Miguel Regueiro, MD: David; Bill, Jessica, and Marla gave an overview of all the biologics and especially focused on Crohn disease, but for ustekinumab in ulcerative colitis [UC] and the UNIFI study looking at some of the results, what's your overall gestalt? What's your feeling about the study results? Talk to us about some of your take-home messages with ustekinumab for ulcerative colitis.
David T. Rubin, MD: Ustekinumab was the first-in-class of its kind for ulcerative colitis. This is an anti-p40 antibody that ends up targeting 2 cytokines: IL-12 [interleukin-12] and IL-23. After its approval for moderate-to-severe Crohn disease in 2016, it was approved for moderately-to-severely active UC in 2019. It offers a new treatment option for us.
The UNIFI study published in The New England Journal of Medicine looked at both induction of remission as well as maintenance. It was an 8-week induction study that looked at weight-based IV [intravenous] dosing: a single dose versus a stable dose of 130 mg compared to placebo. Of patients who responded after that initial single IV dose, they were randomized to placebo or subcutaneous dosing of 90 mg every 8 or every 12 weeks.
What the UNIFI study demonstrated was that patients who received either the 130 mg dose or the weight-based dosing IV were more likely to achieve remission than placebo: about 15.5%. Those who responded, who then went on to the maintenance study at 1 year, whether they got every-12-week or every-8-week subcutaneous 90 mg, they were more likely to be in remission at the end of the year, compared to placebo, with the 8-week interval being more favorable numerically than the 12-week interval. The drug got approved for the single IV loading dose that's weight based, and then 8-week subcutaneous dosing of 90 mg. This is an option for our patients because it's a different mechanism.
In the clinical trial, there were patients who were already TNF [tumor necrosis factor] experienced and those who were TNF naïve. Similar to many of the messages with other therapies, patients who have not already failed TNF do better, so it suggests that choosing this therapy earlier in some patients would be more likely to get you the response you need. It offers the convenience of an injectable therapy at every-8-week interval. The real-world experience has held up. The safety of the drug was similar to placebo, as Bill already alluded to. Interestingly, there's very low immunogenicity with this therapy such that we can feel comfortable administering it as a monotherapy. It offers a new mechanism for many of our patients with UC. I particularly like this therapy in my patients who either need a more convenient strategy for different particular reasons, but also for a patient who has a history of psoriasis. This is also approved for that indication; it's a wonderful option for skin. I've found it to be useful.
We've published our real-world experience that about 20% of the patients in our center at the University of Chicago Medicine needed to go to every-month injection, and that seemed to capture many of the patients with some dose adjustments. It's been a very practical and helpful addition to our armamentarium in UC.
Miguel Regueiro, MD: David, before I leave that study, I want to ask you and then Marla the same question. There was this new end point: this histo-endoscopic mucosal improvement, HEMI. Tell us about that and what that means to you in your practice.
David T. Rubin, MD: A standard end point in ulcerative colitis trials for many years now has been a secondary end point of what was previously called mucosal healing, and now more accurately, is called endoscopic improvement. That looks at the improvement of the mucosa through the colonoscope or a flexible sigmoidoscopy and is usually now done by a standardized reader. The FDA, and frankly all of us, have been interested in whether that's an adequate measure of the mucosal inflammation or healing.
In the UNIFI study, Janssen [Pharmaceutical] designed it to include a novel end point called histo-endoscopic mucosal healing, which not only included the component of how it looks endoscopically, but it also defined histologic remission as less than 5% neutrophils per high-powered field on biopsies. In fact, and maybe not surprisingly but interestingly, when you look at the histo-endoscopic mucosal healing with ustekinumab, both the maintenance dosings achieved that greater than placebo.
Of great interest is whether having histological remission, in addition to endoscopic improvement, leads to better outcomes than either one alone. Bill's looked at that subset, and there's now a manuscript in press that has described some of that. It's of great interest to us because we all believe that what's going on below the surface may be more important in predicting outcomes, and we certainly recognize that histology is most directly correlated to subsequent neoplasia, so that may be something more that we're going to look at in the future.
Histology is not yet a therapeutic target. We shouldn't be treating to histology, but we should certainly appreciate what its value is when you see that there's persistent histological activity, or conversely when you achieve histological remission.
William J. Sandborn, MD: I wanted to add one thing around the extraintestinal manifestations. We've made the case that ustekinumab is quite good for dermatologic indications. TNF blockers are also not bad for psoriasis and pyoderma. Ustekinumab may be a little better, but if you have arthritis, ustekinumab doesn't help much, and it wasn't effective in spondyloarthropathies and ankylosing spondylitis. TNF blockers and JAK [Janus kinase] inhibitors are good for arthritis. If you have multiple sclerosis [MS], TNF blockers are relatively contraindicated. Ustekinumab didn't cause harm, so that's better than a TNF blocker. You can use ustekinumab in a patient with multiple sclerosis or a history of demyelination, but you're going to need a separate therapy for the MS, and you've got to make sure that the sum total of the toxicities are acceptable.
With vedolizumab, you can treat the gut with vedolizumab, and then let the neurologists do whatever they want for the multiple sclerosis because of the safety profile of vedolizumab. In a future world, we might use the small molecule, S1P1 modulators, which would cover MS and IBD [inflammatory bowel disease].
It's interesting how we leverage these different classes of drugs in the subset of patients who have extraintestinal manifestations.
David T. Rubin, MD: That’s an important point, Bill. In the absence of therapeutic biomarkers to help us know which mechanism to use, being thoughtful about comorbid illnesses and extraintestinal manifestations should guide us, not just because we know the drug may work, but it provides insight in to what the pathogenesis might be in that individual patient. It's very interesting stuff.
Miguel Regueiro, MD: Yes, and we'll get into positioning in a minute, but you just mentioned the comorbidities, the extraintestinal manifestations, the age. There are a lot of factors.
Transcript Edited for Clarity