New Safety Signals Seen With Entyvio (CME/CE)

Action Points

• Note that these studies were published as abstracts and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
• Note that this analysis of reported safety data suggests that the integrin-receptor antagonist vedolizumab may have an increased risk of adverse events compared to some TNF-inhibitors.
• Longer and more detailed follow-up will be needed to fully elucidate the safety profile of this novel agent.

SAN DIEGO -- Possible new safety concerns have emerged with real-world use of the α₄β₇ integrin receptor antagonist vedolizumab (Entyvio) in the treatment of inflammatory bowel disease, research presented here suggested.

In a poster session at the annual Digestive Disease Week, Anthony Wang, PhD, of AbbVie in North Chicago, reported that vedolizumab may have a safety profile different from that of the anti-tumor necrosis factor (TNF) agents, in that there appeared to be an increase in cardiovascular events with the drug. AbbVie markets the anti-TNF drug adalimumab (Humira), which is approved for the same IBD indications as vedolizumab.

For instance, among 499 reports in the FDA's database of adverse events among patients treated with vedolizumab, central nervous system hemorrhages and cerebrovascular accidents occurred in nine patients (1.8%), whereas among 119,620 events associated with exposure to anti-TNF therapy, there were 430 events of this type (0.4%), for a proportional reporting ratio (PRR) of 5, Wang reported.

There also were more pulmonary thrombotic and embolic conditions in the vedolizumab-treated patients compared with the anti-TNF-treated patients (1% versus 0.4%, PRR 2.5), and more cases of pulmonary edema (0.6% versus 0.1%, PRR 4.5).

"However, these findings should be considered solely hypothesis-generating," he told MedPage Today.

Biologic therapies for inflammatory bowel disease (IBD) either target general inflammation, as with the TNF inhibitors, or inhibit leukocyte recruitment to sites of inflammation through mediation of integrin receptor activity. Vedolizumab is a gut-specific leukocyte migration inhibitor that was approved for ulcerative colitis and Crohn's disease in 2014.

Most safety information about vedolizumab to date has been from clinical trials, which may underestimate or fail to identify uncommon adverse events, so real-world follow-up is needed, such as through the FDA Adverse Event Reporting Systems database.

PRR was calculated as the ratio of the reporting proportion of adverse events associated with vedolizumab divided by the proportion associated with the comparator, and a safety signal was defined as a PRR of 2 or higher.

Safety signals other than cardiovascular events that have been seen for vedolizumab compared with anti-TNF agents included colorectal neoplasms (PRR 30), central nervous system and spinal infections (PRR 15.6), and liver function abnormalities (PRR 5.1). Adverse events that have been noted in the prescribing information for the drug included infusion site reactions, infections, liver abnormalities, and colorectal neoplasms.

As to the reason why a signal for cardiovascular safety was seen for vedolizumab compared with the anti-TNF therapies, Wang said that "there is some evidence that anti-TNFs may lower cardiovascular risk through blockade of TNF-α systemically."

"Further analysis of the long-term real-world safety of vedolizumab should be conducted before conclusive claims of vedolizumab's safety can be made," he concluded.

In a second poster at the meeting, Khadija Chaudrey, MD, of the Mayo Clinic in Rochester, Minn., also reported that in the real-world IBD Consortium for Health Outcomes with Biologics, some adverse events not previously reported with vedolizumab have now been seen.

These included a case of autoimmune hepatitis in a patients who was antineutrophil antibody positive, a case of optic neuritis in a patient with a previous history of this, a bowel perforation associated with obstruction that could have been treatment related, a case of meningitis in a patient with a previous history of this inflammatory disorder, and fatal septic shock in a patient who was undergoing exploratory laparotomy.

Her analysis included 326 patients whose mean age was 38. The overall rates of serious infections and other serious adverse events were low, with serious infections being reported at a rate of 13.2/100 patient-years of follow-up. Clostridium difficile was the most common enteric serious infection (4.6/100 patient-years).

Serious adverse events occurred at a rate of 9.5/100 patient-years, and on univariate analyses, factors that were associated with the development of serious adverse events included severe disease activity (OR 2.17, 95% CI 1.01-4.07, P=0.050) and concomitant steroid use (OR 2.17, 0.95-4.99, P=0.068). These associations were not maintained in multivariate analysis, however.

There also have been reports of increased abdominal wound infections associated with the drug, but the cause is unclear. "Maybe the drug isn't that gut-specific. Our hypothesis is that it may also have systemic effects," Chaudrey told MedPage Today.

The study by Wang's group was supported by AbbVie.

Wang and co-authors are company employees and consultants.

Chaudrey disclosed no relevant relationships with industry.

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New Safety Signals Seen With Entyvio (CME/CE)