IBD Drive Time: Ben Click, MD, on the Best of UEG Week

In this episode of IBD Drive Time, Dr Raymond Cross and Dr Ben Click review “best of” abstracts on inflammatory bowel disease from United European Gastroenterology Week.

Raymond Cross, MD, is a professor of medicine and director of the IBD Program at the University of Maryland School of Medicine. Ben Click, MD, is a gastroenterologist specializing in inflammatory bowel disease at the Cleveland Clinic in Cleveland, Ohio.

TRANSCRIPT:

Raymond Cross:  Welcome, everyone, to "IBD Drive Time," which is sponsored by the Gastroenterology Learning Network and AIBD. I'm Raymond Cross from the University of Maryland School of Medicine.

I'm delighted that my colleague and friend, Ben Click, from Cleveland Clinic, is here to talk about the best abstracts of UEG in the category of controlled and uncontrolled studies of existing therapy and safety. Ben, welcome to IBD Drive Time.

Ben Click:  Thank you, Ray. It's pleasure to be here.

Dr Cross:  Ben was kind enough to identify what he thought were the 3 best abstracts in this category. He's going to have a few spin-off abstracts that he's going to mention as well. The first one we're going to talk about is OP193, which is entitled, "Discontinuation of infliximab therapy in patients with Crohn's disease and sustained combined clinical biochemical and endoscopic remission."

This was a double-blinded placebo-controlled randomized clinical trial. Ben, tell us about the study design, the key findings, and what the take-home messages here would be for providers.

Dr Click:  Thank you, Ray. You alluded to some of the study design aspects and that this was a multicenter placebo-controlled double-blinded randomized clinical trial originating from Denmark. It included a total of 115 patients with Crohn's disease who were on stable dosing of infliximab for at least 1 year.

Patients were all in what we would all consider deep remission. They were in clinical remission with a CDAI less than 150, biomarker remission, endoscopic radiographic, or capsule endoscopic remission. These patients were randomized 1-to-1 to either continue infliximab or receive placebo infusions.

Of note, approximately 50% of this population was on concurrent immunosuppressive therapy with either thiopurine or methotrexate therapy. The primary endpoint of this study was the time to clinical relapse judged by the CDAI greater than 150 or an increase greater than 70 points or more, or relapsed determined by provider necessitating intervention.

There was 1 withdrawal in the infliximab group compared to 8 in the placebo group. Those 8 patients in the placebo group, 4 out of 8 of those individuals was because of recurrent joint pain.

When looking at the overall clinical remission rates at the end of 1 year after either continuing on infliximab therapy or being transitioned to placebo infusions, 96% of the Infliximab population remained in clinical remission compared to 49% of the placebo group.

When performing survival analysis on time to relapse, notably, the infliximab group essentially did not decrease as mentioned previously. We see that over time, there was a more rapid time to relapse in those patients randomized to the placebo group.

Notably, they did a subanalysis of individuals who were either continued on immunosuppressive therapy or did not have immunosuppressive therapy. There was no significant difference between those 2 groups.

The clinical take-home from this abstract and this excellent placebo-controlled trial is that even in Crohn's disease patients who were in, probably, the deepest of remission, withdrawal of infliximab is associated with an unacceptably high rate of clinical relapse.

It doesn't appear that continuing the immunosuppressive therapy mitigates this risk. We should be discouraging withdrawal of biologic therapy unless an adverse event to that therapy has occurred.

Dr Cross:  I agree, Ben. There's some other aspects of this study that we look forward to seeing. We want to know what happens when the infliximab is restarted. Will they be able to recapture patients? What about histology— does that help predict? They are also doing analysis of drug levels. Just a follow-up question. Are we done with withdrawal studies with anti-TNF after this?

Dr Click:  Given that this was a placebo-controlled trial prospective and in combination with the other data points that we have from other studies, like the STORI trial, the nail in the coffin is pretty much there at this point. We know that patients relapse if we withdraw the biologic therapy.

We should be shifting the conversation that we have with patients because this, as you know, Ray, is one of the most common questions that we get as clinicians is, "When can I stop my medication?"

We should be shifting it to talk about what are the risks of relapse and potentially withdrawing the immunomodulator or immunosuppressive therapy if we're going to be talking about taking one of the combination therapies off.

Dr Cross:  I agree. This is helpful for us as clinicians because we now have data that we can quote to patients, which is very helpful. Before I go to the next abstract, I want to remind everyone that the national AIBD course is coming up December 9th to December 11th. There's plenty of time to register for the course. We hope to see you there.

