Dual Therapy in IBD: Past, Present, and Future

February 20, 2025

Introduction

The objectives of this presentation were to review the data for the use of dual therapy, the simultaneous use of two advanced therapies in IBD, also referred to as advanced combination therapy [ACT]. It also included discussion on the clinical considerations when using ACT and explored future concepts of ACT.

It is important to keep in mind that ACT is “beyond the evidence”, and to date, evidence on its use in inflammatory bowel disease (IBD) is based upon case series and limited early clinical trials. Until the results of controlled trials underway are completed, there are limited data to assess the safety and efficacy of this practice or to identify optimal combinations.

Concepts in Advanced Combination Therapy

Important concepts in combination therapy include synergy, such that there is potential for one therapy to make another therapy “work better”, and timing, in that optimization of induction could lead to potential for downstream de-intensification. Lastly, ACT takes into consideration complementary mechanisms of action (MoA), as engaging multiple targets has potential to improve efficacy and decrease loss of response.

In general, the management of IBD aims to maximize benefits and minimize risk. Potential benefits of appropriate treatment include control of disease and symptoms, and mucosal healing. The potential risks of treatment include adverse effects, inadequate response to treatment, and risk of disease progression/relapse. In practice, an individualized assessment for each patient determines whether the benefits of a particular strategy outweigh its risks, and this also applies to ACT.

Combination Therapy: The Past

Traditional combination therapies used in IBD included oral and rectal 5-aminosalicylic acid (ASA) treatment, corticosteroid co-induction, and anti-tumour necrosis factor (TNF) therapies with either antibiotics or immunomodulators. In general, the use of these combinations has led to improved efficacy compared to monotherapy. However, the reasons for greater efficacy may vary. In the case of infliximab and thiopurine combination therapy, post hoc analysis of the SONIC trial found that higher infliximab concentrations and lower antidrug antibody rates with combination therapy may have contributed¹ and similar results were demonstrated in ulcerative colitis (UC) with the SUCCESS trial.² As for ACT in IBD, it has a surprisingly long history, starting with a long forgotten study of natalizumab given in combination with infliximab for Crohn’s disease (CD).³

Minimizing risks of treatment remains important and as such the price of combination therapy may be in terms of adverse events. For example, there may be an increased risk of infection with anti-TNF/thiopurine combination vs. either alone.⁴

Advanced Combination Therapy: The Present

Most advanced therapies report 1-year clinical remission rates of 30%–60%, even when administered under optimal circumstances in treatment-naïve patients. These rates are substantially lower for patients who have previously failed one or more advanced therapies. Overall, these data suggest a therapeutic ceiling with the use of advanced monotherapy, and advanced combinations provide an attractive opportunity to break through this ceiling.⁵

ACT refers to the combination of at least two biologic agents or a biologic agent and a small molecule drug with different MoAs, an approach commonly applied in other medical specialties. In IBD, ACT strategies are associated with potential benefits and drawbacks (see Figure 1).

Considerations for Rational Combinations

Different combinations are being explored, which vary in the degree of overlap and crosstalk in their MOAs. For example, there may be independent MoAs that have no direct anti-IBD benefit when combined or high MoA overlap with high crosstalk and a concern for safety. The “sweet spot” may be complementary MoAs with crosstalk and synergistic anti-IBD activity when combined.⁷

Advanced Combination Therapy: Clinical Data

Canadian real-world data on ACT is available from a retrospective analysis in 96 patients, which found the most commonly used anchor drug to be vedolizumab or ustekinumab. The other drug that was added was most often a drug the patient had previously failed. The primary endpoint showed that 43% achieved endoscopic improvement, while adverse events (AE) were rare occurring in 3 (13%) patients.⁸

Subsequently, a meta-analysis of 24 ACT trials (observational and randomized controlled trial data) found pooled clinical and endoscopic remission rates of 58.8% and 34.3%, respectively. Furthermore, pooled serious adverse events (SAE), infection, and malignancy rates were 6.5%, 19.7%, and 1.6%, respectively.⁹

In practice, the most common approach is to add on therapy late in the treatment course, but there are also the options of simultaneous co-induction or sequential induction therapy.¹⁰ Clinical studies have started to investigate different approaches and thus far have demonstrated benefits for combination advanced therapy in induction. Specifically, the recent EXPLORER open-label study assessed the approach of simultaneous co-induction with vedolizumab, adalimumab, prednisone and methotrexate, followed by sequentially withdrawing therapy to provide long-term maintenance monotherapy with vedolizumab in biologic-naive patients with newly diagnosed moderate-to-high risk CD. A post hoc Bayesian analysis at week 26 showed the probability of triple combination therapy providing higher endoscopic remission was 86% compared to vedolizumab monotherapy and 71% compared to adalimumab monotherapy with no new safety concerns.¹¹

