Current Evidence for Combined Targeted Therapy for the Treatment of Inflammatory Bowel Disease

Abstract Biologicals and small molecules have revolutionized the medical management of inflammatory bowel diseases (IBD), yet they are only effective in a proportion of patients, and their impact on changing the natural history of the disease is still debatable. Recently, the concept of combining targeted biologics and small-molecule therapies has been introduced to the treatment of IBD. Dual-targeted therapy (sequential and combined), which is the combination of two targeted therapies, might be a reasonable choice for patients to break through the therapeutic ceiling. A recent randomized clinical trial (VEGA) provided the first controlled evidence that the short-term combination of two biological agents may lead to superior disease control than either of the agents alone in patients with ulcerative colitis (UC) without jeopardizing safety. Multiple studies are underway in both Crohn’s disease and UC. Additionally, real-world evidence is accumulating in IBD patients receiving combination therapies with concomitant IBD and extraintestinal manifestations or in patients with medically refractory IBD. Of note, the majority of these patients were exposed to multiple biological agents earlier and lost response to at least one of the agents in the combination. This review summarizes current knowledge regarding this attractive novel therapeutic option in IBD. Clearly, more controlled data are needed to evaluate optimal timing, efficacy, and mitigation of safety concerns.


treatment of inflammatory bowel disease
Biological therapies have become the standard of care for moderate to severely active inflammatory bowel disease (IBD), including Crohn's disease (CD), and ulcerative colitis (UC). 1,2However, the current treatments for IBD achieve control in only two-thirds of users at best. 3 With the available biologic and small-molecule therapies, overall clinical remission rates are at best 50%.Rates of achieving remission with anti-tumor necrosis factor (anti-TNF) therapy for the induction of remission were reported in 18% to 48% of CD patients. 4In UC, a meta-analysis comparing gut-selective anti-integrin α4β7, vedolizumab with anti-TNFs showed that the pooled rates of mucosal healing were similar and varied from 18% to 33% following 32 to 54 weeks of maintenance treatment. 5Similarly, in the VARSITY study, the rate of clinical remission at 52 weeks was low, at only 31.3% and 22.5% for vedolizumab and adalimumab, respectively. 6The efficacy of a Janus kinase inhibitor, tofacitinib for induction of clinical remission at 8 weeks in UC patients was 16.6% to 18.5%, and remission rates at 52 weeks ranged from 34.3% to 40.6% in the initial responders. 7Of note, approximately 50% of patients who initially responded to biological therapy eventually lose their response over time. 8,9As a result, IBD patients who are refractory or have lost their response to a certain biologic therapy need to switch to a different molecule, reducing their treatment options.
The rationale for combining targeted therapy has been initially explored in rheumatologic and dermatologic diseases.Multiple randomized controlled trials (RCTs) have failed to show additional benefit for combination of biological therapy (e.g., etanercept and abatacept, anakinra and etanercept, or rituximab and atacicept) compared to mono-biologic therapy to achieve superior disease control. 10Furthermore, rheumatologic patients receiving combined biologic therapy had a higher frequency of adverse events compared to patients receiving biologic monotherapy. 10,11The majority of the RCTs in the rheumatology literature, however, included biologics that are not approved for the treatment of IBD.Thus, extrapolating data from the rheumatologic literature to the treatment of IBD is not possible because agents approved for the treatment of IBD were not included in rheumatologic studies.
The concept of combined targeted therapy has been proposed in the management of IBD.Given that multiple inflammatory pathways are simultaneously activated in the intestinal mucosa, blocking only one of them may not be enough to optimal control inflammation in each patient.Monotherapy with a biologic agent that is effective for luminal disease may not be as effective for controlling co-existing extraintestinal manifestations (EIMs) or other immune-mediated inflammatory diseases (IMIDs).Therefore, combined targeted therapy with different mechanisms of action appears to be a reasonable strategy for refractory IBD patients who failed or lost response to a single biological agent or who have active coexisting EIMs or IMIDs.In this review, we discuss the current evidence for combined biological and/or small-molecule therapies for the treatment of IBD.

Randomised controlled trials and clinical trials
The summarized RCTs in combined targeted therapy for IBD are shown in Table 1.

