Positioning Therapies in the Management of Moderate to Severe IBD

Precision medicine can and will play a role in the management of ulcerative colitis (UC) and Crohn disease (CD), especially as new agents and decision tools become more available, said William J. Sandborn, MD, at the Advances in Inflammatory Bowel Diseases 2020 virtual meeting on Wednesday, December 9, 2020.

Dr Sandborn is chief of gastroenterology at the University of California at San Diego.

He began by reviewing the currently available treatments for IBD, noting that the 2 most effective agents, based on meta-analyses and head-to-head trials, are infliximab and vedolizumab for biologic-naïve patients with UC. For second-line therapy among patients with UC whose condition has not responded to anti-tumor necrosis factor (TNF) agents, the most effective treatments for achieving and maintaining remission are tofacitinib and ustekinumab, according to results of meta-analyses.

Safety must also be considered, Dr Sandborn stated. There are several safety concerns associated with anti-TNF agents, such as granulomatous infection, serious infections, non-Hodgkin lymphoma, and demyelination. With tofacitinib, the risks include herpes zoster, serious infections, deep vein thrombosis/pulmonary embolism, and hyperlipidemia. He noted that none of these risks has been associated with vedolizumab or ustekinumab.

“Positioning therapies also depends on severity of illness,” he explained. With mild UC the first-line therapies may be “mesalamine, rectal therapies, maybe steroids; with more moderate to severe UC, you go on to the first-line or perhaps second-line therapies. Some cases may have extenuating circumstances, such as if you have a lot of extraintestinal manifestations, comorbidities, and structural damage, which have to be considered when choosing the appropriate therapy.”

Because no Janus kinase (JAK) inhibitors have been approved for use in CD, first-line therapy choices are limited to anti-TNFs, vedolizumab, or ustekinumab, Dr Sandborn said. “The

strongest effects in treatment-naïve patients are seen with the anti-TNFs; for second-line therapies, infliximab and vedolizumab show somewhat less effectiveness, but there is a definite effect seen with ustekinumab.” Although adalimumab also shows more effectiveness, he noted that this is “a bit misleading—it seems limited to patients who responded to infliximab and then lost response.”

The SEAVUE trial, a head-to-head trial of adalimumab and ustekinumab among treatment-naïve patients with CD, will add more information to the mix for clinicians selecting therapies for maximum effectiveness and safety, he said.

Another new therapy, guskelumab, is an interleukin (IL)-23 inhibitor now being tested against ustekinumab in CD. Dr Sandborn noted that the trial design will continue into phase 3. Other new agents in development include the JAK inhibitor filgotinib and upadacitinib; anti-P19 (IL-23) antibody agents risankizumab, mirikizumab, annd brazikumab, as well as guselkumab; and sphingosine-1-phosphate (S1P) modulators ozanimod and etrasimod.

As with the therapies used in UC, Dr Sandborn said, in CD “we have a situation where the anti-TNFs are somewhat more effective as first-line therapies but less safe. As you make these decisions in consultation with patients, these factors will have to be taken into account,” and patients who are risk-averse may prefer the safer therapies even if somewhat less effective.

“Precision medicine definitely has a major role in treatment of IBD,” Dr Sandborn noted, referencing the development of clinical decision support tools such as those developed by his colleague at the University of California San Diego, Parambir Dulai, MD. These tools use factors such as disease duration, baseline endoscopy and albumin, and exposure to anti-TNF medications to indicate the likelihood of a patient responding positively to vedolizumab, as demonstrated in the VICTORY trial for UC. A similar tool is also available for predicting response to vedolizumab among patients with CD.

“Positioning of biologics can be informed by network meta-analyses and head-to-head trials” for patients with IBD, Dr Sandborn stated. “In the future, anti-IL-23 therapy with risankizumab, geselkumab, and mirikiziumab, JAK1 inhibitor therapy with filgotinib and upadacitinib, and S1P modulator therapy with ozanimod and etrasimod, will also be added to our treatment options” for ulcerative colitis, and all these therapies except for the S1P modulators will also be added to the armentarium for CD, he added. “Precision medicine can play a role in the care of patients with IBD,” Dr Sandborn concluded.

—Rebecca Mashaw

Reference:

Sandborn WJ. Positioning biologics and small molecules in the management of moderate to severe IBD. Talk presented at: Advances in Inflammatory Bowel Diseases 2020 virtual meeting. December 9, 2020.