Marla Dubinsky, MD, Icahn School of Medicine at Mount Sinai

One of the issues has been that there does appear to be a therapeutic ceiling with all our agents. We’re seeing about 40% to 60% clinical remissions along those lines, depending on where these drugs are positioned. Both of us have been very aggressive about trying to get these drugs earlier in the course to prevent complications. If you look in the clinical trials with ustekinumab or vedolizumab, the average duration of Crohn disease is 10 years. Patients with 10 years of disease are already developing the problems that we’re trying to prevent. One of the things that I would like to focus on in the future is earlier intervention with these highly effective therapies that we’ve been discussing. What other unmet needs do you see in the pediatric and adult populations for IBD [inflammatory bowel disease]?

 I also have a very keen interest in preconception and fertility in the management of women’s reproductive health, which does tie in to everything we’re talking about. The message to all our female patients is that it’s all about safety and being able to have your disease under control. It is paramount that having anti-inflammatories onboard is what is most important. We know the risk benefit profiles associated with therapies and how to use these therapies in pregnancy, particularly the biologics. We need to be focused on teaching the right thing to our physician partners and patients, that it’s all about controlled inflammation. 

Chronic pelvic inflammation can never end well. That is something I’m vocal about within my preconception clinic, and I counsel women appropriately. But it does have to do with some of these small molecules. We’ll add a layer of complexity when we are looking at bringing these therapies to the clinic. With some therapies, such as the small molecules, we don’t have a lot of real-world experience on the impact in the first trimester because they cross the placenta. That is the question that we need to get more data on. For example, with ozanimod, it will be in the label to stop 3 months before conception. With JAKs you need to stop it. It does add a layer of complexity—we’ve become ob-gyns in terms of figuring out how to use these therapies. An unmet need is also understanding the safety of these therapies in women of reproductive age.

 Did that also apply to pediatric patients? Are there other unmet needs besides improving the efficacy and maintaining a good safety profile in kids?

Marla Dubinsky, MD: It’s a similar concept once you get beyond the VEO [very early onset] IBD. We have the same principles. Similar to what you talked about, whether those extraintestinal manifestations were activity linked or not, the same applies to growth. For all our therapies, just because you heal the intestine, does not equate to growth improvement. We don’t know. We need more data. Does gut-specific therapy have the same impact as systemic therapies? These are things that we need to see from our clinical trials.

There are a couple of unmet needs that you made me think about. I do believe, as I noted before, the future is combination therapy. It could be diet plus biologic. It could be small molecule plus biologic. It could be fecal restorative therapy. It doesn’t matter. The concept of combination means that 1 therapy alone is not going to be the answer. I was addressing your plateau. This is the way I’m thinking about it. Also, sequence will be a hugely important topic to address, meaning understanding the sequence over the long lifetime of a patient who has an evolving immune system based on the therapies we’re using.

I have to plug something that both you and I believe strongly. The plateau may also be the fact that we are not addressing the emotional or behavioral well-being of our patients in clinical trials or the real world, so we can understand how social determinants of behavior, mental health, and comorbidities impact outcomes. We may see a different percentage of remission at week 52. That is an important unmet need that we need to focus on.

I want to amplify your recognition of the social determinants. Certainly in 2021, we’ve seen social determinants of COVID-19 infections and increasingly recognize the disparities of health care in treating chronic illnesses such as ulcerative colitis, Crohn disease, inflammatory bowel disease. We really need to address these disparities and try to improve, whether it’s with psychology, social workers, diet, and education. All these combinations—as your group and our group have shown—really impact patients. They keep them out of the emergency department. Keep them out of the hospital. We need our systems to help us address these disparities. As practitioners, it’s challenging for us and our staff to address this full spectrum of the patients’ needs, from diet to psychological or behavioral support. Economically, 1 of the biggest issues we all have is access to these highly effective therapies. We’re dealing with different insurance programs that may not allow us to use these drugs in the most effective manner that we think we could.

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Current treatment limitations in inflammatory bowel disease and the rationale for earlier initiation and use of newer therapies to manage pediatric and adult patients.

Addressing Current Treatment Gaps in Pediatric and Adult IBD 

What we haven’t discussed is where tofacitinib fits into your disease management in ulcerative colitis.

