AIBD was full of updates on many of the highlights and clinical advances in inflammatory bowel disease (IBD) over the past year. Along these lines there have been several recent trials that impact on clinical practice in IBD as current treatment goals have continued to evolve around the topics of “treat-to-target,” therapeutic drug monitoring, and comparative effectiveness.
One important clinical advance was the recent FDA approval of ustekinumab (Stelara®, Janssen Pharmaceuticals) for the treatment of moderate-severe ulcerative colitis (UC). The approval was based on the phase III UNIFI studies recently reported in the NEJM. The trial included an 8-week randomized induction followed by a 44-week randomized withdrawal maintenance trial. There were several clinically-relevant aspects of the approval. The first novelty of the trial was that it included both endoscopic and histologic outcomes that were used to define “mucosal improvement,” a step beyond endoscopic improvement as histologic activity has independently been associated with a worse prognosis regarding maintenance of remission and the evolution of colonic neoplasia (dysplasia) (1, 2). The second clinically relevant aspect of the FDA approval was the labeling. Whereas prior biologics for IBD (both UC and Crohn’s disease [CD]) were given FDA indications for “moderate-severe UC/CD with an inadequate response to conventional agents or tumor necrosis factor agents” the agency avoided the modifier regarding prior response. This is more in accords with the recent STRIDE guidelines and AGA Pathways for IBD that advocate therapy based on prognostic severity rather than symptoms and prior response to treatment. Over the past several decades, third party payers have used the FDA indications (marketing approval) to approve therapies for patients rather than the standard of care that dictates clinician recommendations (3, 4). The removal of “step therapy” through conventional agents for ustekinumab’s approvals for both UC and now CD speaks to the safety and potential as a first-line agent for patients with “moderate-severe” IBD.
Two other important trials presented previously at UEGW were frequently discussed at AIBD. The SERENE trials with adalimumab that compared higher induction doses (160 mg at weeks 0, 1, 2, and 3, followed by 40 mg every other week at week 4 through week 12) with standard doses (160 mg at week 0 and 80 mg at week two, followed by 40 mg every other week through week 12 in both UC and CD. Most clinicians would have “bet” on the higher induction dosing, however, while both trials showed dose-proportionate increases in blood trough levels there were no differences in clinical or endoscopic outcomes between the high and standard induction dosing schedules. We are still waiting on maintenance results from both trials. Despite the absence of population benefits at the higher doses, there was a signal for higher trough levels associated with endoscopic improvement suggesting that there still may be some individual variations in target blood levels. In any event, these findings do not support early, prospective therapeutic drug monitoring during induction with adalimumab (5).
The “best abstract” at AIBD was awarded to the comparative study of biosimilar adalimumab BI 695501 to the reference product (Humira®) in patients with moderate-severely active CD. The study demonstrated similar outcomes for the CD activity index (both CDAI 70 and 100) after four weeks of inductive treatment and no new safety signals up to 24 weeks. Hopefully, the advent of available biosimilars will both lower the overall costs and increase access to patients with IBD.
Finally, the results of the VARSITY trial that was recently published in the NEJM and has been discussed in recent GI conferences. The trial was a comparative effectiveness study of vedolizumab versus adalimumab for induction and maintenance of moderate-severe UC. Both vedolizumab and adalimumab were administered at their FDA approved doses and dosing schedules in a double-blind manner. The results demonstrated statistical superiority for vedolizumab for the end-points of clinical remission and mucosal improvement but conversely for adalimumab regarding steroid-free remissions. The results were surprising to many clinicians who had perceived a possible “slower onset of action” for vedolizumab and the mechanism of inhibiting leukocyte trafficking compared with neutralization and inhibition of TNF. While the results are relevant, many still question the ultimate dosing and potential dose-adjustments for individual patients that were not allowed in the comparative effectiveness trial. While this was a first head to head study of marketed therapies for IBD, additional comparative effectiveness studies are clearly warranted and the results of the SEAVIEW study comparing ustekinumab to adalimumab in moderate-severe CD are anticipated next year.
Illustration by April Brust