Now I'm going to transition to a poster about ozanimod. We know that ozanimod was just approved. We had Dr. Rubin from University of Chicago give a very nice IBD Drive Time on ozanimod.

This was poster 0442 entitled, "Long-term safety of ozanimod in patients with moderately to severely active ulcerative colitis and relapsing multiple sclerosis study." A composite safety analysis for UC and MS. Ben, design, key findings, and take-home messages here.

Dr Click:  Look, Ray, you hit the nail on the head on why this is important is that this was a recently approved therapy. More and more safety data is always welcomed with these new therapies.

As you alluded to, this was a pooled result analysis from the UC and Multiple Sclerosis Clinical Trial programs incorporating data from over a thousand UC patients with 2,196 person-years up follow up and almost 2,500 relapsing, multiple sclerosis patients with over 7,000 person-years of follow-up.

Again, they pulled this data to look at treatment-emergent adverse events. What they saw was that rates of lymphopenia in both the UC and multiple sclerosis program, we're about 10%. The incidents rate range from about 3 1/2 and a half to a little over 5 1/2 per 100 person-years.

The rate of nasal pharyngitis was about 18% in the MS program and a little over 7% in the UC program.

Then, lower rates of other common treatment-related adverse events, including anemia, headache, and upper respiratory tract infection that we see with many of our agents in clinical trial programs, including adverse events of special interest looking between ulcerative colitis and the multiple sclerosis clinical trial program.

Opportunistic infections were relatively uncommon with an incidence rate of 1.4 to 1.7 per 100 person-years. Serious infections were relatively uncommon, as well as herpes zoster. Just as a note to ozanimod clinical trial program, individuals had to have either a documented vaccination or serologic protection from VZV, so a relatively low rate of that infectious complication.

Then, low rates of bradycardia and macular edema in both the UC and MS clinical trial programs, which was an adverse event of special interest. Overall, the take-home is that lymphopenia, nasal pharyngitis, and anemia were the most commonly reported adverse events in ulcerative colitis in MS-treated patients with ozanimod.

Serious infection rates were quite low at 1.3 per 100 person-years. As I mentioned previously, shingles, bradycardia, and macular edema were uncommon. Just as a note from a related abstract, they did also present more detailed data on the rates and recovery of lymphopenia in the clinical trial program.

Essentially, what that showed is that about a quarter up to a third of patients who are treated with ozanimod do experience a lymphocyte reduction to less than 500. Most patients who receive ozanimod will experience about a 50% decrease in their lymphocyte counts.

Notably, the rates of serious or severe lymphopenia less than 200 were quite low, less than 2% overall. When agents were either held for a short period of time or patients were switched to placebo, those lymphocyte counts did recover quite rapidly. Very reassuring data when it comes to the lymphocyte count, which is likely related to the mechanism of action.

Dr Cross:  Although we discussed this a lot in our group, which we're going to discuss in a second, it didn't seem like all the lymphocyte count reduction is concerning. It didn't seem to have any impact on the rate of serious infections, so very reassuring.

Then, there was a poster also that talked about coadministration of antidepressants. There's been some Twitter chat about whether you can use an antidepressant with this agent. Ben, just one or two sentences on that.

Dr Click:  Yeah, so really quickly. They looked at individuals in both the UC and MS programs who are concurrently treated with SSRIs, and they did not see any noticeable signal of either serotonergic syndrome symptoms or hypertensive-related events in individuals receiving concurrent SSRI therapy. Reassuring when it comes to that potential theoretical drug-drug interaction.

Dr Cross:  Where are you positioning this, Ben, as far as in clinical practice? Are you positioning this first-line for bio-naive patients? Are you positioning this later or not clear yet?

Dr Click:  To be honest, Ray, I'm still waiting a little bit. I have only, in full transparency, prescribed this ! time this far in a routine clinical patient. I'm still dipping my toes in the water, so to speak, but this type of data demonstrating the safety of this first-in-class agent is very reassuring. It'll probably become more routine first-line practice for patients with this available therapy.

Dr Cross:  I agree. It's nice that it's an oral agent, no therapeutic drug monitoring. As I've heard you say before, set it and forget it. A nice therapy for patients. Ben and I covered the best of UEG abstracts as part of the IBD Education Group, of which Med Ed Consultants is a parent company. I just wanted to put that out there.

I'm now going to go to the last abstract that we're going to cover, which is P0393, "Association between efficacy outcomes and prior duration of remission in patients with ulcerative colitis treated with tofacitinib 10 milligrams, twice daily, who were in stable remission and dose reduced to 5 milligrams or remained on 10 milligrams BID."