Before the label got changed—as a reminder for everybody—tofacitinib was approved for use not having failed anything, meaning you had moderate to severe ulcerative colitis and you were eligible. You didn’t have to fail anything. Because of safety concerns in another population, not even in the IBD [inflammatory bowel disease] population that changed. You have to fail anti–TNF [tumor necrosis factor]. Historically, I would have used it differently. I would have used it as an alternative to anti-TNF in someone whom I need speed. It gets back to rapidity. That would have been the situation. In this situation, for me, the same rules apply: Someone is failing steroids. They’re sick. They may have never responded to anti-TNF. Whatever the reason, it is my go-to for speed. I’m not starting to throw ustekinumab or vedolizumab at someone who’s refractory to steroids. This isn’t the time for that. In my opinion, I need something with speed, and that speaks to where I put tofacitinib. Are you using it similarly?

 I am, because I’m very distressed by the FDA’s applying the population of older men with rheumatoid arthritis who have risk factors for cardiovascular disease, where we do see a signal for increased risk vs a TNF inhibitor. In contrast, in the studies with tofacitinib in ulcerative colitis in our patients tend to be younger, who don’t have those same risks. The risks for these cardiovascular or thromboembolic events were not increased compared with patients with placebo. I am much more liberal in my thinking about tofacitinib in ulcerative colitis because it does have the advantage of being an oral agent and does work relatively quickly. 

That brings us to several other drugs that are nearing FDA approval. They have several mechanisms. One is the interleukin-23 inhibitors that are nearing approval. A second class is the S1P agents that are lymphocyte-tracking inhibitors into the lymph nodes. As you’ve already mentioned, there are a number of new JAK inhibitors. What are you looking forward to in the next year or so with these therapies entering the IBD [irritable bowel disorder] marketplace?

 I’m excited about what’s going to happen over the next few years because since 1998, we have progressed. We have on average about 4 different classes that we can approach. Now I’m thinking about all these changes that are going to come out over the next 18 months to 2 years, depending on whether all phase 3 data pan out. Already, ozanimod which is the S1P receptor modulator that you mentioned, the plan or hope is that it’s actually going to be FDA approved in June. We’re already moving toward having a completely new class in ulcerative colitis, and it’s more like a trafficking concept, but it works differently through the lymph node and is selective. And then having JAK1 inhibition only, which is the next JAK inhibitor, we won’t know whether that translates and has the same safety profile. We still need to evaluate that because what you said about tofacitinib may apply to the next generation of JAK inhibitors, so we’ll have to follow that closely. Are we going to interpret the same? 

Are we going to have the same black-box warnings? It may impact our ability to use these effective drugs—like you, I am extremely distraught at the application from a completely different patient population. These very effective therapies are not being used to their optimization. Patients will suffer if we’re not able to use them for fear of perceived safety in our population, whether it’s real or not. What I’m excited about is this IL-23 revolution, because there are many different pharma partners who are studying them. With risankizumab for example, we just saw the induction. We just saw the induction data, and they’re very exciting early on. All the same things we’re talking about—rapidity to onset, having a great safety profile. Who knows, as you get more selective in the JAK inhibitors and in this p40, which is ustekinumab and is blocking IL-12 and IL-23, as we take away the blockade of IL-12, are we even going to get better and more direct and selective and safer results? That’s what I’m looking forward to: seeing how our upgrades along the way are going to improve efficacy and safety.

Drs Marla Dubinsky and Stephen B. Hanauer react to newer therapies currently being explored for inflammatory bowel disease and discuss where each may fit into future therapeutic algorithms. 

Therapies Under Investigation to Treat IBD 

One of the problems that we’ve had to date is that all of our drugs, for regulatory approval, are tested vs placebo. It’s an efficient way of demonstrating a safe and effective drug, at least short term. But it doesn’t allow us to compare agents. I mentioned the network meta-analyses before. Most recently, however, we have had a head-to-head trial in the setting of ulcerative colitis [UC] that compared vedolizumab to adalimumab. What’s your perspective of that trial and how has that impacted your practice?

I want to remind everybody that was really to look at, in a patient predominately naïve to anti-TNF therapy, which of either vedolizumab or adalimumab was superior. Based on the primary end point at week 52, vedolizumab was superior when it came to remission compared to adalimumab. We saw that. However, as I noted, that was predominantly driven by the fact that these [patients] were naïve to infliximab. What this told us is that there may be a place for deciding sequence, and this is what I’m always thinking about, where is the best place for a non-infliximab therapy? This gets back to that whole speed concept, and where do you place these therapies? 