In UC, the VEGA randomized controlled study combined anti-TNF (golimumab) and anti-IL-23 inhibitor (guselkumab) compared with either monotherapy. Rates of clinical remission, endoscopic remission, histologic remission, and complete endohistologic healing were higher with combination therapy compared with either monotherapy, which was maintained over time. Furthermore, adverse events and serious infections were similar between groups.¹²

Advanced Combination Therapy: Future Directions

There are several new MoAs under investigation in IBD that open the door to future combination options. There is a range of ongoing research on combination therapies combining current and new agents, and studies of monoclonal antibodies in combination with dietary changes, dietary supplements, or agents that modify the gut microbiome.^13,14

Advanced Combination Therapy: Clinical Considerations

It is crucial to consider each patient’s unique situation when choosing ACT. The questions to consider include who, when, where, why, and how to use ACT (see Table 1).

With respect to the different combination options, the landscape is evolving, but to date there is the most evidence for combinations with vedolizumab or IL-12/23 or -23 inhibitors with either anti-TNF or JAK inhibitors. A combination that remains controversial is JAK inhibitors with anti-TNFs since they are both broad immunosuppressants.

Conclusions

In conclusion, traditional combination strategies such as immunomodulators and biologics still have a role. ACT combining monoclonal antibodies and/or targeted small molecules are a consideration in select populations. Future combination regimens will need to be adequately studied to determine the best combination and the ideal benefit-risk profile, while challenges such as access and cost need to be addressed, in order to be integrated into a wider clinical context.

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Clinical Case

• Justine is an otherwise healthy 32-year-old air traffic controller who was diagnosed with Crohn’s disease 5 years ago. She presented with a perianal abscess requiring incision and drainage with placement of a Seton suture. Colonoscopy discovered a 30 cm segment of ileal disease with serpiginous ulcers and aphthous ulceration in the rectum (SES-CD 8). Despite minimal luminal symptoms, she was treated with antibiotics and infliximab.

Commentary

• Evidence is limited in this area, so most gastroenterologists are not comfortable removing the Seton suture, and for those that are, many are not comfortable deciding when to take it out.
• It is important to control luminal disease and optimize medical therapy before removing the suture.
• Integrate a multidisciplinary plan for collaborating with the surgeon, which can also help increase gastroenterologists’ comfort in managing Seton sutures.

Case Evolution

Justine had a good response to infliximab. The Seton suture was left in place but fell out spontaneously after 9 months. A repeat colonoscopy after one year showed distortion of the ileocecal valve without stricture and rectal erythema, but no ulceration.

After two years on therapy, Justine noted increasing urgency and occasional rectal bleeding. Repeat colonoscopy revealed active proctitis with aphthous ulceration and erythema in the ileum with a non-ulcerated passable stricture (SES-CD 6). She noted occasional drainage from the old Seton suture site but no perianal pain. Her infliximab was increased to 10 mg/kg and repeat therapeutic drug monitoring showed a trough level of 15.563 mcg/mL. A flexible sigmoidoscopy showed persistent rectal disease despite dose optimization, so she was switched to ustekinumab.

On ustekinumab her bowel habits improve and repeat full colonoscopy shows only minor residual aphthous ulceration in the rectum. However, Justine reports daily discharge from her fistula tract and had another small abscess drained in the ER 6 weeks ago. She says she felt a lot better on infliximab. She and her partner are keen to have children, and she wants to feel better. You previously told her to conceive when in remission.

Commentary

• The majority of gastroenterologists would choose upadacitinib given she is not responding fully to infliximab and there are recent data on fistula management with upadacitinib.
  • However, some would avoid upadacitinib due to her desire to have children, so would instead consider vedolizumab, which shows similar efficacy as other post hoc studies in fistulizing disease.
  • Some would add an antibiotic as a bridge, using tolerability to guide the choice of antibiotic.
• Given she is on therapy that is controlling her luminal disease, but has breakthrough perianal disease, some would consider dual biologic therapy (i.e., adding an anti-TNF) to get the perianal disease under control, however there is limited evidence supporting this approach.
  • ACT may be better earlier than later, however, it may be best to reserve it for select cases, when there are no other options. Thus, the question of timing is equally important as who to use it for, and ideally prediction models will be developed to help identify ideal candidates.
  • Experience to date has not demonstrated substantial side effects with ACT, and for IBD uncontrolled disease is the greatest risk for patients.
• Combination with risankizumab as the anchor (with anti-TNF or JAK inhibitor) is another option, as risankizumab has a reasonable benefit-risk ratio, though to date there is less clinical experience with it used this way.