There's a little bit more to that title, but it's too long. This is super timely because we're getting a lot of pressure given the new FDA warnings from pharmacists and payers to dose-reduce very early. Ben, design, key findings, and a take-home message.

Dr Click:  This was an analysis from the RIVETING Trial. Just to review the RIVETING Trial, it was a phase three study of individuals who were in stable remission from the tofacitinib OCTAVE Open Trial Program. Patients who were in stable remission at the end of OCTAVE Open were eligible to be included in RIVETING.

In RIVETING, they were randomized 1-to-1, as you alluded to, Ray, to either continue 10 milligrams BID, which all of these patients were on from the OCTAVE Open program, or to dose-reduce to 5 milligrams BID.

We're going to focus on a subgroup analysis that looked at the response and the outcomes to this dose reduction by the duration of remission going into the RIVETING clinical trial program or this particular study.

Essentially, what this abstract suggested is that individuals who have a shorter duration of remission before they are dose-reduced from 10 milligrams to 5 milligrams BID had lower proportion of achieving important clinical outcomes. As you expanded the duration of remission to about 24 months, which was the extent that they looked at, those proportions did improve.

Now, this was a small sample size because they were doing some post-hoc analysis. An important grain of salt. There's this suggestion that in individuals who are just achieving their remission with tofacitinib, there's the risk that when you dose-reduce, you don't achieve the same outcomes, as say continuing individuals on 10 milligrams BID before attempting that dose reduction.

Dr Cross:  We learned that as in RIVETING and we learned as part of the placebo group after induction that not all patients that restart or dose-escalate their therapy are able to recapture response. By dose-reducing, you potentially can lose a patient in remission.

What are you doing in clinical practice, Ben? Are you dose-reducing? Are you keeping everyone on 10 BID, or does it depend?

Dr Click:  Largely, Ray, I have stopped dose-reducing. I have an informed discussion with patients about the potential risks related to tofacitinib, especially in light of the recent FDA warnings. I reiterate this important data that's emerging that we're seeing potential risks with those reduction.

We're not gaining all that much when you look at the safety data. There was some abstracts presented at UEG as well in terms of updates from the tofacitinib program that you're not gaining that much safety-wise by dose-reducing. As you alluded to, you are potentially increasing the hazards in terms of clinical outcomes.

Dr Cross:  We're not seeing the thromboembolic and cardiovascular events and all sort of colitis that they documented in that single rheumatoid arthritis study. The safety continues to be reassuring. I agree there's not much benefit by dose-reducing.

Ben, the best question of the podcast. Tell us something about yourself that the audience would not know.

Dr Click:  Oh, gosh. That's a good question. As my wife likes to remind me, there was a point in time in my life when I had green hair. Growing up, I was a very avid skateboarder and into the alternative lifestyle, if you will. As part of that, I completely dyed my hair green. It started off as a Halloween costume, but then I found out after dyeing my hair, that the hair dye I used was quite permanent.

Much to my mom's chagrin. I had green hair for about 2 months before my hair was long enough to cut.

Dr Cross:  That may be the most awesome personal disclosure on IBD Drive Time. I would never have guessed that. Ben, thank you very much for being our guest. We hope to have you back again. For the listeners, we have two more podcasts upcoming on IBD Drive Time that are going to focus on additional best of UEG abstracts. Stay tuned.

References:

OP 193 Discontinuation of Infliximab Therapy in Patients with Crohn’s Disease in Sustained, Combined Clinical-Biochemical-Endoscopic Remission: A Double-Blinded, Placebo-Controlled, Randomized Clinical Trial.

P0442 Long-Term Safety of Ozanimod in Patients With Moderately to Severely Active Ulcerative Colitis (UC) and Relapsing Multiple Sclerosis (MS) Studies

P0386 Effect of Ozanimod Treatment and Discontinuation on Absolute Lymphocyte Count in Patients With Moderately to Severely Active Ulcerative Colitis: Results From a Phase 3 Randomized Trial

P0441 Safety of Concurrent Administration of Ozanimod and Serotonergic Antidepressants in Patients With Ulcerative Colitis

P0393 Association Between Efficacy Outcomes and Prior Duration of Remission in Patients With Ulcerative Colitis Treated with Tofacitinib 10mg Twice Daily (BID) Who Were in Stable Remission and Dose Reduced to 5mg BID or Remained on 10mg BID: 6-Month Data From the Double-Blind, Randomised RIVETING Study