This showed me, and this has applied to my practice, that if the patient is naïve to anti-TNF, they’re moderate, moderate to severe, but lower end of the moderate to severe, and they haven’t gotten “the bubble in my head saying” they earn infliximab, or needed tofacitinib for speed, needing hospitalization, then I use vedolizumab as my go-to ulcerative colitis therapy. Now, I’ve started to also introduce the use of ustekinumab for ulcerative colitis because we now have that available, and we talked about the durability. I put them at the same level for safety, and I just say, “This is how this drug works, and this is how this drug works. One’s intravenous [IV]; one’s IV followed by subq [subcutaneous]. What would you prefer?” I don’t impose my ways on a patient when I believe all are on the table.

The significance of conducting future head-to-head trials of therapies used to treat inflammatory bowel disease and implications for treating ulcerative colitis (UC) with vedolizumab based on recent data demonstrated when the drug was tested in a first-ever head-to-head biologic clinical study in UC. 

Vedolizumab Vs Adalimumab for Ulcerative Colitis 

 One of the problems we’ve had with TNF inhibitors when we institute therapy with them, both induction and maintenance, is by the end of the year, whether it’s infliximab or adalimumab, nearly 50% of patients are already off therapy. There are a few potential reasons for that. First and foremost, we’re starting effective treatment too late in that population. But nevertheless, we’re still stuck with a significant proportion of patients with a time-limited duration of disease. Now, most recently we’ve seen some publications with ustekinumab, with data out to 3 or even 5 years about potential durability. What do you think about those data with ustekinumab?

This again goes to the sprint vs marathon discussion we were having. When we think about durability, everyone needs to understand that if a patient is in remission at 6 months, the chances are no matter what drug you use, even with the TNFs, if you remember originally with adalimumab and the CHARM data we looked at, if you got to 6 months, the chance of you dropping off at a year and then you go into your open label, was low. Once you make it past a certain point, especially out to the end of the year, and then you go into these long-term extension trials, the chance of you falling out because of ineffective therapy is low. I look at all durability sort of the same. I view that, unless there’s a safety reason that over time you get more safety issues, and that may be a TNF issue, to be fair; the advantages with vedolizumab and ustekinumab, the durability is driven also by the safety, not just that there’s lower immunogenicity and maybe you’re not using a combination as much. Whatever, if we don’t have a SONIC-like [combination] in these drugs I understand, but the lack of immunogenicity compared to TNFs, the ability to maybe use it as monotherapy, people aren’t getting as many infections, things that cause you to stop TNF, that’s the way I’m looking at the durability data from the other 2 therapies.

Marla, in addition to the long-term efficacy data with ustekinumab in both ulcerative colitis and now in Crohn Disease going out to 5 years, we’ve seen the persistence of benefits, but what about the safety profile over the duration of up to 5 years with ustekinumab?

Remember we first had 3-year data, and we were very excited about the safety profile, and now we have it for another 2 years, another safety cut. The infection rates are around the same, about a 4% serious infection rate. There was no surprises. We concluded the same as what we concluded, interestingly, after a year of a trial and then 3 years, and 5, which is great. It means that we continue to have faith in the safety of ustekinumab.

 I also would mention that getting rid of the concomitant therapies such as steroids and immunosuppressives on a long-term basis can help to improve the safety profile as well.

 As you noted, we don’t have controlled randomization, monotherapy vs combination, but if indeed based on SONIC, the combination may be advantageous because of its reduction in maybe immunogenicity, or increasing the drug concentrations, as has been looked at, again post hoc. But that’s where some of the discussion was, is that if these therapies have lower immunogenicity compared to anti-TNFs, is there really an advantage of adding a thiopurine, for example? That is something we need to continue to message out, that it appears that the safety profile may be improved by needing to use a thiopurine or methotrexate.

Indeed, in those long-term data, the majority of patients who were in remission were in steroid-free remission as well. That combines to the statements that we were both making.

We can’t underestimate the impact of corticosteroids. When you look at the role of combination therapy, a lot of patients are also on corticosteroids. Are we looking at the right thing? That adds to this idea that we need to be able to get patients off steroids and minimize the use of immunosuppressants if we can and keep our patients in deep remission.

The rationale for treating inflammatory bowel disease with ustekimumab based on more recent safety and efficacy data demonstrated by a trial that followed patients for up to 5 years. 

Marla Dubinsky, MD, Icahn School of Medicine at Mount Sinai

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