AURORA, COLO. – Only sparse evidence supports the use of dual-targeted therapy for patients with severe, refractory inflammatory bowel disease (IBD) -- and additional evidence will be hard to come by, according to a leading IBD researcher.
Dual-targeted therapy consists of either sequential or concomitant treatment with drugs from different classes of agents with distinct, specific mechanisms of action such as the use of a drug targeted against tumor necrosis factor (anti-TNFs) with an interleukin-12/23 inhibitor. There have been only a handful of randomized clinical trials exploring such combinations, however. In addition, there are barriers to new trials, including the costs and risks of randomized trials, the need for cooperation rather than competition between pharmaceutical companies, and identifying patients who might optimally benefit from dual-targeted therapy, Laura Targownik, MD, said in a presentation at the annual Crohn's & Colitis Congress®, a partnership of the Crohn's & Colitis Foundation and the American Gastroenterological Association.
"In Canada we have absolutely no chance of getting coverage for this, and I imagine in hearing about the fights you have with insurers here in the [United] States, that you're anticipating similar problems. So what do we do with this information? I think if we're going to get answers on this question, it's probably going to come from real-world evidence, from all of our experiences," said Dr. Targownik of the Zane Cohen Centre for Digestive Diseases at Mount Sinai Hospital in Toronto.
Who might benefit?
Dual-targeted therapy has the potential to benefit patients with severe disease who may need intensive therapy upfront to prevent complications such as fistulas, strictures, or chronic abdominal pain. It may also benefit those who may require only short-term acute disease control; patients with meaningful yet incomplete responses to single-agent therapy who might have better outcomes with the addition of a second agent; and, patients with a unique phenotype that might be responsive to dual-targeted agents, Dr. Targownik said.
Another reason to consider dual-targeted therapy in IBD comes from applying data from recent clinical trials of upadacitinib (Rinvoq, Abbvie) for ulcerative colitis (UC) and risankizumab-rzaa (Skyrizi, Abbvie) for Crohn's disease to hypothetical cohorts.
For example, of 1,000 persons with moderate to severe UC treated with upadacitinib, 736 would have a clinical response at the end of the induction, and at the end of the maintenance phase 191 would have endoscopic remissions, and 382 would remain in clinical remission.
Similarly, of 1,000 persons with moderate to severe Crohn's disease treated with risankizumab, 434 would have a clinical response at the end of induction, and at the end of the maintenance phase, 172 would have endoscopic remissions, and 234 would remain in clinical remission.
"So, the vast majority of our patients are not achieving the targets that we want to hit," she said.
Evidence from research clinical trials
Data from one of the few trials that have explored dual targeted therapy in IBD were presented at United European Gastroenterology Week in 2022.
The randomized double-blind phase 2a VEGA study looked at induction therapy with either a combination of the IL-23 inhibitor guselkumab (Tremfya, Janssen) and the anti-TNF monoclonal antibody golimumab (Simponi Aria, Janssen) followed by maintenance guselkumab, or each agent alone as induction monotherapy and maintenance.
The study population included 214 patients with moderate to severe UC with a modified Mayo Disease Activity Index scores of 6 or greater and endoscopy scores of 2 or 3 who had not received either anti-TNF or anti IL-23 agents.
At 12 weeks of follow-up, 36.6% of patients who started on combination therapy had clinical remissions, compared with 22.2% of patients on golimumab monotherapy and 22.1% of those on guselkumab alone, a clinically significant difference, Dr. Targownik said.
The combination also resulted in better endoscopic improvement over baseline (49.3% vs. 25% and 29.6%, respectively), although the study was not powered for this outcome.
At 38 weeks, 22.2% of patients who started on golimumab alone were in clinical remission, compared with 31% of those assigned to guselkumab monotherapy and 43.7% of those who started on the combination.
Endoscopic normalization at 38 weeks was seen in 6.9%, 15.5%, and 25.4% of patients, respectively.
"Even in the patients who went back on guselkumab monotherapy that were induced with dual therapy, there were statistically higher rates of clinical remission and endoscopic normalization at the end of the study," Dr. Targownik said, although she noted that it's unknown whether the benefit of the combination would be sustained over longer follow-up.
In the open-label EXPLORER Crohn's disease trial, among 55 patients with high risk Crohn's disease, within 24 months of diagnosis investigators looked at the triple combination therapy of the anti-integrin agent vedolizumab (Entyvio, Takeda), the anti-TNF agent adalimumab (Humira, Abbvie) and methotrexate. An interim analysis at week 26 of the 34-week trial showed clinical remissions in 54.5% of patients and endoscopic remissions in 34.5%, "which I would argue for an open-label study are not terribly high results," she said.
Dr. Targownik pointed to a systematic review and meta-analysis of the safety and effectiveness of combining biologic agents and small molecules in patients with IBD as evidence for how combinations work in the real world.
The analysis included data from 1 clinical trial and 12 observational studies on a total of 266 patients treated with one of seven different combinations. It showed estimates of clinical efficacy ranging from about 40% to 80%, albeit with wide and overlapping confidence intervals, making it difficult to come to any conclusions about the relatively superiority of one combination over another, Dr. Targownik said.
The authors of the meta-analysis did note, however, that the incidence of serious adverse events was relatively low, ranging from 9.6% for the combination of vedolizumab and anti-TNF, to just 1% for the JAK inhibitor tofacitinib (Xeljanz, Pfizer) plus vedolizumab.
Registry data may help
The use of registry data will shed more light on the potential benefits and drawbacks of dual-targeted therapy.
"If we can identify...the patient phenotypes that we want to evaluate dual therapy in, and try to catalog their experiences in a regimented way with defined outcomes and periods of follow-up, we may be able to get more meaningful information," Dr. Targownik said.
Dr. Targownik disclosed fees, grant support, and/or scientific advisory board participation with multiple companies.
This article originally appeared on MDedge.com, part of the Medscape Professional Network.
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Cite this: Proof Lacking for Dual-Targeted Therapy Benefit in IBD - Medscape - Jan 27, 2023.