Dr Dubinsky reviews two abstracts she presented at the ACG Scientific Meeting concerning the use of subcutaneous infliximab— as an induction strategy after a drug 'holiday' and as in treating patients with ileal or ileocolonic Crohn's disease.

Marla Dubinsky, MD, is a professor of Pediatrics and Medicine (Gastroenterology) at the Icahn School of Medicine and chief of Division of Pediatric Gastroenterology at Mount Sinai Kravis Children's Hospital in New York, New York.

Subcutaneous Infliximab: Drug Interruption and Small Bowel Crohn’s Disease

• LIBERTY phase 3 analysis: Patients were randomized after a 3-dose standard on-label induction regimen of 0 to 6 weeks, 5 milligrams per kilogram. Patients were then randomized to either placebo injection every 2 weeks or actual sub-Q infliximab, 240 milligrams every 2 weeks.  Antidrug antibody status did not significantly affect clinical outcomes, biomarkers, or drug concentrations after induction with sub-Q infliximab.
• US dosing caveat: FDA approval covers 120 mg every 2 weeks, not 240.
• Crohn’s disease: A matched indirect comparison of approximately 140 patients across 4 registration trials favored subcutaneous over IV maintenance for clinical and endoscopic outcomes in ileal or ileocolonic disease.

Hello, I'm Dr. Marla Dubinsky from the Icahn School of Medicine at Mount Sinai New York, and I'm delighted to be sharing with you two specific research abstracts that I had the pleasure of presenting at ACG in Nashville.

The first one I want to talk about is this interesting concept of looking at what happens when people take a drug holiday, not from what we classically think about, which is IV infliximab, but actually when someone takes a drug holiday between IV and the introduction of sub-Q [subcutaneous] infliximab. So as part of the LIBERTY trial, patients were randomized after a 3-dose standard on-label induction regimen of 0 to 6 weeks, 5 milligrams per kilogram. Patients were then randomized to either placebo every 2 weeks injection or actual sub-Q infliximab, 120 milligrams every 2 weeks. And in those patients who went from an IV induction last dose at week 6, their third induction, then patients were randomized to placebo.

The question that came about from that is how interesting that typically in a drug holiday, we are concerned about reintroduction or an interval or break and patients getting antidrug antibodies. This ability to say that when you have a long drug holiday or an interruption in therapy, we were somewhat concerned about reintroducing IV infliximab mainly because of the recurrence, if there was in the past, or new onset antidrug antibodies when you reintroduce the drug. So in this arm of the LIBERTY phase 3 trial, we looked specifically at those individuals during their honeymoon and up until the point that they were actually introduced—it wouldn't be a reintroduction because they had not seen sub-Q yet, but it would be at their first dose of introduction of sub-Q infliximab. And we looked at antidrug antibody (ADA) positivity that were measured between week 10 and towards their introduction of infliximab out to week 56.

What I should note is that in individuals who were in that placebo arm—actually, to correct myself, it wasn't 120 milligrams every 2 weeks, it was actually 240 milligrams that they were introduced after they had this honeymoon period. And in order to get the sub-Q infliximab of 240, they had to have actually had symptoms, so considered a loss of response.

So what was interesting is what we found is that individuals who, again, had IV infliximab, had a honeymoon, then were having symptoms, declared to be loss of response after their IV induction, and then were introduced to 240 infliximab sub-Q every 2 weeks, we looked at whether or not the outcomes of whether or not someone was successful after they were introduced to sub-Q infliximab, whether the antibodies that they developed during this honeymoon, did they impact clinical outcomes? We looked at clinical remission. There was no difference in those who were antibody positive or antibody negative when they were introduced to sub-Q infliximab.

