David Hudesman, MD, on Efficacy of Tofacitinib Induction for Ulcerative Colitis

Dr Hudesman reviews the findings of a post hoc analysis he and colleagues at NYU Langone Health conducted to assess associations between C-reactive protein, partial Mayo score, and efficacy outcomes during tofacitinib induction.

David Hudesman, MD, is an associate professor of the Department of Medicine at the NYU Grossman School of Medicine and medical director of the Inflammatory Bowel Disease Center at NYU Langone Health in New York, New York.

TRANSCRIPT:

GLN:

Welcome to this podcast from the Gastroenterology Learning Network. I'm your moderator, Rebecca Mashaw. I'm very pleased to have Dr. David Hudesman, who is an associate professor of medicine and codirector of the IBD Center at NYU Langone Health in New York, here with us to discuss the findings of his study that he and colleagues conducted, assessing associations between C-reactive protein, partial Mayo Score, and efficacy outcomes during tofacitinib induction in ulcerative colitis. Thanks for joining us today, Dr. Hudesman.

Dr. David Hudesman:

Thanks for having me.

GLN: Why did you decide to make this topic the focus of your study?

Dr. Hudesman:

I think one of the more difficult challenges in managing patients with Crohn's and ulcerative colitis, whether it's with tofacitinib or our other agents, is, when can we predict if a patient's going to respond to therapy? How long do we keep them on therapy if they're not responding? When do we say, "Look, they're not getting better, maybe it's time to move on."?

And we don't have any great data looking at that. A lot of it's our clinical impression. We look at some biomarkers but we haven't looked at this too much in a good way. And with tofacitinib, what we do have is we have nice data that this medication, these JAK inhibitors, they work quickly, and that by day 3 we see improvement in stool frequency and rectal bleeding in patients with ulcerative colitis. But how about those patients that aren't getting better by day 3? How long do we continue them on it? And that was, I think, the main question, and really that's very practical, because that's what we deal with all the time in the office.

GLN: So give us an overview of the study, if you would.

Dr. Hudesman:

Sure. So what we did is we looked at both the phase 2 induction data on patients on tofacitinib 10 mg twice a day, specifically in the phase 2 studies, and in the phase 3 studies as well. And they were all 10 mg twice a day. And we combined the induction studies, phase 2 and phase 3, and we looked at C-reactive protein and partial Mayo scores to see if the C-reactive protein, or changes in C-reactive protein, and changes in the partial Mayo score will predict clinical response, clinical remission, endoscopic response, or endoscopic remission at week 8.

And then what happened in our phase 3 program, or in tofa's phase 3 program, was patients that did not meet response, clinical response at week 8, based on the study criteria, they were able to get another 8 weeks of tofacitinib 10 mg twice a day. And we also, in this particular study, looked at week 8 and week 12 CRP and partial Mayo Score, and see if that predicted patients that had a delayed response.

So essentially, to summarize, looking at CRP and partial Mayo score to see if that could predict response to therapy during induction, or in extending induction out to week 16.

GLN: And what did you find?

Dr. Hudesman:

Specifically, so we had CRP at time points week 0, so before starting tofa at week 4, and as well as at week 8. And then we had partial Mayo scores at more frequent time points, so week 2, week 4, week 8, and week 12 in those delayed responders. And what we found is, if we're looking at clinical response, clinical remission, and endoscopic response, using multivariate analysis— so taking into account the severity of their disease, past steroid use, past biologic and immunosuppressive use—that if there was a significant drop, or if there was a drop in CRP, or a drop in partial Mayo score, so really speaking towards the rectal bleeding and the stool frequency by week 4, that predicted that patients were more likely to have a true clinical response, be in clinical remission, or have an endoscopic response by week 8.

Interestingly, for endoscopic remission, only the partial Mayo acore using multivariate analysis, not the CRP, showed a significant benefit in remission. So showing that symptoms are still pretty important, and especially that rectal bleeding subscore. Secondly, in the patients that did not meet clinical response by study criteria at week 8, if you did have an improvement in partial Mayo score, but not enough to be a clinical response at week 8, or, and that improvement continued through week 12, those patients were more likely to be, have a clinical response, in remission, at week 16.

GLN: What does that tell you about the importance of C-reactive protein? It appears there was a disconnect between what you were seeing in terms of CRP and what you were seeing in terms of partial Mayo?

