番茄社区

The study is the first head-to-head trial that compares the safety and efficacy of prescription biologics in the treatment of Crohn's disease, and results were presented during the 2021 Digestive Disease Week virtual meeting.

In this second of four exclusive roundtable episodes, 番茄社区 brought together three leaders in the field -- moderator , of Baylor College of Medicine in Houston, is joined by , of Michigan Medicine in Ann Arbor, and , of Yale School of Medicine in New Haven, Connecticut -- for a virtual roundtable discussion about how the (Safety and Efficacy of Adalimumab Versus Ustekinumab for One Year) trial results might impact their practice.

Episode one: Do COVID-19 Vaccines Protect IBD Patients?

Following is a transcript of their remarks:

Hou: Hello, everybody. I am Dr. Jason Hou. I am an associate professor of gastroenterology at Baylor College of Medicine. I'd like to welcome you to the DDW Virtual Roundtable on 番茄社区. We're really fortunate to be joined by two panelists here today: Dr. Shirley Cohen-Mekelburg, she's an assistant professor at the University of Michigan, as well as Dr. Jill Gaidos, associate professor at Yale University.

The topic that I'd like to bring up for discussion for the panel is a recent abstract that was presented as an oral presentation at DDW 2021, which is called the SEAVUE study. This was a very interesting study. We're definitely moving into a new realm of clinical trials, which I think both providers and the patients have been demanding, and now the FDA for some time, which are head-to-head studies of active agents.

For the longest time, most of our landmark trials are comparing a new agent to placebo. We obviously know placebo is not going to work, but that's left us with this large dilemma of how to pick amongst many potential options.

SEAVUE was a trial, head-to-head, our first head-to-head biologic randomized placebo-controlled trial for Crohn's disease. This trial compared, interestingly, a bio-naïve population of patients ... for either ustekinumab, which is the IL [interleukin]-12/23 antagonist, compared to standard-dose adalimumab, which is a TNF [tumor necrosis factor]-alpha antagonist.

Again, these were all bio-naïve patients with moderate to severe Crohn's disease, and again, the dosing ... also was only prescribed as monotherapy, which I think is a relevant thing to point out, for the study.

The patients were blinded. They received dummy placebos because the dosing schedules are different for both of these drugs. The primary endpoint ... was clinical remission at week 52 based on CDAI [Crohn's Disease Activity Index], but there are multiple secondary endpoints and, of course, analyzed in a hierarchical fashion as expected for this study.

It's a study of nearly 400 patients that were randomized, and in the end the headline is not a significant difference between the two at the primary endpoint, and again, of the hierarchical comparison, but for those reported secondary endpoints, also not really a lot of difference.

I'm curious about the panelists' thoughts on this study and how this would impact their practice.

Cohen-Mekelburg: I think it's great to see more and more investigators planning head-to-head trials. With the larger armamentarium, the drugs that we have available now, I think one of the big questions is how do we position these therapies. This is a great study to see. I think a lot of people were waiting for this.

While I don't think anyone is necessarily shocked that the study came out as negative overall, I think some of the important points to think through are is this really representative of the real world -- which, obviously, in the clinical trial setting, isn't always.

I think one of the larger criticisms of this trial is that the adalimumab and the ustekinumab were given kind of at a standard dose throughout the entire 52-week period and there was not really an opportunity for a dose escalation, for example. We're still learning about dose escalation in the context of ustekinumab, but with adalimumab it is very common for us to dose escalate.

I think that's really one of the disadvantages, at least as far as the adalimumab arm, and kind of makes me question whether the findings would be different if patients were able to increase their adalimumab dosing.

I know the reasons why it was not done, which it is very difficult to kind of maintain blinding while dose escalating, so that's a methodological question for another day. But it's the big takeaway in interpreting the data.

Gaidos: I also thought this study was very interesting. I really... it's very nice. One of the pushes for treatment when we talk about treatment of our IBD [inflammatory bowel disease] patients now that we have what seems like a lot more choices for drug positioning, and how do you pick one over the other?

I think we still are not there for personalized medicine. I think it would be really nice if I could tell if my patients' inflammation was driven by TNF or if it was driven by IL-12-23, and that would really help to break out who's going to respond and who's not.

I think this is really encouraging in that it sort of supports our understanding that your first drug is the one that you have the best chance of getting your patient into clinical and endoscopic remission, and so we can't just blow through our therapies. We really need to be serious about appropriate dosing duration, allowing the medicine enough time to work.

I still get kind of disappointed that the primary endpoint is a clinical remission when we know that clinical symptoms don't always correlate with histologic or endoscopic healing, but I know that's one of the easiest targets to meet, which is why that's their primary endpoint as far as approval in getting these drugs approved for use.