Anti-integrin α4 antibody (natalizumab) plus infliximab
This was the first RCT to evaluate the safety and efficacy of the combination of natalizumab and infliximab in patients with active CD despite ongoing infliximab treatment. 12In this study of 79 CD patients (52 receiving natalizumab plus infliximab and 27 receiving placebo plus infliximab), the patients receiving combination therapy showed a trend to have higher rates of clinical remission throughout 32 weeks of follow-up compared with patients receiving infliximab monotherapy, but these differences were not statistically significant.However, there were concerns about the safety of natalizumab due to the possibility of progressive multifocal leukoencephalopathy, especially in patients who have had prior immunosuppressive treatment. 17,18Due to this, the use of natalizumab in CD treatment has been extremely low and limited to the United States only. 19e open-label phase 4 "EXPLORER trial," assessed the efficacy of the triple combination of vedolizumab, adalimumab, and methotrexate therapy in biologic-naive patients with high-risk CD.An interim analysis was undertaken of 55 patients treated with triple therapy (vedolizumab 300 mg IV on day 1 and week 2, week 6 and then every 8 weeks, adalimumab 160 mg SC on day 2, 80 mg at week 2, and then 40 mg every 2 weeks until week 26, methotrexate 15 mg orally weekly until week 34); after the triple therapy and by week 34, every patient received vedolizumab monotherapy until week 102.At week 26, endoscopic response and endoscopic remission were observed in 54.4% and 34.5%, respectively.There were no safety signals related to the triple therapy. 13e VEGA study The most recent ongoing phase 2a RCT, evaluated the efficacy of a combination induction therapy with selective interleukin (IL)-23, guselkumab and anti-TNF, golimumab compared to guselkumab or golimumab monotherapy in patients with moderately to severely active UC.14 214 patients naive to an anti-TNF and refractory or intolerant to conventional therapy were randomly assigned to receive guselkumab 200 mg GOL (30%) Endoscopic remission: GUS+GOL (18%) vs. GUS (8%) vs. GOL (10%) At week 38 of maintenance treatment: Clinical response: GUS+GOL (69%) GUS (72%) vs. GOL (58%) Clinical remission: GUS+GOL (44%) GUS (31%) vs. GOL (22%) Endoscopic improvement: GUS+GOL (49%) vs. GUS (32%) vs. GOL (22%) Endoscopic remission: GUS+GOL (25%) vs. GUS (15%) vs. GOL (7%) DUET-CD and DUET-UC trial (ongoing phase 2 RCTs) 15,16 Expected 715 Moderate to severe active refractory CD Expected 550 moderate to severe active refractory UC

JNJ-78934804 (combination of guselkumab and golimumab)
An ongoing phase 2b randomized, double-blind, placebocontrolled trial in patients with moderate-to-severe active CD (DUET-CD trial) and moderate-to-severe active UC (DUET-UC trial).The patients are being randomized into six arms, including guselkumab, golimumab, and JNJ-78934804 (combination guselkumab and golimumab, high-dose, mid-dose, and low-dose) and a placebo arm.The primary outcome of this study is to compare clinical remission and endoscopic response at week 48 among the treatment arms.Both studies are recruiting patients.ClinicalTrials.govidentifiers: NCT05242471 (DUET-CD) and NCT05242484 (DUET-UC). 15,16al-world evidence Evidence to support a combination biological treatment strategy is also accumulating from everyday practice.However, one of the main problems with the real-world evidence studies is that the patients were already exposed or lost response to one or both agents used as combination therapy.The summary of the main findings of selected real-world studies on combined targeted therapy in IBD are shown in Table 2.
A retrospective study by Glassner et al. 22 evaluated 50 patients with IBD who were treated with various combinations of biologics or small-molecule therapy; approximately 50% were vedolizumab plus anti-interleukin (IL)-12 and IL-23 (ustekinumab) for persistent disease activity (n = 47) or concomitant rheumatological or dermatological disease (n = 3).There were significantly more patients in clinical remission at 4 months (50% vs. 14%, P = 0.0018) and endoscopic remission at 8 months (34% vs. 6%, P = 0.0039) compared to baseline. 22nother case series revealed that dual biologic therapy was safe and effective in 22 patients with severe refractory CD who had a total of 24 dual biologic treatments after multiple failed biologics.Seven different combinations of biologics were evaluated, including traditional anti-TNF agents (infliximab, adalimumab, golimumab, or certolizumab pegol) combined with vedolizumab or ustekinumab.Clinical response and clinical remission were seen in 50% and 41% of patients, respectively.Endoscopic improvement and remission were found in 43% and 26%, respectively.The presence of active perianal fistula decreased from 50% at baseline to 33% after treatment. 26In another case series of 16 patients who received various dual biologic therapies for uncontrolled luminal disease (n = 7) or uncontrolled EIMs despite inactive IBD (n = 9), the most frequently used combinations were vedolizumab plus ustekinumab and vedolizumab plus adalimumab.A clinical response was reported in all study patients. 20n 2021, the most recent large European multicentre retrospective study by Goessens et al., 21 reported 98 patients (104 combinations) who started combination therapy for active IBD (67%), active IMID or EIMs (22%), or both (10%), in the setting of multiple biologic failures.The median duration of combination therapy was 8 months (interquartile range, (IQR) 5-16).IBD disease activity was clinically improved in 70% of patients, and IMID/EIM activity was clinically improved in 81%. 23A recent multicentre retrospective study, reported on 92 patients receiving combined biologic therapy for active IBD or EIMs.The most common combinations were vedolizumab and ustekinumab (32%), or vedolizumab and anti-TNF (31%).The clinical response rates at 3 and 6 months were 46% and 34%, respectively. 21he efficacy of combining tofacitinib with other biological therapies was evaluated in two retrospective cohorts.Alayo et al. 23 reported that 35 patients (25 with UC and 10 with CD) were started on combination therapy due to a lack of response to their current biologic, despite dose optimization.The most common biologics combined with tofacitinib were vedolizumab (69%), infliximab (17.1%), and ustekinumab (14.3%).At week 8, 50% achieved clinical response, and 35% achieved endoscopic or radiographic remission. 23imilarly, another study by Lee et al. 25 reported 19 patients with refractory CD who received tofacitinib combined with ustekinumab (58%), vedolizumab (37%), and certolizumab pegol (5%).Clinical response and remission were observed in 80% and 60%, respectively.Endoscopic improvement and remission occurred in 54% and 36% of patients, respectively.
The outcomes of these open-label combined therapy reports must be viewed in the context of enrolling patients who had failed multiple advanced therapies already. 25

