

Centers for Disease Control and Prevention estimates that approximately 1.4 million people in the US are suffering from Inflammatory Bowel Disease (IBD). It significantly affects the gastrointestinal tract; under the IBD umbrella, the two most common indications are Ulcerative Colitis (UC) and Crohn’s Disease (CD).


Abnormal immune response is the root cause of both illnesses; the immune system misidentifies food, bacteria, and other material in the intestine for foreign substance and directs its white blood cells into the intestinal lining causing inflammation. This article focuses on the present scenario of IBD with a specific focus on the peptide based treatment. It intends to highlight the likely future evolution of treatment regimes based on the emerging oral peptide therapy.


In Ulcerative Colitis, tiny ulcers leading to pus and mucous can be seen on patient’s large intestine. Ulcerative Colitis likes to restrict itself to the colon and the inflammation can be seen only on the mucosal layer of colon. Patients show loosening of the stool as early signs of the disease. The loosening is progressive and accompanied by blood and mucous in the stool. The ongoing inflammation produces other symptoms, like abdominal pain, cramping, diarrhoea and fatigue. The disease can be categorized as mild, moderate, and advanced depending on the severity of the symptoms. On the other hand, in Crohn’s Disease, any part of GI tract can be affected and any layer of bowel wall can be inflamed.


A Widespread Occurrence

Centers for Disease Control and Prevention, USA estimated that as many as 1.4 million people in USA are suffering from IBD. The worldwide incidence rate of Ulcerative Colitis varies between 0.5 - 24.5 per 100,000 persons, while that of Crohn’s disease varies between 0.1 - 16 per 100,000 persons. The prevalence rate of IBD has been reported to be up to 396 per 100,000 persons. The disease is more prevalent amongst people aged 15 - 30 years, although people of any age group can be affected; in fact, about 10% of the cases are known to occur in individuals younger than 18 years. It has also been reported that Ulcerative Colitis is slightly more common in males whereas Crohn’s disease is marginally more frequent in women. About 10%-20% of people with UC have family members previously suffering from the disease. The disease has been more frequently diagnosed amongst people with European origin and people of Jewish heritage. Across the world, the highest incidents occur in the US, Canada, the UK, and Scandinavia. The cause of the disease is still unknown. However, researchers have indicated that intestinal inflammation is the product of a combination of factors: the inherited genes, the hyperactive immune response, and environmental factors (diet, unhygienic conditions, pollutants, etc.).


In addition, 20%-25% of people with IBD in US and Europe are also known to suffer with other extra-intestinal complications (Table 1).


TABLE 1: Common Extra-Intestinal Complications of IBD, Prevalence in the US and Europe


altSource: Larson S, Bendtzen K, Nielsen OH. Extraintestinal manifestations of inflammatory bowel disease: epidemiology, diagnosis and management. Ann Med. 2010; 42:97-114



Multiple Treatments Exist

The treatment for IBD varies depending upon the severity of the disease. In the mild form of this disease, aminosalicylates (available as oral and topical forms) are used as a first line of defence and offer effective treatment. Aminosalicylates contain the active ingredient 5-aminosalicylic acid (5-ASA). These drugs are broken down in the colon with the action of bacteria residing in the colon. Once they are released, they act by inhibiting prostaglandin and leukotrine synthesis, free radical scavenging, immunosuppressive activity, impairing white cell adhesion and inhibiting cytokine synthesis. The major drugs in this category are sulfazine (Azulfidine), mesalamine (Asacol, Pentasa), olsalazine (Dipentum), balsalazide (Colazal).  In 2007, the Food and Drug Administration approved Lialda that may be taken once daily for patients with Ulcerative Colitis.


Moderate IBD is generally controlled by the introduction of corticosteroids which can be given as tablets, injections, or topically. These are very helpful in reducing inflammation in the entire body. It is not clearly known how they act; researchers believe that they might inhibit cytokine release by NFKβ, reducing lymphocyte recruitment. Some of the popular examples are  methylprednisolone (Medrol), prednisone (Deltasone),  budesonide (Entocort EC), hydrocortisone  (Cortef and Cortisol).


When 5-ASAs and corticosteroids fail, immunosuppressant drugs are used in managing moderate IBD symptoms. These drugs suppress the immune system and bring down the immune activity on intestinal cells. Some of the major drugs in this category are Azathioprine (Imuran, Azasan), 6-mercaptopurine (6-MP, Purinethol), Cyclosporine A (Sandimmune, Neoral) and Tracrolimus (Prograf). Amongst these, Cyclosporine A (manufactured by Novartis) is a peptide drug consisting of 11 amino acid lipophilic peptide that acts by decreasing interleukin-2 (IL-2) and tumor necrosis factor alpha (TNFα) activity.


