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Dual Approaches, Added Challenges: Complexities of Combination Therapy Trials in IBD Part 2

By Kremena Stoyanova

Senior Director, Medical Monitoring & Consulting

A Brief History of Combination Therapies in IBD

This is the second post in a series on combination therapies in the treatment of inflammatory bowel disease (IBD). In Part 1, we covered the reasons for rising interest in combination therapy’s potential to bring relief for refractory IBD patients or those with extraintestinal manifestations (EIMs). In this post, we’ll discuss the history of research in combination therapies for IBD. 

I. The beginning: Biological agent with immunosuppressors

The first biologic for Crohn’s disease, Infliximab, was approved by the Food and Drug Administration in 1998, but it would be more than a decade before the first significant comparative study of combination therapy for the treatment of IBD. The breakthrough came in 2010 with the publication of results from the SONIC (Study of Biologic and Immunomodulator Naïve Patients in Crohn’s Disease) trial.xi Researchers compared the effects of infliximab monotherapy, azathioprine (an immunomodulator) monotherapy, and the two drugs combined in adults with moderate-to-severe Crohn’s disease. At week 26, patients receiving the combination therapy were more likely to achieve corticosteroid-free remission than those receiving either drug on its own and also achieved higher rates of mucosal healing. The UC-SUCCESS study demonstrated comparable results in UC.xii This led to further research and evaluation of the safety and efficacy of pairing a biologic and immunomodulator, and such regimens have since become standards of care for many physicians.

II: The introduction of dual-targeted therapies

Recent attention has focused on a new treatment modality with the potential to bring relief to two underserved groups:xiii

  • patients with well-managed IBD and uncontrolled EIMs such as arthritis or psoriasis
  • patients with refractory, uncontrolled IBD

This approach involves pairing one or more biologics and/or small molecules and is known as dual-targeted therapy. One of the first opportunities emerged with the introduction of biologics with targets other than the traditional TNF-α. Research into this area was published as early as 2007, pairing infliximab with natalizumab, an at-the-time novel biologic that targets the protein α4β1 integrin.xiv The combination was well-tolerated with a similar incidence of adverse events (AEs) across the combination and infliximab monotherapy groups, and several positive trends suggested that the combination therapy had greater efficacy than treatment with infliximab alone.

Research into the efficacy of DTT since then has been sparse but promising. In a 2018 study, 10 IBD patients received vedolizumab, an agent targeting the integrin α₄β₇, after a median time of 13 months since initiating anti-TNFα treatment.xv All patients were in clinical remission at the end of follow-up with no more AEs than expected with anti-TNF-α alone. Eight of the patients were able to discontinue anti-TNF-α and continue with vedolizumab monotherapy, while two required combination therapy throughout follow-up to sustain remission.

III: Present day: Expanding combination therapy’s potential

In 2023, the first randomized controlled trial (RCT) of combination biologic therapy in ulcerative colitis – and the first RCT of dual biologics in IBD since the 2007 trial – was published.xvi The VEGA Phase 2 trial assessed whether the anti-TNF-α golimumab in combination with guselkumab (targeting interleukin-23) was more effective for treating ulcerative colitis than either monotherapy. At week 12, the study found that 83% of patients in the combination therapy group had achieved clinical response compared with 61% of the golimumab monotherapy group and 75% of the guselkumab monotherapy group. However, the findings require confirmation in larger trials.

Recent studies have also begun investigating the use of dual-targeted therapy involving a biologic in combination with a small molecule therapy such as tofacitinib.xvii In a 2021 retrospective institutional review board–approved review of CD and UC patients prescribed tofacitinib in combination with a Biologic Therapy (TBT), researchers showed that 50% of a significantly refractory subset of IBD patients on TBT achieved clinical response at week eight and 34.8% achieved endoscopic/radiographic remission without any new safety signals.xviii Such data suggest the potential to bring relief to a sizeable subset of patients who currently find themselves without viable treatment options.

While the results so far have been promising, there has yet to be a consensus on the path forward for combination therapies. For instance, should dual biologic therapy be recommended solely for an induction period, or should it also have a role in maintenance therapy?i Only future research will answer these questions. But first, sponsors must understand the unique challenges faced by trials of combination therapies in IBD – and how to overcome them, as we’ll discuss in Part 3.

xiColombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010;362(15):1383-1395. doi:10.1056/NEJMoa0904492

xiiPanaccione R, Ghosh S, Middleton S, et al. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology. 2014;146(2):392-400.e3. doi:10.1053/j.gastro.2013.10.052

xiiiPrivitera G, Pugliese D, Lopetuso LR, et al. Novel trends with biologics in inflammatory bowel disease: sequential and combined approaches. Therap Adv Gastroenterol. 2021;14:17562848211006669. Published 2021 Apr 27. doi:10.1177/17562848211006669

xiiiiSands BE, Kozarek R, Spainhour J, et al. Safety and tolerability of concurrent natalizumab treatment for patients with Crohn’s disease not in remission while receiving infliximab. Inflamm Bowel Dis. 2007;13(1):2-11. doi:10.1002/ibd.20014

xvBuer LCT, Høivik ML, Warren DJ, Medhus AW, Moum BA. Combining Anti-TNF-α and Vedolizumab in the Treatment of Inflammatory Bowel Disease: A Case Series. Inflamm Bowel Dis. 2018;24(5):997-1004. doi:10.1093/ibd/izx110

xviFeagan BG, Sands BE, Sandborn WJ, et al. Guselkumab plus golimumab combination therapy versus guselkumab or golimumab monotherapy in patients with ulcerative colitis (VEGA): a randomised, double-blind, controlled, phase 2, proof-of-concept trial. Lancet Gastroenterol Hepatol. 2023;8(4):307-320. doi:10.1016/S2468-1253(22)00427-7

xviiGilmore R, Hilley P, Srinivasan A, Choy MC, Grace JA, De Cruz P. Tofacitinib Is Safe and Effective When Used in Combination With Infliximab for the Management of Refractory Ulcerative Colitis. Clinical Gastroenterology and Hepatology. 2021;19(6):1302-1303. doi:10.1016/j.cgh.2020.07.046

xviiiAlayo QA, Khatiwada A, Patel A, et al. Effectiveness and Safety of Combining Tofacitinib With a Biologic in Patients With Refractory Inflammatory Bowel Diseases. Inflamm Bowel Dis. 2021;27(10):1698-1702. doi:10.1093/ibd/izab112

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