I think there's still room to improve our clinical trials, and I agree with Shirley that it would have been nice to allow a little bit of flexibility in the dosing for those patients that lost response, because we don't really know how many we can recapture, particularly with ustekinumab. I think it's a good study. I think it's helpful, but there is still a lot more work to be done, yeah.

Hou: How does this impact any decision making you have for your patient in the clinic?

Gaidos: I think for me when patients say, "well, which one should I use?" I now have evidence to support my recommendation, and so I can now tell them there is really no clinical difference in the two of them. The endoscopic response was similar. The clinical response was similar.

I think there is still the issue of insurance approval, and I think overall, when I present these two agents to patients as potential treatment options, I think as far as safety, which they also included here, there wasn't a huge difference in safety or the increase in adverse side effects or infections. But really, I think the biggest issue is still getting it paid for, getting approval from insurance.

Cohen-Mekelburg: Yeah. I think a minor point but one of the reassuring things about this study is it basically showed that both drugs are well tolerated. I think 76% of the adalimumab arm and 85% of the ustekinumab arm completed the studies, so that is pretty high and good to tell patients.

But, yeah, I agree, as Jill said, a lot of this is a conversation with patients, and part of the conversation is all the factors that are important to the patient and their trajectory, and while comparative efficacy is one of those factors there are other things that need to be considered as well. Can the patient do injections? Are they able to travel to a facility to get their first infusion? I think all those are factors as well.

I know for some of our older patients in our clinic we're able to actually have the nurses bring them in for injections, and so a medication like ustekinumab in that context is logistically a little bit easier.

Gaidos: One of the problems ... clearly we always need more data for evidence-based medicine. But I would say the majority of my patients, probably 85%, are not biologic naïve, so unfortunately this doesn't address the positioning for those who have already been exposed to an anti-TNF agent or some other biologic.

Hou: Yeah, I think I agree with both of your comments. I think that's a very insightful way to view the study and put it into clinical context. I think this was ... I applaud the investigators, as you've already said, for giving us this information with a head-to-head trial. It's a lot of work, a lot of expense, to run a trial. Again, some people say it's a negative study. Some people say it's a positive-positive study. We have two medicines that were very effective. I think there are some other additional nuances.

As I mentioned in the intro section, these are all monotherapy patients, and I think we're aware that at least for TNF inhibitors, there may be some benefit of using a combination with a thiopurine in that setting. Would that have changed the results significantly? Unclear. But that's, again, one nuance.

Another thing, which is the numbers, again, I was actually a little surprised at how similar the numbers are. When you look at all of the endpoints, they're within ... most of the outcomes were within a delta of 5%, which is remarkably close, given that these are two different agents, different MOAs [mechanisms of action], and have very similar rates.

That part, and even looking at some of the time trends in terms of time to remission and things like that, the lines were almost on top of each other, which I think is encouraging, and also higher than I think sometimes we may expect.

Things to keep in context -- again, because it's not placebo-controlled -- what is the placebo response when you're having two active arms? That's why you can't really compare these numbers with other prior studies.

Others, because it was, as you already mentioned, Dr. Gaidos, is these are bio-naïve, the duration of disease in this study was only about 3 years, that median duration of disease, which is much shorter than typical phase III trials that we're seeing, and which may explain why some of these numbers may be a little bit higher.

It's encouraging. I think it's what some of us are probably seeing in real life, and that you look at the real-world data, these numbers match, that are probably closer than we do with typical phase III data, which are often lower than what we see in real-life data because those are sicker patients, multi-failure patients, and things like that.

But those are, I think, very important things to take into account. Again, to summarize what I think both of you all were commenting on, is it's encouraging that we have two. These two medicines both appear to be quite efficacious and it's going to come down to shared decision-making. What is it with the patients? What are the factors that are important to them? Access, cost, and things like that. That's where I think the impact will be.

It gives us in some ways more freedom, more flexibility to tell patients that we have two good ... these are both good options if these are the two agents that you're deciding between for your patient with moderate to severe Crohn's disease. Any other final comments?

Cohen-Mekelburg: Yes. My only final comment is I hope that this study encourages further studies like it rather than fewer.

Gaidos: Absolutely, and we get some to include biologic-experienced patients as well.

Hou: Yeah. I think another thing to make the stories even more nuanced, as I think you mentioned, Dr. Cohen, is adding some component of dose adjustment to factor in closer to what real-world use would be for us in most clinical settings will provide additional data for us to make decisions in the clinic for our patients with these meds.

Thank you for that great discussion, Dr. Cohen and Dr. Gaidos. Thank you for your time, for the audience, for listening in, and hopefully you'll join us for one of the other sessions.

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