IBD Drive Time: Jennifer Seminerio, MD, on Advanced Combination Therapy

Drs Cross and Seminerio discuss advanced combination therapy, which involves use of more than one biologic or a biologic and an advanced small molecule, including trial results to date, types of combinations, safety considerations, and which patients are most likely to benefit.

Raymond Cross, MD, is Medical Director of The Center for Inflammatory Bowel and Colorectal Diseases​ in the Melissa L. Posner Institute for Digestive Health and Liver Disease at Mercy Medical Center​, in Baltimore, Maryland​.

Advanced Combination Therapy (ACT)/Dual Biologic Therapy in Inflammatory Bowel Disease (IBD): Clinical Use, Efficacy, Safety, and Emerging Trial Data

• Advanced combination therapy (ACT)/dual biologic therapy in IBD refers to combining 2 biologic agents or a biologic plus a small molecule to improve disease control in selected patients. Common combinations discussed include vedolizumab plus anti-TNF, IL-12/23 or IL-23 inhibitors, or JAK inhibitors, as well as JAK inhibitors combined with IL-23 inhibitors. ACT is typically used in a minority of patients (approximately 5%–10% in the speakers’ practices) and is generally reserved for refractory disease, recurrent loss of response to monotherapy, or patients with extraintestinal manifestations/other immune-mediated conditions.

• Available evidence suggests ACT is efficacious, particularly in treatment-refractory patients with prior exposure to multiple advanced therapies. The speakers emphasized that monotherapy remains preferred when effective and that ACT should follow confirmation that symptoms are driven by active IBD rather than alternative causes. Common practice is a stepwise “stacking” approach, with close follow-up and contingency planning rather than routine upfront dual induction.

• Safety data to date have not shown major new safety signals with ACT, although some studies report increased infections. At Digestive Disease Week (DDW), the DUET phase 2b trial evaluating golimumab plus guselkumab in Crohn’s disease and ulcerative colitis reported improved clinical remission and endoscopic outcomes in refractory patients versus monotherapy, with no observed difference in safety signals between combination therapy and guselkumab monotherapy; the program is advancing to phase 3 evaluation.

Welcome everyone to IBD Drive Time. I'm Raymond Cross from Mercy Medical Center in Baltimore, Maryland, and I'm delighted to have my friend Jen Seminario, who's at AdventHealth and University of Central Florida. And we're going to talk about dual therapy and IBD. Jen, welcome to IBD Drive Time.

Dr Seminario:

Thank you so much for having me. It's a pleasure to be here.

Dr Cross:

So Jen, when we talk about combination therapy, most people think about the old days when you and I were training when it was anti-TNFs and an immune suppressant, either thiopurine or methotrexate. But can you give the listeners an idea of what we're going to talk about today?

Dr Seminario:

Yeah, I think that you'll start to see some new terms that we use associated with this. One term that many people are using is ACT or Act, which is advanced combination therapy or dual biologic therapy. You'll see both phrases used. Combination therapy as you already alluded to is more along the lines of a biologic or advanced therapy in addition to some traditional immunosuppressive wherein advanced combination therapy or dual biologic therapy is using that and taking it a step further wherein we use 2 known biologic agents within the field or a biologic agent and a small molecule and we combine them together for ongoing enhancement of the efficacy value and treatment of the disease.

Dr Cross:

So we do an IBD retreat in our region, which is multidisciplinary, not only surgery, but also other medical subspecialties. And we include community providers that take care of a lot of IBD. And one of the former trainees that I helped train came up to me and said, it's really good to hear about this, although I don't have that many patients. I don't have any patients on combined advanced therapies. And so I said, "That's good because you're not supposed to have a lot." So I told her that in my practice it's probably 5% of my patients or less. What would you say your practice is, a number that are on advanced combination therapies?

Dr Seminario:

Yeah, I would say for me, it's a little bit higher, probably closer to about 10% is usually what I estimate. And I think that living in Florida and getting a large population referred to me from not only my state but surrounding states that typically has advanced disease is part of the reason for that. I think that I agree with what you just said. It is not meant to be the majority of the patients that we're treating and it is meant to be an avenue to gain traction in some of these more difficult to treat patient populations that we may be accustomed to in these specialty centers.

Dr Cross:

And what are the common combinations that are being used, Jen?

Dr Seminario:

So as we think about it, our portfolio within the inflammatory bowel disease world has obviously grown substantially, especially within the last 5 years, with expectations that this is going to continue to grow in the coming years. And amongst our portfolio, I think that you will see different variations and combinations. Now, based on the historic anti-TNF and anti-integrin classes being the oldest, I think that a lot of the times that was where this idea started from. In fact, one of the earliest papers used an anti-integrin—natalizumab in combination. And now I think that you will see a lot of vedolizumab use in combination with either an anti-TNF, an IL-1223 or an IL-23 specific molecule, or even a vedolizumab in combination with a JAK inhibitor. So that I think historically has been the easiest one to combine for a variety of different reasons.

I think part of this is because when we're thinking about the combination therapies, there are 2 big barriers and we'll talk about this. One is safety, but the other is access. And what vedolizumab allowed a lot of us to do was combine a infusion molecule, which went through the medical side of an individual's benefits, with something that might be an injectable and oral through their specialty side. So I think that was part of the reason vedolizumab was such an easy target to use. But additionally to that, the vedolizumab molecule has a very nice safety profile. And on of the reasons that it works so synergistically with other molecules, beyond it being very safe historically, is the fact that it works via an antitrafficking mechanism, is considered to be gut-specific, wherein the majority of its efficacy is only in the gut. So you don't have a lot of negative additive effects from a safety profile, but you do get a lot of positive synergistic effects because of the mechanism of action.