We looked at clinical response. Again, no difference in their actual outcomes, whether they were ADA positive during that break or right up until the day that they received their sub-Q infliximab. We looked at partial clinical remission as well in UC. We looked at clinical remission in UC, and again, no significant difference in outcomes. We also looked at CRP levels and fecal calprotectin levels to say, "Hey, maybe not symptom-wise, but maybe biologic markers or biomarkers would be different in those who had that antidrug antibody status of positive up until, again, the moment that they are introduced to 240 milligrams of sub-Q infliximab”— no difference across the 2 groups, whether they were antibody positive or antibody negative.

So I think overall, what's really interesting to think about this idea that perhaps after an IV infliximab period of time, and if there's a honeymoon, the question that I got asked the most after the presentation and even probably during the presentation when questions were coming in, is could it be a way for us to avoid the reintroduction of IV infliximab as well as with the onset of antidrug antibodies and possible infusion reactions that happen on the second reinduction dose, not the first, because that's the first time they've been reintroduced to IV infliximab. So that's where you get this antigen load and that's what drives the antibodies.

But our biggest concern is, are they going to have a horrible infusion reaction at that second infusion because of all the antidrug antibodies? And what we're seeing here is that potentially—not tested, this is my theory—around whether or not this would be a better way to reintroduce infliximab for those patients who are circling back or have said, "I never felt better than when I was on infliximab,” for example, and we felt like we wanted to reintroduce it. Could it be that we would reintroduce it not with an IV, but would we introduce it with sub-Q infliximab? Now, the problem is that 240 milligrams as of now in the US, the FDA approval is not for 240, it's only for 120 milligrams every 2 weeks. So that does remain a little bit of a caveat to my sort of thinking around this ability to reintroduce patients with a honeymoon with the sub-Q as opposed to the IFX.

But also what's interesting is when you introduce back the sub-Q, which the other thing other than the antibodies of relevance is what happens to the drug concentrations, because what we're typically used to is you get this influx of antidrug antibodies, you negate the IFX concentrations, and therefore patients don't respond, get infusion reactions. But what was interesting here is that you did not see a significant difference in drug concentrations in those that were ADA positive or ADA negative, and patients were able to sustain that level that we see with sub-Q infliximab, this constant durable level, with my theory being is if you have enough drugs sort of flogging the system, the antibody positivity does not influence efficacy and is not what I would call neutralizing at that moment because you have enough drug to actually have effect. So this is a very fascinating concept, still needs to be tested, but I think in my mind, I felt this to be an interesting thought or interesting finding from the LIBERTY trial that we didn't think about originally as to what happens when you have a honeymoon and then introduce sub-Q.

So I think for me, the clinical utility here is to consider that instead of reinducing with IV infliximab, to consider sub-Q IFX as a way to reintroduce infliximab to your patients.

Now, in addition to that, there was a second late breaker abstract that I also had the pleasure of presenting, which again included sub-Q infliximab. And the purpose of that was to say we know that in Crohn's disease, small bowel disease, whether it's isolated or small plus large bowel, is often considered a difficult to treat population. I would venture to tell you the small bowel is the more difficult piece, even in the ileocolonic patients, and that there was a question about if you look at registration trials that included IV infliximab and/or sub-Q infliximab, can we look at the subset of patients who had ileal only or ileocolonic disease and look at whether sub-Q performed better than IV in these trials?

So it was a matched indirect comparison study where we adjusted for any of the variables that may impact the validity of the comparison. And once they were matched, we ended up with about 140 patients that were matched between the IV and the sub-Q maintenance components of these 4 registration trials. And no matter what outcome, again, that we looked at, it did indeed show that individuals performed better with sub-Q infliximab in this cohort of patients that had ileal or ileocolonic disease compared to IV. The purpose was not to compare colonic only versus small plus large bowel versus small bowel alone. The purpose was to say in the more difficult to treat Crohn's disease population, is it possible that sub-Q infliximab may have greater impact on outcomes, including endoscopy and clinical outcomes than IV infliximab?

So I think these 2 abstracts address two different ideas or thoughts or theses in our clinic, and I think this just adds more information to as we learn about the application and the utilization and the benefits of sub-Q infliximab over IV infliximab in these two particular clinical scenarios.

So thank you.