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27April2023
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Y-ECCO Literature Review: Dean Seah

Dean Seah

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

Feagan BG, Sands BE, Sandborn WJ, et al.

Lancet Gastroenterol Hepatol 2023;8:307–20.


Dean Seah 
© Dean Seah 

Introduction

Despite a growing armamentarium of advanced therapies for Ulcerative Colitis (UC), fewer than 40% of patients maintain clinical remission at 12 months [1]. Combination therapy utilising dual biologic or small molecule agents can be considered in highly selected, medically refractory cases; however, robust data to support dual therapy in routine clinical practice are still lacking [2]. Inhibitors of TNF-α and IL-23 have demonstrated efficacy in the treatment of UC [3,4]. Data emerging from animal studies have suggested that their use in combination reduces colitis synergistically and may be more efficacious than treatment with either monotherapy [5].

This randomised double-blinded controlled phase 2 trial, named the VEGA trial, was conducted across 54 sites internationally and aimed to determine the efficacy and safety of combination therapy with guselkumab (GUS), an IL-23 p19 antagonist, plus golimumab (GOL), a TNF-α inhibitor, compared with either monotherapy in UC.

Key Findings

A total of 214 patients with moderate to severe UC, with a Mayo score of 6–12 and a Mayo endoscopic subscore ≥2, were randomised into three treatment arms (1:1:1): (1) combination therapy with GUS and GOL induction therapy followed by GUS maintenance (71 patients), (2) GOL monotherapy (72 patients) and (3) GUS monotherapy (71 patients).

Patients who had previously received treatment with a TNF-α, IL-12/23 or IL-23p19 antagonist were excluded. Efficacy was assessed following induction at week 12 and also at week 38.

At week 12, the rate of clinical response in the combination therapy group (83%, 59/71) was significantly higher than that in the GOL monotherapy group (61%, 44/72) (adjusted treatment difference 22.1%, p=0.0032) but was similar to that seen after GUS monotherapy (75%, 53/71) (adjusted treatment difference 8.5%, p=0.2155). This was mirrored at week 38, with rates of clinical response similar between GUS monotherapy and combination therapy (72%, 51/71 vs 69%, 49/71, respectively) but lower following GOL monotherapy (58%, 42/72). Rates of clinical remission were numerically higher at both timepoints following combination therapy (37%, 26/71 at week 12 and 44%, 31/71 at week 38) compared to either monotherapy; however, these differences were not statistically significant.

Rates of endoscopic improvement at weeks 12 and 38 were higher in the combination therapy group (49%, 35/71 at both timepoints) than in either monotherapy group, with an adjusted treatment difference ranging between 15% and 25% when compared to both GUS and GOL groups. A greater proportion of the combination group also achieved endoscopic normalisation and histological remission as well as composite outcomes of histological remission with endoscopic improvement or remission. In addition, combination therapy patients achieved higher rates of both 7-day and 60-day corticosteroid-free remission and a lower median faecal calprotectin at weeks 12 and 38.

Rates of adverse events, infection and serious infection were similar across all three treatment groups. There were no safety signals associated with combination therapy. Serious infection was observed in 1% of patients (1/71) receiving combination therapy (influenza B and concurrent sepsis). Two deaths were reported following final intervention dosing at week 34, one in the combination therapy group (poisoning with an unknown substance) and one in the GUS monotherapy group (COVID-19).

Conclusion

Although the investigators were not able to demonstrate a statistically significant difference in rates of clinical response between combination therapy and GUS monotherapy, numerically higher rates of clinical, biochemical, endoscopic and histological improvement were observed following dual induction therapy, with no safety concerns raised. These findings are clinically significant and successfully serve as a proof of concept for further work investigating combination IL-23 and TNF-α inhibition in UC.

Several questions remain unanswered. The deleterious impact of previous biologic failure is now well recognised in IBD, with higher rates of treatment failure observed in biologic-experienced patients [6]. In current practice, combination advanced therapy is utilised only in treatment-refractory IBD; however, patients previously treated with TNF-α, IL-12/23 or IL-23p19 antagonists were excluded from this trial, resulting in a largely advanced therapy-naive cohort. As therapeutic sequencing in UC becomes increasingly relevant, more evidence is needed to position combination GUS and GOL therapy within existing treatment algorithms. The effect of combination maintenance therapy following dual induction therapy is also unknown, as is the efficacy of combination GUS and GOL in Crohn’s Disease. These questions will hopefully be addressed by ongoing clinical trials (NCT05242471, NCT05242484) [7,8].

References

    1. Bokemeyer B, Picker N, Kromer D, Rosin L, Patel H. P506 Rates of clinical remission among patients with Ulcerative Colitis from real-world clinical practice settings from Germany. J Crohns Colitis 2022;16, Issue Supplement 1: i466–i467.
    2. 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. doi:10.1016/j.cgh.2021.03.034
    3. The efficacy and safety of guselkumab induction therapy in patients with moderately to severely active ulcerative colitis: Phase 2b QUASAR study results through week 12. Gastroenterol Hepatol 2022;18(4 Suppl 1):12.
    4. Reinisch W, Gibson PR, Sandborn WJ, et al. Long-term benefit of golimumab for patients with moderately to severely active ulcerative colitis: Results from the PURSUIT-maintenance extension. J Crohns Colitis 2018;12:1053–66
    5. Perrigoue J, Muniz-Bongers L, Ong L, et al. P328 In silico evaluation and pre-clinical efficacy of anti-TNF and anti-IL-23 combination therapy in Inflammatory Bowel Disease. J Crohns Colitis 2022;16, Issue Supplement 1: i348.
    6. Gisbert JP, Marín AC, McNicholl AG, Chaparro M. Systematic review with meta-analysis: the efficacy of a second anti-TNF in patients with inflammatory bowel disease whose previous anti-TNF treatment has failed. Aliment Pharmacol Ther 2015;41:613–623. doi:10.1111/apt.13083
    7. A study of combination therapy with guselkumab and golimumab in participants with moderately to severely active ulcerative colitis (DUET-UC). ClinicalTrials.gov identifier: NCT05242484. Updated March 15, 2023. Accessed March 25, 2023. https://clinicaltrials.gov/ct2/show/NCT05242484
    8. A study of combination therapy with guselkumab and golimumab in participants with moderately to severely active Crohn's disease (DUET-CD). ClinicalTrials.gov identifier: NCT05242471. Updated March 15, 2023. Accessed March 23, 2023. https://clinicaltrials.gov/ct2/show/NCT05242471

Dean Seah - Short Biography

Dean Seah is a gastroenterologist from Melbourne, Australia, currently undertaking a clinical and research fellowship in Inflammatory Bowel Disease at Guy’s & St Thomas’ Hospitals in London, United Kingdom. His interests include gastrointestinal immunology and the development of novel therapies for IBD.

Posted in ECCO News, Y-ECCO Literature Reviews, Committee News, Volume 18, Issue 1, Y-ECCO