Now after vedolizumab, we have seen a lot happen beyond that. And I would say that of late, one of the favorite combinations has been using the JAK inhibitors with either an IL-23 or vedolizumab, like I already mentioned. And so this sort of adds onto that idea of different mechanisms of action because you take a small molecule and then you combine it with a traditional biologic.

Dr Cross

Welcome everyone to IBD Drive Time. I'm Raymond Cross from Mercy Medical Center in Baltimore, Maryland, and I'm delighted to have my friend Jen Seminerio, who's at AdventHealth and University of Central Florida. And we're going to talk about dual therapy and IBD. Jen, welcome to IBD Drive Time.

Dr Seminerio:

Thank you so much for having me. It's a pleasure to be here.

Dr Cross:

So Jen, when we talk about combination therapy, most people think about the old days when you and I were training when it was anti-TNFs and an immune suppressant, either thiopurine or methotrexate. But can you give the listeners an idea of what we're going to talk about today?

Dr Seminerio:

Yeah, I think that you'll start to see some new terms that we use associated with this. One term that many people are using is ACT or Act, which is advanced combination therapy or dual biologic therapy. You'll see both phrases used. Combination therapy as you already alluded to is more along the lines of a biologic or advanced therapy in addition to some traditional immunosuppressive wherein advanced combination therapy or dual biologic therapy is using that and taking it a step further wherein we use 2 known biologic agents within the field or a biologic agent and a small molecule and we combine them together for ongoing enhancement of the efficacy value and treatment of the disease.

Dr Cross:

So we do an IBD retreat in our region, which is multidisciplinary, not only surgery, but also other medical subspecialties. And we include community providers that take care of a lot of IBD. And one of the former trainees that I helped train came up to me and said, it's really good to hear about this, although I don't have that many patients. I don't have any patients on combined advanced therapies. And so I said, "That's good because you're not supposed to have a lot." So I told her that in my practice it's probably 5% of my patients or less. What would you say your practice is, a number that are on advanced combination therapies?

Dr Seminerio:

Yeah, I would say for me, it's a little bit higher, probably closer to about 10% is usually what I estimate. And I think that living in Florida and getting a large population referred to me from not only my state but surrounding states that typically has advanced disease is part of the reason for that. I think that I agree with what you just said. It is not meant to be the majority of the patients that we're treating and it is meant to be an avenue to gain traction in some of these more difficult to treat patient populations that we may be accustomed to in these specialty centers.

Dr Cross:

And what are the common combinations that are being used, Jen?

Dr Seminerio:

So as we think about it, our portfolio within the inflammatory bowel disease world has obviously grown substantially, especially within the last 5 years, with expectations that this is going to continue to grow in the coming years. And amongst our portfolio, I think that you will see different variations and combinations. Now, based on the historic anti-TNF and anti-integrin classes being the oldest, I think that a lot of the times that was where this idea started from. In fact, one of the earliest papers used an anti-integrin—natalizumab in combination. And now I think that you will see a lot of vedolizumab use in combination with either an anti-TNF, an IL-1223 or an IL-23 specific molecule, or even a vedolizumab in combination with a JAK inhibitor. So that I think historically has been the easiest one to combine for a variety of different reasons.

I think part of this is because when we're thinking about the combination therapies, there are 2 big barriers and we'll talk about this. One is safety, but the other is access. And what vedolizumab allowed a lot of us to do was combine a infusion molecule, which went through the medical side of an individual's benefits, with something that might be an injectable and oral through their specialty side. So I think that was part of the reason vedolizumab was such an easy target to use. But additionally to that, the vedolizumab molecule has a very nice safety profile. And on of the reasons that it works so synergistically with other molecules, beyond it being very safe historically, is the fact that it works via an antitrafficking mechanism, is considered to be gut-specific, wherein the majority of its efficacy is only in the gut. So you don't have a lot of negative additive effects from a safety profile, but you do get a lot of positive synergistic effects because of the mechanism of action.

Now after vedolizumab, we have seen a lot happen beyond that. And I would say that of late, one of the favorite combinations has been using the JAK inhibitors with either an IL-23 or vedolizumab, like I already mentioned. And so this sort of adds onto that idea of different mechanisms of action because you take a small molecule and then you combine it with a traditional biologic.

Dr Cross:

Yeah, I completely agree. I like to think of it as, and I'm going to step back one second and just remind the listeners that what we clearly recognize now is poorly controlled disease activity and steroids are the big drivers of adverse events, particularly infection. So I would not, from a standpoint of controlling disease and eliminating steroids, even putting an anti-TNF and a JAK together would probably be safer. But generally when you're thinking about combinations of advanced therapies, we're generally thinking about the safest MOAs like the IL-23 inhibitors and maybe an S1P and an anti-integrin that's not natalizumab and then an anti-TNF or a JAK. Those are the most common combinations. Although again, I think in certain subsets you could combine very potent therapies together and it still would likely be safe. So how are you doing this in clinical practice, Jen? So what are your patient scenarios where you're using combination of advanced therapies?