Dr. Hudesman: Yes. So that's a great question. So I think 2 things. I think we know well that symptoms don't necessarily correlate with what's happening on the inside, more so with Crohn's than ulcerative colitis, but rectal bleeding, I think, is a pretty good sign of what's happening. And CRP is an important marker, but it's nonspecific, and in this program, only about 65%, give or take, so about two thirds, had an elevated CRP at baseline. I think, these programs did not include fecal calprotectin in the study, and I think this is another important biomarker. And hopefully, looking at future studies in tofa, as well as with other agents, we'll be able to use that, and my guess is we'll see a little bit better of a result with calprotectin. But I think it shows that rectal bleeding is important.

GLN:  Well it sort of predicts my next question is, are you going to continue to do further studies, and do you think you will put calpro into the mix in the future?

Dr. Hudesman: Yeah. I think it's important to do more of these studies. And these studies can be done through using the registration data, so the larger studies than doing a post-hoc analysis, or this could also be generated in a real-world fashion. And I think, yeah, I hope there is more data. And I think we are going to be doing this, because, what this study, to me, shows is, again, you start somebody on tofa, you're going to have a good percentage by day 3 that are going to be better. But how about those patients that are on a month of therapy and they're not getting better? Do we give it 2 months? Do we give it 3 months? And I think, pretty much, what this is telling us is, if there's a signal at 1 month that a patient's doing well, whether it's a decrease in stool frequency or rectal bleeding, or a drop in their CRP, we want to continue.

To that same note, they say, and most of our agents have this, right? We have patients that respond during induction, whether that's, whatever week that is, whether it's 4, 6, 8, 10, 12, depending on the study, but in this study, week 8. So we have patients that respond well. But we also have patients that don't respond by week 8, or after induction. And if you give them an extended induction, they do get better. But the question is, how long are you going to keep the patient on a therapy where they're not doing so well? Are you going to give them another month or 2, when they're not feeling well or not?

And I think what this study shows is, you really need to have a signal. Right? So by week 8, even though you didn't truly meet clinical response by study criteria, there was improvement in the partial Mayo score. The patients that didn't have any response at week 8, still a small percentage did well at week 16, but a small percentage, and definitely by week 12. So I think this could help guide where, if there's really no signal that a patient's getting better by week 8, and definitely by week 12, it doesn't make sense to continue them on. But if there is a signal, depending on their severity, you are going to capture more of those patients, so I think giving them more of a chance to work, and hopefully when we add in calprotectin and look at different agents, we can give a little better criteria on how we make these decisions.

GLN: So you're just trying to find that sweet spot at which you can comfortably make a decision to continue or to stop and try something else.

Dr Hudesman:  Exactly. And that's, again, one of the more difficult things to do. We are all looking at biomarkers. Everybody's looking, trying to find that marker, whether it's blood or stool or tissue, that could say you will or won't respond. Hopefully, we'll have that. I don't know if we will, or when we will, but we do have good clinical data from these larger trials and from the real world that could help guide treatment. And I think we should continue to look into this, and I think this will be very impactful for our patients, right? Continuing them on something a little bit longer where we think it's high likelihood that it's going to work, and on the flip side, stopping something where look, maybe it's time to move on, and not letting them continue to have symptoms for another month or two.

GLN: Did you find any significant adverse effects showing up?

Dr Hudesman:  Yeah. So this is an important question with this class, with JAK inhibitors. And I think, with this study, this was mainly an induction study, so it was only out to week 16. So there's really no significant adverse events, but I don't think this study is well-equipped to speak to that. I think, just my own personal opinion, I think there is a risk of infection with JAK inhibitors, risk of shingles, we could vaccinate for Shingrix. I think the cardiac events, the MACE events, the clotting events, that's really still only been shown in a select population of older, over the age of 50, with rheumatoid arthritis, most of these patients were smokers, and on methotrexate, they're really a select patient population. And when you look at the tofa data, whether they're young or old, and ulcerative colitis, we haven't seen those signals. And with our other JAK inhibitors that's been approved for ulcerative colitis, we haven't seen those signals as well. So important to discuss with the patient, but I really think our patients are different than the patients that we're studying.

GLN: We appreciate your time, and I look forward to hearing about what you do next along these lines and what you find.

Dr.  Hudesman: All right. Well great speaking to you, and thank you so much.