Biologics: Already on the Rise

The newest group of drugs used in IBD therapy is biologics which can control severe symptoms such as fever, nausea, weight loss and bone pain. These are peptides targeting the specific chemicals involved in the body’s immune response to harmful substances that are overactive or work inappropriately in people suffering with the disease. All the biologics are available in injection forms, either intravenously or subcutaneously. The five biologics approved by FDA for IBD treatment are

  • Remicade (infliximab)
  • Humira (adalimumab)
  • Cimzia (certolizumabpegol)
  • Tysabri (natalizumab)
  • Simponi (golimumab)


Amongst these biological drugs, Remicade and Tysabri require intravenous administration, whereas other three can be injected subcutaneously and can be self-administered. Remicade became the first biologic to be approved for both Crohn’s Disease and Ulcerative Colitis (approved in 1998 for Crohn’s Disease and in 2005 for Ulcerative Colitis, Table 2). Simponi was approved for Ulcerative Colitis in 2013 where as the other drugs are approved only for Crohn’s disease (Humira in 2007, Cimzia and Tysabri in 2008). All of these, except Tysabri, work by binding TNF-alpha, immune cells that are thought to be overproduced in IBD. Tysabri works by inhibiting certain immune cells called integrins from binding to other cells in the intestinal lining. Humira, Cimzia, Simponi and Tysabri are humanized antibodies (antibodies from non-human species), whereas Remicade is a chimeric protein created through recombinant DNA technology. Humira and Remicade were reported to be amongst the top 15 best-selling drugs of 2012. The former achieved worldwide sale of USD 9.48 billion in 2012 while the latter set its mark at USD 7.67 billion in the same period. Cimzia recorded worldwide sale of EUR  467 million in 2012. According to the annual report of Biogen Idec, global in-market sales of Tysabri for the full year of 2012 were USD 1.6 billion. Recently approved in 2013 for Ulcerative Colitis, Simponi (developed by Johnson & Johnson) is currently marketed in the US and Canada.


Since biologics suppresses the immune system, side effects include frequent allergies, cold and diseases such as tuberculosis, histoplasmosis, and hepatitis B. Malignancy is also observed as a potential side effect. Despite these observed side effects, biologics serve as an important rescue for  the  patients  with  advanced  disease  conditions and for whom other treatment options have failed or have been relatively less successful.


TABLE 2: Approved Biologics for IBD



Source: Roots Analysis Research


The biological therapy is a boon to the patients who don’t respond to any conventional method. Given a choice between corticosteroids and biologics, many people are opting biologics as corticosteroids have many unfavorable effects such as weight gain, mood swings, bone loss, skin bruising, high blood pressure, and high blood sugar. The overall patient compliance with injectable biologics is much better than other conventional methods, in cases of severe form of the disease. In moderate cases, physicians are considering biologics as a shorter approach and an aggressive method to treat IBD. Continuous monitoring of Hepatitis B and Tuberculosis (TB) and other infections prevents the patient being treated with biologics from adverse medical situations. In addition, most patients with IBD are young, employed and favour the flexibility of subcutaneous administration of biologics. The success of Humira is a testament to this hypothesis. However, the adoption of these drugs is not governed only due to the flexibility offered by subcutaneous administration. This is evidenced by the success of Remicade which is injected intravenously and still has high sales compared to some other subcutaneous counterparts. The drug has gained a wider acceptance over the last few years it has been in the market.


Oral Biologics: Not Very Far Behind

Although these IBD biologics are garnering a whole lot of attention in pharmaceutical community, many hurdles remain. The major disadvantage of using anti-TNF biologics in the form of injections is that they travel throughout the body and suppress the immune system that takes part in inflammation, affecting the normal immunological response as well. To get a more targeted and user friendly approach, scientists are trying to formulate oral version of these injections. Avaxia Biologics is developing an oral anti-TNF antibody, AVX-470, which is currently in phase I clinical trials. As an alternative to anti-TNF products, Cosmo pharmaceuticals is trying to develop an oral colon release formulation of a LMW Heparin using MMX technology, which is currently under phase IIb trials for mild to moderate Ulcerative Colitis. LMW Heparin is a biological sulfated glycosaminoglycan from heparin family widely used for thromboembolic diseases. SP-333 is another phase II candidate from Synergy Pharmaceuticals. SP-333 is a synthetic analog of uroguanylin, a natural human peptide hormone produced in the lumen of the gastrointestinal (GI) tract. Uroguanylin functions by binding to a unique guanylate cyclase-C (GC-C) receptor located throughout the GI tract and regulates critical gastrointestinal (GI) functions.  Scientists have identified alternative signaling pathways of GC-C agonists that may be beneficial. Synergy is using the company’s GC-C agonist technology to make oral version of the peptide.


Apart from being flexible and patient friendly, the oral route is safer and can be even incorporated early in the treatment as a first line therapy. This will bypass other non-effective therapies and improve the quality of life of patients by limiting the progression of the disease, especially in patients intolerant to conventional treatments. With oral biologics having a lot to offer, their presence marks a huge relief to the IBD community.


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