Dr Seminerio:

Yeah, I think this is where the finesse of inflammatory bowel disease really comes into play. For me, I think there are a few different sets of scenarios that I really home in on. Probably foremost, and to your point, this is an area where I typically use combination therapy for refractory disease. And by refractory disease, we're talking about patients who have gone a traditional course either with monotherapy or several monotherapies prior to being in that situation. So that is usually the type of patient that I consider. But I will add that there is a lot of talk about using these in very high risk patient populations, I think this is where precision medicine will come into play. But for me, definitely refractory disease. I think secondarily, I typically will think about a patient who has had a history of being on a monotherapy that works for a period of time and then there's either a secondary loss of response or an efficacy loss for whatever reason, and then they went on another monotherapy and the same thing happened and there's sort of that platform because if you think about it this way, inflammatory bowel disease hits on.. hits because of many different cytokine pathways, there is many different mechanisms for which the immune system can attack the GI tract.

And so in these patients with refractory disease, if we can find different ways to interrupt the immune escape pathway and lead to resolution of disease, then that's going to be beneficial. I think the last one that you're going to really start to hear people talking about for combination therapy is extraintestinal manifestations or synergistic effects. One molecule works better for a certain phenotype and another molecule for another phenotype, or they have another autoimmune disease in place. And I think that what you can see there is that you are then hitting on not only different disease states in which a specific molecule may be approved, but also again, you're targeting the immune system from different modalities and getting that sort of synergistic benefit from these different combination therapies.

Dr Cross:

In my practice, it's really the latter, which are the majority. And maybe if I included other immune-mediated illnesses that aren't considered EIM, so if I included my MS population for that or psoriasis where I have one thing for their gut, something else for either the EIM or the immune-mediated disease, that is going to be the most common scenario. I agree with you where I've utilized therapies together has been in super-refractory patients. And my preference is to do a monotherapy always, but in certain patients that like Jen's talking about that you're talking about where we're now on their fourth or fifth treatment and you look back and you do a good careful history and you realize that Jane Doe had a decent response to ustekinumab, but then it was switched out to something else and then something else. And then maybe at the very beginning of their treatment, they were on an anti-TNF and had a good response but not complete. And so you then look at it and say, well, maybe we can put those 2 together and maybe plus one will equal two or 50 cents plus 50 cents will equal a dollar, however you want to say it. I think that's the most common.

I guess what gives me pause is I see sometimes these therapies just get stacked. It's like the old days, Jen, when everyone got a 5, it was step therapy. Everyone got a 5-ASA, then a thiopurine, and then they got an anti- TNF and everything kept getting drug along and continued and I see a little bit of that. The other thing is I had a scenario this morning where I saw a patient with IBD type undetermined who just left the hospital; prior excellent response to combination therapy with infliximab, azathioprine, monotherapy with infliximab, and then got an infected biopsy site and got antibiotics and disease just got out of control and didn't really respond to steroids, got put on upadacitinib in the hospital, actually didn't respond and then got switched to tofa and actually has had a partial response and he shows up a day after discharge and he's there in the office. And my thought as I'm talking to him is, should I give this the full 7 weeks with the tofacitinib to see how he does or should I just immediately add an IL-23 inhibitor?

Now, I decided I'm going to give him time because he's about 60% better than where he was although he got off-label dosing of the tofa and now he's on standard dosing at 10 BID. But I'd like to get your thoughts. I don't know that we know exactly what to do there. I don't think it would've been wrong to try to add the IL-23 inhibitor right now for this patient, but just wonder what you would've done there.

Dr Seminerio:

No, I think it's a good case. And I think that a lot of this comes down to communication and how you're going to follow up with the patient. So if you're giving them ... In my scenario, I will give patients different options and I kind of try to tease out, have I seen anything? What we're very lucky with the JAK inhibitor class is that we can a lot of the time see a pretty quick onset. I had one similar to that where we did a 2-week trial and then I brought them back in to see if we had gotten anywhere. And these are typically, like you said, in these severe refractory cases. So I think that it makes sense to give monotherapy a try. What's the motto in inflammatory bowel disease? We want the least amount of medical therapy necessary to get the disease under control.

And I agree with what you said previously that I do fear a little bit about this phenomenon of stacking drugs, just like we in the past have seen where we just go from drug to drug to drug without really figuring out what the reason why it wasn't getting us to the endpoint we were looking for is we also just don't want to add on drugs without really exploring why we're doing that. And then we also obviously need to come to a point where we make some decisions on pulling back after we hit hard. I think that in that scenario, like you said, you could have gone the other way, but I think starting with monotherapy, having a quick follow-up time with the patient, making them come back in. I am really big on contingency plans with patients, so I will give them scenarios. So that way when they come back in, if that's the route we need to take to add on a second therapy, I'm not coming from out of the blue for them and they've already thought it through and they've been able to look things up and take some time.

And then the other thing I will bring up is when you do monotherapy first, which most of us as we use combination therapy do it as a stackable approach. I think it's much more rare to co-induce or induce and then immediately sequentially add on a second drug. But I think that when you are additive, you've got one that's already approved via the insurance and I think it makes access a little bit easier as you add in a second because you make more of a point to the insurance companies. You can write your narrative in the note, explain why you're doing this. You also have the opportunity that to have one approved and then make some decisions on how you're going to go about the second one. Is it going to be one's through, say, specialty pharmacy and the other one's going to be through a patient assistance program with the pharmaceutical company? So I think that as much as we want to just focus on the disease state, access has to be a part of the conversation when we talk about combination therapy.

Dr Cross:

There's many important things in what you said, but there's two really important things I want to highlight. One is the contingency plan. So for this specific example, I told the patient if he backslid and was getting very sick, my plan was to retry the infliximab at double dose because he was on single dose and had undetectable levels. And if he came back at that 6-week follow-up and was still sort of stuck where he was that we were going to add a therapy to what he was on.

