Optimizing Treatment Strategies to Manage Inflammatory Bowel Disease - Episode 12

SEAVUE: Ustekinumab vs Adalimumab in Crohn Disease

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Details of the head-to-head SEAVUE study of ustekinumab vs adalimumab for induction and maintenance therapy in patients with moderate to severe Crohn disease.

William Sandborn, MD: In the pivotal studies, we were missing endoscopies for patients on both vedolizumab and ustekinumab, so you’re treating symptoms and we didn’t have that piece of information. The SEAVUE trial came out recently, and it showed similar outcomes with adalimumab in the treatment of Crohn, which we know is a good drug. Ustekinumab is also an option, including similar rates of endoscopic healing. We know that class of drugs and ustekinumab are safer, so that strengthens my way of thinking. If you have a patient that has significant alteration, or somebody whom you would ordinarily give a TNF [tumor necrosis factor] blocker or 2—that trial, to me, says, “If you wanted to emphasize safety, you could give ustekinumab as a first-line treatment and expect the similar amount of efficacy that you’re going to get with the TNF blocker.” I like that. I agree, the positioning by payers is problematic part of the time, but in a perfect world, that’s a great fit for first-line therapy because of the mixture of safety and efficacy.

Remo Panaccione, MD, FRCPC: We already touched on the SEAVUE trial, but we should unpack it and address the significance that it may have in clinical practice. The SEAVUE trial was a head-to-head trial of ustekinumab and adalimumab per label, so there was no dose escalation. It included an early patient population that was bio-naive. Arguably, endoscopic activity was less than what we would usually see in a typical patient with moderate to severe Crohn disease. With that being said, powered for superiority, we didn’t see any difference in either the clinical or endoscopic outcomes. From each one of you, what is your overall take on it and how is it going to change your clinical practice? I’ll start with Jessica. Did you have any expectations going in?

Jessica Allegretti, MD, MPH: Yes; I’m not surprised by the results. It shows what would potentially be considered a well-known first-line agent, adalimumab, in the treatment of Crohn disease; ustekinumab performed just as well, and this agent has a superior safety profile. I don’t think that’s arguable, and you give it less frequently: Dosing is every 8 weeks compared to 2 weeks. In that sense, when you see that data as a prescriber, you might say, “Why wouldn’t I go with the more convenient, safer choice if the efficacy is essentially equivalent?” That’s the takeaway for me from that study; all things—payers and whatnot—being considered, they’re both injectables, so you have that convenience factor, but there’s less dosing with ustekinumab. In the end, even though there wasn’t a superior result for ustekinumab, from an efficacy standpoint, that’s still a positive outcome.

Remo Panaccione, MD, FRCPC: Yes; Ed?

Edward Loftus Jr., MD: Yes; there were hints in there that, for most end points, they were the same. There were hints of some favorability of ustekinumab regarding safety. The number of people who discontinued the trial due to adverse events was almost twice as high in the adalimumab arms. It was 11% vs 6%. Then, among the week 16 responders, the percentage of patients who were doing well at week 52 was about 10 percentage points higher in the ustekinumab group. That fits with the sense that there is less drop-off. If you’re a responder, you tend to maintain your response with ustekinumab—there’s less loss of response. Those are the hints that those are some of the positive features of ustekinumab. I view it as a win-win because these are probably the 2 most common drugs I use in the treatment of Crohn disease, so they’re both good drugs. In an ideal world, if we didn’t have insurance barriers or cost access, sure, you would use the ustekinumab all the time. In the real world, it’s twice as expensive, so that plays a role. Anecdotally, I do feel that it has a bit of a target on its back lately. Since the first of the year, it seems like we have had much more pushback in issues related to either starting ustekinumab or changing the dose of ustekinumab, including right here. It is an issue, and it’s only going to get worse in 2 years when we get 6 biosimilars hanging out, waiting for activation.

Remo Panaccione, MD, FRCPC: Welcome to my world.

William Sandborn, MD: I would like to press you on 2 things; I see it the same way you guys do. The only other thing is the issue around dose escalation. I’m helping the launch of this therapeutic drug monitoring [TDM] stuff. I feel like there’s an epidemic of dose escalation that’s not adding a lot of value. With ustekinumab, that adequacy of dosing is good for most patients. If you looked at the pharmacokinetic and pharmacodynamic paper that we published in Gastroenterology, for both UC [ulcerative colitis]and Crohn, 75% of the patients plateau efficacy at about the 25th percentile of drug concentration for the labeled dose. Most patients have enough of the drug, and I don’t see much utility in empirically dose escalating for something that’s never been shown to work. You take an expensive drug and make it mega expensive, and we don’t know if it works. If you measure the drug level, you get off the hook for dose escalating 75% of the time. With adalimumab, there’s much more of it. Now we have the SERENE trials that show it doesn’t work well in terms of more intensive dosing, but it’s an inconvenient fact in the way that we’ve built our practice guidelines and come to practice now. I feel less pressure to dose escalate with ustekinumab, which I like. I don’t know how you guys see all that.

Jessica Allegretti, MD, MPH: It is interesting; we do a lot of dose escalating up here [Brigham and Women’s Hospital] and we have looked at this. One of our fellows, Rahul S. Dalal, MD, published a few things on this at DDW [Digestive Disease Week] this year. Essentially, what we found is if you’re a primary nonresponder to ustekinumab, there’s absolutely 0 utility in dose escalating. However, there does seem to be some recapture in the patients who had an initial response and then lost response. We saw about 50% recapturing clinical response. There seemed to be no difference between Q6 and Q4, so how people decide the level that they’re escalating to is provider dependent. There are no data that suggests that one is better than the other, but we saw some recapture and we’re studying this prospectively now, so we shall see. There might be some utility in some of those secondary nonresponders, but I don’t know how to use TDM for ustekinumab in my practice. I don’t routinely check levels. I don’t know what to do with them. If the patient does lose response, I’m almost reflexively dose escalating to try to recapture response with a low threshold to move on if it doesn’t work.

Remo Panaccione, MD, FRCPC: Do you think the results of some of these new trials are going to influence how we prescribe biologics in bio-naive patients? Is the SEAVUE trial going to change anything?

Jessica Allegretti, MD, MPH: I do think these head-to-head trials are important. When the VARSITY trial was published, it was a pivotal moment in this space. We have been asking for these head-to-head trials to try to understand positioning and we’re finally starting to get them, and we are going to get more. Having data like these and seeing the results can influence practice patterns. I appreciate having data with these head-to-heads to understand how I’m going to position therapies in my own practice. These things matter. We have been guessing at positioning and using things like network meta-analyses to try to understand. Until we have actual biomarkers or actual tests where we can test patients up front and say, “This is the therapy you need to be on first,” this is the type of data that we need to help inform our practices.

Remo Panaccione, MD, FRCPC: Thank you for watching this HCPLive® Peer Exchange. If you enjoyed the content, please subscribe to our e-newsletters to receive upcoming peer exchanges and other great content right to your inbox. I am sure you will see the folks in front of you on future programs. With that, thank you very much.

Transcript edited for clarity.