Gastroenterology News Update

Innovations in IBD Therapy at Penn Medicine

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The Inflammatory Bowel Disease Program

Among the largest of its kind in the world, the inflammatory bowel disease (IBD) program at Penn Gastroenterology treats more than 3000 patients with ulcerative colitis (UC) and Crohn's disease (CD) per year on average.

The breadth of the IBD treatment program at Penn Gastroenterology encompasses the disease in all of its manifestations from the treatment of acute flare-ups in mild-to-moderate disease to the long-term management of chronic, severe IBD in patients with debilitation symptoms. Between these extremes, the Program strives to be responsive, comprehensive in its approach and sympathetic to the needs of patients experiencing a mutable disease that is linked to their emotional well-being as well as their physical condition. 

The series of far-reaching efforts at Penn to improve and enhance the treatment of patients with IBD includes nutritional guidance and counseling as well as immunological biological and steroid-based therapies, and surgery. These treatments are offered in the context of a program that encourages continuing interaction between the patient and his or her family with the caregiver. 

The management of IBD has the goal of inducing and sustaining remission, maintaining adequate nutrition; ameliorating disease-related complications and the potential adverse effects of short-term and maintenance therapy, as well as improvement in patient quality of life.

Clinical Research In IBD

A hub of research for novel medical approaches to IBD, Penn Medicine is rapidly transitioning from the antibiotics, glucocorticoids and biologic therapies now used to treat UC and CD. 

Gastroenterologists at Penn Medicine are pursuing an extensive program of clinical trials to develop a new generation of therapies for inflammatory bowel disease (IBD). The objective of this program is to improve upon the efficacy and safety of the current standards of treatment for moderate-to-severe IBD, including the corticosteroids,* immunomodulators and TNF-alpha inhibitors. The current paradigm for the pathophysiology of IBD involves genetic susceptibility to antigenic stimulation by environmental or enteric bacteria, fungi or viruses, leading to an unremitting immune response and chronic inflammation.

One of the strategies now being explored in clinical trials at Penn Gastroenterology and elsewhere involves disruption of the molecules that provoke leukocyte migration and retention, particularly the integrins expressed on the surface of leukocytes.

The integrins represent a large family of transmembrane proteins with potential roles in the inflammatory process in IBD, including leukocyte adhesion and infiltration of the GI tract. A single integrin, alpha-4/beta-7, is expressed by more than 90% of lymphocytes found in the small bowel. Other therapies under investigation at Penn involve the integration of recent advances in our understanding of the microbiology and genetics of gastrointestinal disease.

Other new approaches to IBD therapy under investigation at Penn have the objective of improving upon the efficacy and safety of these treatments. All involve the integration of recent advances in our understanding of the physiology, microbiology and genetics of gastrointestinal disease.

*For a review of corticosteroid use and increased mortality in patients with IBD authored by Penn gastroenterologists James Lewis, MD, MSCE and Kimberly A. Forde, MD, et al, see Am J Gastroenterol. 2008;103:1428-1435.

Fecal Microbiome Transfer

At Penn GI, Gary Wu, MD, is investigating fecal microbiota transplantation (FMT), a biological alternative to antibiotic therapy for patients who have had repeated recurrences of Clostridium difficile despite antibiotic therapy. Patients who have three or more recurrences of C diff are considered to have chronic infection, a course characterized by repeated episodes of treatment followed by disease relapse in which each relapse increases the likelihood of subsequent occurrences.

FMT involves infusing donor fecal micro biota in saline into the small bowel via a nasoduodenal tube. In a recent comparative clinical trial, FMT effectively cured 94% of patients with recurrent 

C diff vs. 31% of patients receiving vancomycin 500 mg 4x daily for five days. [1]

Donors for FMT therapy at Penn Medicine are closely screened to avoid exposing recipients to pathogens, transmissible diseases and inflammatory disorders. The Food and Drug Administration currently considers FMT investigational, and its use is restricted to patients with recurrent C diff infection who do not respond to standard therapies.

[1] van Nood E, Vrieze A, Nieuwdorp M, et al. N Engl J Med. 2013; 368:407-415.

Agent AMG-181 

Penn Gastroenterology is involved in a clinical trial of the investigational agent AMG-181, a gut-specific human anti-alpha 4/beta 7 antibody for the treatment of IBD. Alpha 4 and beta 7 are T cell integrin subunits. The alpha 4 integrin is involved in lymphocyte recruitment and infiltration of the gut endothelium during chronic bowel inflammation. The beta 7 subunit is a component of the adhesion molecule pathway. In the small bowel, greater than 90% of lamina propria T cells express alpha 4/beta 7. AMG-181 acts to block inflammation by antagonizing the B7 subunit.

Methotrexate in Induction and Maintenance of Steroid Free Remission in Ulcerative Colitis (Merit-UC) Trial

Penn GI is participating in a multicenter double-blind, placebo-controlled, randomized study to investigate the safety and efficacy of 25 mg methotrexate (MTX) applied subcutaneously once weekly in patients with UC who have either failed 5-ASA therapy, or are refractory to, intolerant of, or failing to respond to azathioprine/6-mercaptopurine therapy or infliximab. In patients with Crohn's, subcutaneous methotrexate 25 mg once weekly is an efficient therapy to induce and maintain steroid free remission. Completion of this trial will define the therapeutic value of MTX in UC, potentially changing the current therapeutic strategy for the disease.

The specific aims of the trial are to: evaluate the safety and tolerability of the regimen over 48 weeks; evaluate the relapse-free survival of MTX maintenance therapy compared to placebo over 32 weeks; evaluate the efficacy of MTX over 16 weeks to induce steroid free remission; and establish a DNA, plasma and serum library to enable the evaluation of clinical and pharmacogenomic models to predict response to MTX therapy in patients with UC.

An Efficacy and Safety Study of Golimumab in Participants with Moderately to severely Active Ulcerative Colitis

Researchers at Penn GI took part in the multicenter Phase 3 study to evaluate golimumab (Simponi®) in patients with moderately to severe UC. Simponi was approved in March 2014 for the treatment of adults with moderately- to-severely active UC to induce and maintain clinical responses, induce clinical remission and achieve and sustain clinical remission in induction responders who have demonstrated corticosteroid dependence or who have had an inadequate response or failed to tolerate prior therapy with oral aminosalicylates, corticosteroids, azathioprine or 6-mercaptopurine.

About this Blog

The Gastroenterology News Update is a biyearly publication that highlights the diagnostic and treatment advances at Penn Gastroenterology, as well as the Division's renowned faculty and clinical research efforts.

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