The other really important thing is once you have a diagnosis of IBD, every squirt of diarrhea, every abdominal cramp, everything is your IBD. But Jen and I and the listeners, you know that that's not true, that people can have concurrent celiac, overlapping functional bowel, SIBO, disaccharidase deficiency infection. So certainly before you're going to do any adjustment in IBD therapy, including adding an advanced therapy, you want to make sure that the majority of those symptoms are being driven by active disease. You're not missing a stricture that you can send your colorectal surgeon and do a short anastomotic or fibrotic stricture resection. So before adding another therapy that has some potential side effects, make sure what you're treating.

Along those lines, Jen, what do we know about the efficacy of combination advanced therapies? And I think I know the answer, any combinations found to be more or less effective? And then lastly, what about safety?

Dr Seminerio:

Yeah, so I think the general consensus is that they are efficacious. And I don't think that there's a lot of question as towards why that would make sense. You're again, synergistically hitting on 2 different forms of the inflammatory cascade that can be targeting the intestinal system, or again, outside of the intestinal system if there's extraintestinal manifestations. So I think that the data that exists right now do show that we've got improvements. And I would say, and we've kind of touched on this, the data really shows that we're seeing the best improvements in the individuals who have had refractory disease. And by that I mean have been on previous degrees of advanced therapies, whether or not it's a biologic or a small molecule. And that's because if you've got a naive patient, it's not that combination therapy won't work. It will work, but you don't necessarily need it. And we have lots of data out there and you guys have talked about this on the podcast, that getting somebody started on therapy in many, many trials has been shown to be the most important thing that we do. So for a naive patient, it's not that combination therapy isn't going to be advantageous, it's that it's not necessary. So I think you just have to clarify there, but overall we've seen very good efficacy.

Safety, I think, has been one of the fears of using combination therapy or an advanced combination therapeutic approach. And your point earlier about the community not doing this, I think makes sense. This is something that you want to be in a center and have experience doing. Overall though, we are not seeing massive safety signals that show us that this isn't something that we can pursue in the right settings. I think that the data have shown some increases in infections, but some of our clinical trials, which we'll get to don't show that much of a difference between monotherapy and combined therapy and these trials are very limited, but I think that we can expect a little bit of an increase in infection.

I just always want people to understand when you're looking at trial data or even small studies or retrospective, an infection can happen and we will put everything into a trial. We try to make sure that if something happens, an event occurs, that we're made aware of it, but that doesn't necessarily mean that that event led to discontinuation of the drug or that event changed the overall outcome of the disease. So that's where the infections become important because there's a difference between getting any infection or getting a severe infection. And so I think that additional data and looking at whether or not these infections are leading to discontinuation are going to become important because in any clinical trial, the most common reason for an individual to discontinue drug is that the disease wasn't controlled in the first place. So you're balancing that safety, but overall we have not seen thus far with the combinations any massive safety signal.

And to your point, we talk about a very systemic combination of an anti-TNF and a JAK inhibitor, which there is some small data out there in UC, and even within that, despite there being a little bit of an increase in infections, we didn't see any substantial safety signal aside from that.

Dr Cross:

Yeah, I'm going to come back to safety and then combination efficacy in one second. But I just want to remind the listeners that IBD Drive Time is sponsored by the AIBD Network. In fact, we are the podcast of the AIBD Network and I wanted to remind the listeners that we are on Apple Podcasts and we are also on Spotify so you can find us there. And then last announcement really is that our next regional AIBD meeting will be July 11th and 12th in Dallas and I am going to be leading that meeting. So I hope to see you there.

I wanted to come back to two…I wanted to make one comment, two comments. One is about safety. And if you look at clinical trials, again, you see the more efficacious drugs, you see less side effects in general. But sometimes you look at those serious infection rates and for an IL-23 inhibitor, it might be 3 or 4 per 100 patient years. And you think about it, do I really see that in clinical practice? And I think you made a really good point about the bar in a clinical trial when something serious happens to either go into the hospital or stay in outpatient is different. And remember that many patients are coming outside of the US and Canada and Western Europe. And so the threshold to get admitted in some of these other sites is different. There are some infections, like for example, tuberculosis, they're going to be endemic in some areas of the world. So I'd really like to see some of that adverse event reporting, particularly infection, although the numbers will get smaller, really broken down to region because I suspect that that does have an influence and then obviously the influence of coexisting corticosteroids. And some of these combination studies in retrospective studies, patients have been actually on things like methotrexate and steroids plus 2 other therapies. So how much is it the 2 therapies or the steroids or their bad disease as well? So it can be really hard to disentangle.

And I agree that if you get a patient diagnosed early and get them on drug, that's a win and you're likely going to have a patient that does well. But I think if you gave Jen or I an anti-TNF, an IL-23 inhibitor or a JAK and an IL-23 inhibitor, I think, and maybe I'm wrong, but I think we could get probably to 80 to 90% with a newly diagnosed patient with that combination. I think that combination could be that good. And really exciting trial data with guselkumab and perianal disease, that's an area of unmet need we didn't really talk about. But man, I think if you put infliximab and potentially GUS together, should that really be the combination instead of doing an immune modulator and infliximab or adalimumab? I really wonder if that could maybe get us closer to the ceiling in perianal Crohn's.

So Jen, what are we learning now from clinical trials on combination therapy? So exciting data presented at DDW.