Case Evolution

After discussion, you jointly decide to continue ustekinumab with the addition of an adalimumab biosimilar. For convenience, you also switch the ustekinumab to a biosimilar from the same company.

Justine does well and feels better than ever, but she is tired of so many injections and wants to stop one of her medications.

Commentary

• In practice, therapy is only de-escalated when there is a good reason, as if a patient needed both drugs to control the disease, withdrawing one will likely lead to problems.
• In this case, the drug levels are sufficient, suggesting there is unlikely to be any benefit in escalating the dose, and it could negatively impact safety.
• There is limited data on ACT in pregnancy, but in general will continue ACT if each individual drug is considered safe in pregnancy.

Case Evolution

You reconvene to recommend continuing both therapies, but Justine tells you she stopped her adalimumab a month ago. She had been developing a skin rash, which she Googled, and thought was consistent with a psoriasiform reaction to adalimumab. Unfortunately, she is already sensing more discharge from her perianal fistula. She and her partner are worried as they fear they will again have to delay their plans to start a family.

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References

1. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010;362:1383–95.
2. Panaccione 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;146:392–400.
3. Sands 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;13:2–11.
4. Kirchgesner J, Lemaitre M, Carrat F, et al. Risk of serious and opportunistic infections associated with treatment of inflammatory bowel diseases. Gastroenterology. 2018;155(2):337–34.
5. Raine T, Danese S. Breaking through the therapeutic ceiling: What will it take? Gastroenterology. 2022;162(5):1507–11.
6. Solitano V, Ma C, et al. Advanced combination treatment with biologic agents and novel small molecule drugs for inflammatory bowel disease. Gastroenterol Hepatol (NY). 2023;19(5):251–63.
7. Stalgis C Deepak P, Mehandru S, et al. Rational combination therapy to overcome the plateau of drug efficacy in inflammatory bowel disease. Gastroenterology. 2021;161(2):394–9.
8. Yang E, Panaccione N, Whitmire N, et al. Efficacy and safety of simultaneous treatment with two biologic medications in refractory Crohn’s disease. Aliment Pharmacol Ther. 2020;51(11):1031–8.
9. Ahmed W, Galati J, Kumar A, et al. Dual biologic or small molecule therapy for treatment of inflammatory bowel disease: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2022;20:e361–79.
10. Battat R, Chang JT, Loftus EV Jr, Sands BE. IBD Matchmaking – Rational combination therapy. Clin Gastroenterol Hepatol. 2024:S1542–65.
11. Colombel JF, Ungaro RC, Sands BE, et al. Vedolizumab, adalimumab, and methotrexate combination therapy in Crohn’s disease (EXPLORER). Clin Gastroenterol Hepatol. 2024;22(7):1487–96.
12. Feagan BG, Sands BE, Sandborn WJ, et al. for the VEGA Study Group. 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):307–20.
13. Spyre is uniquely positioned to deliver next-generation monotherapies and paradigm-changing combinations. Available at: https://spyre.com/pipeline/. Accessed: January 2025.
14. Wolter M, Grant ET, Boudaud M, et al. Leveraging diet to engineer the gut microbiome. Nat Rev Gastroenterol Hepatol. 2021;18:885–902.

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Editor-in-Chief

John K. Marshall, MD MSc FRCPC CAGF AGAF
Professor, Department of Medicine
Director, Division of Gastroenterology
McMaster University
Hamilton, ON

Contributing Author

Remo Panaccione, MD FRCPC
Professor of Medicine
University of Calgary CCC Chair in IBD Research
Director, Inflammatory Bowel Disease Unit
Director, Gastrointestinal Research
Assistant Dean of MD Admissions
Undergraduate Medical Education
Cumming School of Medicine
University of Calgary
Calgary, AB

Mentoring in IBD Curriculum Steering Committee

Alain Bitton, MD FRCPC, McGill University, Montreal, QC
Karen I. Kroeker, MD MSc FRCPC, University of Alberta, Edmonton, AB
Cynthia Seow, MBBS (Hons) MSc FRACP, University of Calgary, Calgary, AB
Jennifer Stretton, ACNP MN BScN, St. Joseph’s Healthcare, Hamilton, ON
Eytan Wine, MD PhD FRCPC, University of Alberta, Edmonton, AB

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