Clinical implications of combined targeted therapy in IBD management
The rationale for initiation of combined biologic or smallmolecule therapy for treatment of complex IBD has been proposed by Privitera et al. 30 in two clinical scenarios.First, "complicated IBD patients" with poorly controlled luminal disease, where initial co-induction or adding a second agent as sequential induction can be used in case of partial or inadequate response to the first agent.In addition, in high-risk patients who were exposed to multiple biological agents, induction therapy with two agents at the same time may be used as concomitant induction. 30he second scenario, "double indication", involves patients who have concomitant EIMs or IMIDs, where the second agent can be added to control active intestinal inflammation or EIM symptoms. 30In IBD patients with uncontrolled luminal symptoms and quiescent EIM symptoms. 30][33] The practical guidance for combined targeted therapy in IBD is shown in fig. 1.
There is currently insufficient evidence to suggest routine combination biological or small-molecule therapy in patients with refractory disease or EIMs.Most evidence comes from case reports, case series, retrospective cohorts, and metaanalyses of observational studies where patients were exposed to or refractory to one or both agents used as combination therapy.Thus, the data on combination targeted therapy are restricted by the low level of evidence.Uncontrolled luminal activity and double indications with co-existing EIMs or IMIDs are the two clinical scenarios for starting combination targeted therapy, but more data are needed to better evaluate the benefit-to-risk ratio.

Safety concerns and adverse events of combined targeted therapy
A major concern of combining biological therapies/small molecules is a possible worsening safety and AEs profile, particularly an increased risk for serious infections or malignancy. 10The majority of the data on combined biological therapy come from the rheumatologic literature.A metaanalysis by Boleto et al., 11 which included a total of 623 rheumatoid arthritis (RA) patients (410 on combined biologic Figure 1.The practical guidance for combined targeted therapy in IBD, adapted from Privitera et al. 30 therapy and 213 on single biologic) with a median follow-up of 9.5 months, suggested that combined biologic therapy in RA appeared to increase the risk of SAEs (14.9% vs. 6.0%). 11owever, combined biologic or small-molecule therapy in the treatment of IBD seems to have a safer profile and fewer reported SAEs.In a meta-analysis by Ahmed et al, 28 the proportion of patients or trials that experienced AEs and SAEs was 35% and 6%, respectively.Of those, infections and malignancies accounted for 19% and 1%, respectively. 28f note, a recent meta-analysis by Alayo et al. 29 in 2022 reported SAEs regarding specific combination types; the pooled rates of SAEs for these were 12.3% for vedolizumab and ustekinumab, 9.6% for vedolizumab and anti-TNF, and 1.0% (95% CI, 0.0-7.6)for tofacitinib and vedolizumab. 29In the combination of guselkumab and golimumab studies there was no new single safety concern, One case of tuberculosis was reported in the combination therapy group, and one case of colon adenocarcinoma was reported in the guselkumab monotherapy group. 14hus, the safety of combined biological or small-molecule therapy appears to be acceptable so far, but more data are needed due to limited patient numbers and short-term follow-up.

Conclusion
The use of combined biological or small-molecule therapies with different targets for the treatment of IBD patients opens a new avenue for the treatment of IBD."Complex refractory IBD," where no monotherapeutic option was efficacious, and "double indication," with active EIMs, are the two clinical scenarios where evidence is accumulating on combined target therapy. 26At present, combined targeted therapy cannot be recommended for bio-naïve IBD patients outside of a clinical trial setting.It is unclear whether combination therapy should be used only for the induction period or as maintenance therapy.Furthermore, the optimal combination agents or optimal mechanisms of action for the agents used in combination have not been clearly identified.
Recent findings from the VEGA trial indicated that the combination of novel biologics (guselkumab and golimumab) may become a new treatment option for high-risk UC patients. 14he ongoing DUET-CD and DUET-UC trials investigating combining guselkumab and golimumab in refractory IBD patients, are likely to provide additional data on the efficacy of guselkumab and golimumab in CD and UC patients who have failed biologic therapy.However, the treatment armamentarium for IBD is expanding, with the recent approval of multiple non-TNF biologics and small molecules. 34In the near future, the combination of these novel agents may also be investigated in clinical trials or in the real-world practice.A further concern of combined targeted therapy is the possible change in safety signals.Although safety seems to be unchanged so far, the data come from small studies with a limited follow-up period.Further large prospective studies with longer follow-up are required to confirm the efficacy and safety of this strategy.

Table 1 .
The RCT studies with combined targeted therapy in IBD.

Table 2 .
The selected retrospective studies in combined targeted therapy in IBD.