Dr Seminerio:

Yeah, we really have. And it's funny that you bring up infliximab. I think that obviously given the fact that especially in perianal fistulizing disease, we had infliximab data, we had the stem cell trial data, and then now we've got the guselkumab data. There was always this idea of combining those two, but in clinical trials, you really have to have the right environment. And we were really lucky to have the ability to combine an anti-TNF—it wasn't infliximab, but it was an anti-TNF in golimumab. And this was done in two different trials in combination with guselkumab. And the first was VEGA, which was a ulcerative colitis study, which had already previously been reported. And overall, again, we saw some good efficacy. This trial in the UC patient population looked at both patients that were naive and patients that had previous drug exposures, but just recently at DDW and hot off the press came our phase 2b data, which is otherwise known as DUET.

And this is a Crohn's disease and UC combined trial, which is now getting set to move into phase 3 data. And what we found out here is a lot of what we've already talked about. In the data, monotherapy, especially for individuals that didn't have high exposure rates, did very well and we didn't necessarily see any huge statistical significance between combination and monotherapy. However, in the refractory patients, in the individuals, especially who had had multi-advanced therapy exposures, we saw better rates of clinical remission and better endoscopic outcomes in the patients that were given combination therapy with golimumab and guselkumab. And I think as we move this now forward into phase 3 studies to your point, Ray, I hope that we put a little bit of emphasis onto some of these populations where we all have questions. I think specifically these are your individuals with perianal fistulizing disease or fistulizing disease in general and Crohn's disease.

And then I think in ulcerative colitis, your refractory patients, your acute severe ulcerative colitis, your ulcerative colitics who have already seen a JAK inhibitor and infliximab, can combination bring these patients back and can we start to answer some of these questions on is there a point where medical therapy is just going to be completely unresponsive? So I think that as we look forward to the phase 3 data, those would be the populations that I would be most excited about.

And then the other really great thing that came out of DUET is that we did not see any differences in the safety signals between the combination of golimumab and guselkumab versus guselkumab monotherapy. And so I think that as we look at some of that and we talk about the things that we already stated with regards to infections, not seeing any new safety signals or anything that would give us pause is always going to be beneficial, especially when we're dealing with a severe population.

And you already mentioned this, that sometimes in the real world, these severe populations are on corticosteroids or have other medications, even something like a mesalamine or sulfasalazine on board. So we need to be aware that it isn't always just our 2 advanced therapies that we're talking about and there may be more there or even a history of being on some of those things. And when we look at safety, I think it's going to be a part of the clinical trial data and then we'll hopefully see that translate into the real world.

Dr Cross:

I completely agree. The only additive comment I would make is that this in DUET, they have a unique delivery system so that you're giving both medications together. So it's not like you're separately taking these medications. And the way that dosing turns out, it makes it conducive to be able to do that. So patients won't be doing multiple injection devices. The other thing that I think is going to be the devil in the details here, if phase 3 confirms these findings, it's probably going to be in refractory patients, which I think is the sweet spot and the data support that. But the other thing is it can't be twice as expensive. So if it's going to be twice as expensive, payers are going to resist. Although if they're really treatment refractory, they may not have a choice. So it'll be interesting to see what the price point is of this compound if it makes it through, which I think it will.

So Jen, this has been great. I think the listeners will have learned a lot. I learned a lot. What's your fun fact? So tell us something about yourself that I might not know, maybe the listeners certainly wouldn't know.

Dr Seminerio:

So my fun fact is that I have a pretty big family. I actually have 5 kids and I am very, very blessed. I had twins during the pandemic, which I was largely able to hide from the world because I was only showing myself from my midsection up and we have a lot of fun. It's a little bit of a crazy household, but one of the things that I've found from a career standpoint is the ability to talk to younger providers both male and female about having a larger family and work-life balance. And I will always say to people that it isn't a 50-50 split and that there are times in my life where work is a larger factor. And then there are times where I get to be there for my kids and do fun stuff and that it is possible to have kids and still have a very full-time career and that is something that not isn't always necessary, but something that I'm proud of.

And I was telling Dr. Cross before we started, my twins are 5 and they just graduated from BBK because we graduate from everything now in this world. And I've had 3 kids already get past this point, none of which have any interest in medicine. And then one of my twins, for whatever reason, said he wants to be a chef. But finally, number % has claimed at the age of % that they want to be a doctor. They don't want to be a doctor like me. They want to be the kind of doctor that helps people, but I like to think that I'm still doing that.

Dr Cross:

That's funny. Yeah, I don't know how you've been able to do that and how you can juggle. And I think work-life balance is super important, obviously. And people that take care of IBD, it's really important that we help each other because people burning out and not taking care of people and helping patients, that's a travesty to lose people. So talk to Jen, see how she does it. I have 2 boys, not 5. I couldn't do that, but I have 2 that I juggled and coached, and so it can be done. So don't think you can't. Jen, this is great. Hope to have you back on IBD Drive time another time.

Dr Seminerio:

Love to. Thank you so much.

Yeah, I completely agree. I like to think of it as, and I'm going to step back one second and just remind the listeners that what we clearly recognize now is poorly controlled disease activity and steroids are the big drivers of adverse events, particularly infection. So I would not, from a standpoint of controlling disease and eliminating steroids, even putting an anti-TNF and a JAK together would probably be safer. But generally when you're thinking about combinations of advanced therapies, we're generally thinking about the safest MOAs like the IL-23 inhibitors and maybe an S1P and an anti-integrin that's not natalizumab and then an anti-TNF or a JAK. Those are the most common combinations. Although again, I think in certain subsets you could combine very potent therapies together and it still would likely be safe. So how are you doing this in clinical practice, Jen? So what are your patient scenarios where you're using combination of advanced therapies?

