Dual Approaches, Added Challenges: Complexities of Combination Therapy Trials in IBD Part 1

Treatment for inflammatory bowel disease (IBD), the family of chronic gastrointestinal disorders that includes Crohn’s disease (CD) and ulcerative colitis (UC) and dramatically impacts the lives of approximately 7 million patients around the world, is at a crossroads.ⁱ

In recent decades, the advent of biological agents, particularly anti-Tumor Necrosis Factor (TNF)-α agents such as infliximab (IFX), adalimumab (ADA), and golimumab, has transformed the standard of treatment for these diseases, shifting the therapeutic strategy from controlling symptoms to a treat-to-target strategy aimed at durable remission and prevention of damage progression and disability.^ii,iii But while effective in achieving remission in more than half of IBD patients, significant unmet needs remain.^iv

In addition to the high cost of these treatments, anti-TNF-α agents are prone to secondary loss-of-response over time due to factors such as development of anti-drug antibodies, loss of drug in the stool, or mechanism escape.^ii,v 30 to 50 percent of patients with IBD either fail to respond to anti-TNF therapy or see decreased efficacy over time.^vi IBD is also frequently associated with extraintestinal manifestations (EIMs), including arthritis, uveitis, erythema nodosum, and primary sclerosing cholangitis, further complicating the effective management of the disease.^vii

For many refractory IBD patients, surgery remains an all too likely possibility. Living with this prospect only heightens the disease’s well-documented patient burden, which ranges from the immediate impact on the patient’s physical well-being to time lost due to illness and recurring hospital visits.^viii In addition, IBD carries a significant financial burden for both patients and national healthcare systems, and one that continues to grow. For instance, annual U.S. healthcare spending on IBD increased from $6.4 billion to $25.4 billion between 1996 and 2016.^ix

A potential solution has emerged in the form of combination therapies. These currently fall into two general groups:ⁱⁱ

• the combination of biological agents with immunosuppressors
• dual-targeted therapy (DTT), combining one or more biologics and/or targeted small molecules^x

It’s believed these therapies may be able to achieve greater outcomes through additive or synergistic effects, or by acting on different inflammatory pathways in the case of DTTs, representing an opportunity to overcome the “ceiling effect” of biologic and advanced monotherapies.ⁱⁱ In addition, they may represent an effective strategy for refractory IBD patients or those with EIMs. However, there are still many unanswered questions about this new avenue, as well as obstacles to future research.

Overcoming these obstacles starts with a clear understanding of the current treatment landscape and operational considerations. In this series, we will review the state of development of combination therapies in IBD today and primary considerations for future research, including:

• Addressing safety concerns and the risk of increased safety risks
• Navigating complex regulatory pathways
• Recruiting and retaining patients for lengthy trials, including the need for long-term follow-up