Dr Seminario:

Yeah, I think this is where the finesse of inflammatory bowel disease really comes into play. For me, I think there are a few different sets of scenarios that I really home in on. Probably foremost, and to your point, this is an area where I typically use combination therapy for refractory disease. And by refractory disease, we're talking about patients who have gone a traditional course either with monotherapy or several monotherapies prior to being in that situation. So that is usually the type of patient that I consider. But I will add that there is a lot of talk about using these in very high risk patient populations, I think this is where precision medicine will come into play. But for me, definitely refractory disease. I think secondarily, I typically will think about a patient who has had a history of being on a monotherapy that works for a period of time and then there's either a secondary loss of response or an efficacy loss for whatever reason, and then they went on another monotherapy and the same thing happened and there's sort of that platform because if you think about it this way, inflammatory bowel disease hits on.. hits because of many different cytokine pathways, there is many different mechanisms for which the immune system can attack the GI tract.

And so in these patients with refractory disease, if we can find different ways to interrupt the immune escape pathway and lead to resolution of disease, then that's going to be beneficial. I think the last one that you're going to really start to hear people talking about for combination therapy is extraintestinal manifestations or synergistic effects. One molecule works better for a certain phenotype and another molecule for another phenotype, or they have another autoimmune disease in place. And I think that what you can see there is that you are then hitting on not only different disease states in which a specific molecule may be approved, but also again, you're targeting the immune system from different modalities and getting that sort of synergistic benefit from these different combination therapies.

Dr Cross:

In my practice, it's really the latter, which are the majority. And maybe if I included other immune-mediated illnesses that aren't considered EIM, so if I included my MS population for that or psoriasis where I have one thing for their gut, something else for either the EIM or the immune-mediated disease, that is going to be the most common scenario. I agree with you where I've utilized therapies together has been in super-refractory patients. And my preference is to do a monotherapy always, but in certain patients that like Jen's talking about that you're talking about where we're now on their fourth or fifth treatment and you look back and you do a good careful history and you realize that Jane Doe had a decent response to ustekinumab, but then it was switched out to something else and then something else. And then maybe at the very beginning of their treatment, they were on an anti-TNF and had a good response but not complete. And so you then look at it and say, well, maybe we can put those 2 together and maybe plus one will equal two or 50 cents plus 50 cents will equal a dollar, however you want to say it. I think that's the most common.

I guess what gives me pause is I see sometimes these therapies just get stacked. It's like the old days, Jen, when everyone got a 5, it was step therapy. Everyone got a 5-ASA, then a thiopurine, and then they got an anti- TNF and everything kept getting drug along and continued and I see a little bit of that. The other thing is I had a scenario this morning where I saw a patient with IBD type undetermined who just left the hospital; prior excellent response to combination therapy with infliximab, azathioprine, monotherapy with infliximab, and then got an infected biopsy site and got antibiotics and disease just got out of control and didn't really respond to steroids, got put on upadacitinib in the hospital, actually didn't respond and then got switched to tofa and actually has had a partial response and he shows up a day after discharge and he's there in the office. And my thought as I'm talking to him is, should I give this the full 7 weeks with the tofacitinib to see how he does or should I just immediately add an IL-23 inhibitor?

Now, I decided I'm going to give him time because he's about 60% better than where he was although he got off-label dosing of the tofa and now he's on standard dosing at 10 BID. But I'd like to get your thoughts. I don't know that we know exactly what to do there. I don't think it would've been wrong to try to add the IL-23 inhibitor right now for this patient, but just wonder what you would've done there.

Dr Seminario:

No, I think it's a good case. And I think that a lot of this comes down to communication and how you're going to follow up with the patient. So if you're giving them ... In my scenario, I will give patients different options and I kind of try to tease out, have I seen anything? What we're very lucky with the JAK inhibitor class is that we can a lot of the time see a pretty quick onset. I had one similar to that where we did a 2-week trial and then I brought them back in to see if we had gotten anywhere. And these are typically, like you said, in these severe refractory cases. So I think that it makes sense to give monotherapy a try. What's the motto in inflammatory bowel disease? We want the least amount of medical therapy necessary to get the disease under control.

And I agree with what you said previously that I do fear a little bit about this phenomenon of stacking drugs, just like we in the past have seen where we just go from drug to drug to drug without really figuring out what the reason why it wasn't getting us to the endpoint we were looking for is we also just don't want to add on drugs without really exploring why we're doing that. And then we also obviously need to come to a point where we make some decisions on pulling back after we hit hard. I think that in that scenario, like you said, you could have gone the other way, but I think starting with monotherapy, having a quick follow-up time with the patient, making them come back in. I am really big on contingency plans with patients, so I will give them scenarios. So that way when they come back in, if that's the route we need to take to add on a second therapy, I'm not coming from out of the blue for them and they've already thought it through and they've been able to look things up and take some time.

And then the other thing I will bring up is when you do monotherapy first, which most of us as we use combination therapy do it as a stackable approach. I think it's much more rare to co-induce or induce and then immediately sequentially add on a second drug. But I think that when you are additive, you've got one that's already approved via the insurance and I think it makes access a little bit easier as you add in a second because you make more of a point to the insurance companies. You can write your narrative in the note, explain why you're doing this. You also have the opportunity that to have one approved and then make some decisions on how you're going to go about the second one. Is it going to be one's through, say, specialty pharmacy and the other one's going to be through a patient assistance program with the pharmaceutical company? So I think that as much as we want to just focus on the disease state, access has to be a part of the conversation when we talk about combination therapy.

Dr Cross:

There's many important things in what you said, but there's two really important things I want to highlight. One is the contingency plan. So for this specific example, I told the patient if he backslid and was getting very sick, my plan was to retry the infliximab at double dose because he was on single dose and had undetectable levels. And if he came back at that 6-week follow-up and was still sort of stuck where he was that we were going to add a therapy to what he was on.

The other really important thing is once you have a diagnosis of IBD, every squirt of diarrhea, every abdominal cramp, everything is your IBD. But Jen and I and the listeners, you know that that's not true, that people can have concurrent celiac, overlapping functional bowel, SIBO, disaccharidase deficiency infection. So certainly before you're going to do any adjustment in IBD therapy, including adding an advanced therapy, you want to make sure that the majority of those symptoms are being driven by active disease. You're not missing a stricture that you can send your colorectal surgeon and do a short anastomotic or fibrotic stricture resection. So before adding another therapy that has some potential side effects, make sure what you're treating.

Along those lines, Jen, what do we know about the efficacy of combination advanced therapies? And I think I know the answer, any combinations found to be more or less effective? And then lastly, what about safety?

Dr Seminario:

Yeah, so I think the general consensus is that they are efficacious. And I don't think that there's a lot of question as towards why that would make sense. You're again, synergistically hitting on 2 different forms of the inflammatory cascade that can be targeting the intestinal system, or again, outside of the intestinal system if there's extraintestinal manifestations. So I think that the data that exists right now do show that we've got improvements. And I would say, and we've kind of touched on this, the data really shows that we're seeing the best improvements in the individuals who have had refractory disease. And by that I mean have been on previous degrees of advanced therapies, whether or not it's a biologic or a small molecule. And that's because if you've got a naive patient, it's not that combination therapy won't work. It will work, but you don't necessarily need it. And we have lots of data out there and you guys have talked about this on the podcast, that getting somebody started on therapy in many, many trials has been shown to be the most important thing that we do. So for a naive patient, it's not that combination therapy isn't going to be advantageous, it's that it's not necessary. So I think you just have to clarify there, but overall we've seen very good efficacy.

Safety, I think, has been one of the fears of using combination therapy or an advanced combination therapeutic approach. And your point earlier about the community not doing this, I think makes sense. This is something that you want to be in a center and have experience doing. Overall though, we are not seeing massive safety signals that show us that this isn't something that we can pursue in the right settings. I think that the data have shown some increases in infections, but some of our clinical trials, which we'll get to don't show that much of a difference between monotherapy and combined therapy and these trials are very limited, but I think that we can expect a little bit of an increase in infection.

I just always want people to understand when you're looking at trial data or even small studies or retrospective, an infection can happen and we will put everything into a trial. We try to make sure that if something happens, an event occurs, that we're made aware of it, but that doesn't necessarily mean that that event led to discontinuation of the drug or that event changed the overall outcome of the disease. So that's where the infections become important because there's a difference between getting any infection or getting a severe infection. And so I think that additional data and looking at whether or not these infections are leading to discontinuation are going to become important because in any clinical trial, the most common reason for an individual to discontinue drug is that the disease wasn't controlled in the first place. So you're balancing that safety, but overall we have not seen thus far with the combinations any massive safety signal.

And to your point, we talk about a very systemic combination of an anti-TNF and a JAK inhibitor, which there is some small data out there in UC, and even within that, despite there being a little bit of an increase in infections, we didn't see any substantial safety signal aside from that.

Dr Cross:

Yeah, I'm going to come back to safety and then combination efficacy in one second. But I just want to remind the listeners that IBD Drive Time is sponsored by the AIBD Network. In fact, we are the podcast of the AIBD Network and I wanted to remind the listeners that we are on Apple Podcasts and we are also on Spotify so you can find us there. And then last announcement really is that our next regional AIBD meeting will be July 11th and 12th in Dallas and I am going to be leading that meeting. So I hope to see you there.

I wanted to come back to two…I wanted to make one comment, two comments. One is about safety. And if you look at clinical trials, again, you see the more efficacious drugs, you see less side effects in general. But sometimes you look at those serious infection rates and for an IL-23 inhibitor, it might be 3 or 4 per 100 patient years. And you think about it, do I really see that in clinical practice? And I think you made a really good point about the bar in a clinical trial when something serious happens to either go into the hospital or stay in outpatient is different. And remember that many patients are coming outside of the US and Canada and Western Europe. And so the threshold to get admitted in some of these other sites is different. There are some infections, like for example, tuberculosis, they're going to be endemic in some areas of the world. So I'd really like to see some of that adverse event reporting, particularly infection, although the numbers will get smaller, really broken down to region because I suspect that that does have an influence and then obviously the influence of coexisting corticosteroids. And some of these combination studies in retrospective studies, patients have been actually on things like methotrexate and steroids plus 2 other therapies. So how much is it the 2 therapies or the steroids or their bad disease as well? So it can be really hard to disentangle.

And I agree that if you get a patient diagnosed early and get them on drug, that's a win and you're likely going to have a patient that does well. But I think if you gave Jen or I an anti-TNF, an IL-23 inhibitor or a JAK and an IL-23 inhibitor, I think, and maybe I'm wrong, but I think we could get probably to 80 to 90% with a newly diagnosed patient with that combination. I think that combination could be that good. And really exciting trial data with guselkumab and perianal disease, that's an area of unmet need we didn't really talk about. But man, I think if you put infliximab and potentially GUS together, should that really be the combination instead of doing an immune modulator and infliximab or adalimumab? I really wonder if that could maybe get us closer to the ceiling in perianal Crohn's.

So Jen, what are we learning now from clinical trials on combination therapy? So exciting data presented at DDW.

Dr Seminario:

Yeah, we really have. And it's funny that you bring up infliximab. I think that obviously given the fact that especially in perianal fistulizing disease, we had infliximab data, we had the stem cell trial data, and then now we've got the guselkumab data. There was always this idea of combining those two, but in clinical trials, you really have to have the right environment. And we were really lucky to have the ability to combine an anti-TNF—it wasn't infliximab, but it was an anti-TNF in golimumab. And this was done in two different trials in combination with guselkumab. And the first was VEGA, which was a ulcerative colitis study, which had already previously been reported. And overall, again, we saw some good efficacy. This trial in the UC patient population looked at both patients that were naive and patients that had previous drug exposures, but just recently at DDW and hot off the press came our phase 2b data, which is otherwise known as DUET.

And this is a Crohn's disease and UC combined trial, which is now getting set to move into phase 3 data. And what we found out here is a lot of what we've already talked about. In the data, monotherapy, especially for individuals that didn't have high exposure rates, did very well and we didn't necessarily see any huge statistical significance between combination and monotherapy. However, in the refractory patients, in the individuals, especially who had had multi-advanced therapy exposures, we saw better rates of clinical remission and better endoscopic outcomes in the patients that were given combination therapy with golimumab and guselkumab. And I think as we move this now forward into phase 3 studies to your point, Ray, I hope that we put a little bit of emphasis onto some of these populations where we all have questions. I think specifically these are your individuals with perianal fistulizing disease or fistulizing disease in general and Crohn's disease.

And then I think in ulcerative colitis, your refractory patients, your acute severe ulcerative colitis, your ulcerative colitics who have already seen a JAK inhibitor and infliximab, can combination bring these patients back and can we start to answer some of these questions on is there a point where medical therapy is just going to be completely unresponsive? So I think that as we look forward to the phase 3 data, those would be the populations that I would be most excited about.

And then the other really great thing that came out of DUET is that we did not see any differences in the safety signals between the combination of golimumab and guselkumab versus guselkumab monotherapy. And so I think that as we look at some of that and we talk about the things that we already stated with regards to infections, not seeing any new safety signals or anything that would give us pause is always going to be beneficial, especially when we're dealing with a severe population.

And you already mentioned this, that sometimes in the real world, these severe populations are on corticosteroids or have other medications, even something like a mesalamine or sulfasalazine on board. So we need to be aware that it isn't always just our 2 advanced therapies that we're talking about and there may be more there or even a history of being on some of those things. And when we look at safety, I think it's going to be a part of the clinical trial data and then we'll hopefully see that translate into the real world.

Dr Cross:

I completely agree. The only additive comment I would make is that this in DUET, they have a unique delivery system so that you're giving both medications together. So it's not like you're separately taking these medications. And the way that dosing turns out, it makes it conducive to be able to do that. So patients won't be doing multiple injection devices. The other thing that I think is going to be the devil in the details here, if phase 3 confirms these findings, it's probably going to be in refractory patients, which I think is the sweet spot and the data support that. But the other thing is it can't be twice as expensive. So if it's going to be twice as expensive, payers are going to resist. Although if they're really treatment refractory, they may not have a choice. So it'll be interesting to see what the price point is of this compound if it makes it through, which I think it will.

So Jen, this has been great. I think the listeners will have learned a lot. I learned a lot. What's your fun fact? So tell us something about yourself that I might not know, maybe the listeners certainly wouldn't know.

Dr Seminario:

So my fun fact is that I have a pretty big family. I actually have 5 kids and I am very, very blessed. I had twins during the pandemic, which I was largely able to hide from the world because I was only showing myself from my midsection up and we have a lot of fun. It's a little bit of a crazy household, but one of the things that I've found from a career standpoint is the ability to talk to younger providers both male and female about having a larger family and work-life balance. And I will always say to people that it isn't a 50-50 split and that there are times in my life where work is a larger factor. And then there are times where I get to be there for my kids and do fun stuff and that it is possible to have kids and still have a very full-time career and that is something that not isn't always necessary, but something that I'm proud of.

And I was telling Dr. Cross before we started, my twins are 5 and they just graduated from BBK because we graduate from everything now in this world. And I've had 3 kids already get past this point, none of which have any interest in medicine. And then one of my twins, for whatever reason, said he wants to be a chef. But finally, number % has claimed at the age of % that they want to be a doctor. They don't want to be a doctor like me. They want to be the kind of doctor that helps people, but I like to think that I'm still doing that.

Dr Cross:

That's funny. Yeah, I don't know how you've been able to do that and how you can juggle. And I think work-life balance is super important, obviously. And people that take care of IBD, it's really important that we help each other because people burning out and not taking care of people and helping patients, that's a travesty to lose people. So talk to Jen, see how she does it. I have 2 boys, not 5. I couldn't do that, but I have 2 that I juggled and coached, and so it can be done. So don't think you can't. Jen, this is great. Hope to have you back on IBD Drive time another time.

Dr Seminario:

Love to. Thank you so much.