Activity Transcript

Aline Charabaty, MD, AGAF, FACG: Hello, everyone. I'm Dr Aline Charabaty. I'm the clinical director of the IBD Center at the Johns Hopkins School of Medicine at Sibley Memorial Hospital in Washington, D.C. Welcome to this Medscape program titled "New Targets and Opportunities in Inflammatory Bowel Disease." I'm very pleased to be joined today by Dr Bruce Sands, who is a Dr Burrill B. Crohn Professor of Medicine at the Icahn School of Medicine at Mount Sinai in New York City and system chief of the Division of Gastroenterology at Mount Sinai Health System. Bruce, welcome.

Bruce E. Sands, MD, MS: Thank you.

Dr Charabaty: Over the next 30 minutes, we will be discussing new and emerging therapeutic targets in the treatment of ulcerative colitis and Crohn's disease. We are going to use patient cases to frame our conversation and provide clinical context for approved therapies and how these agents fit into the current IBD treatment paradigm.

Bruce, before we get into the cases and clinical data, I think it would be useful to briefly review the different classes of targeted IBD therapies and the approved indications with a caveat that there are a number of other agents in late-stage clinical trials and some nearing approval. Our limited time will not allow us to discuss all of the various therapies in clinical trial.

Dr Sands: Sure, it'd be my pleasure, Aline. Well, as we all know, 25 years ago, we saw the advent of the first biologic therapies with the approval of infliximab for Crohn's disease, but we have three other TNF-alpha antagonists and these include the subcutaneous injectable forms of anti-TNF, which include adalimumab, certolizumab pegol, and golimumab. As you recall, golimumab is approved only for UC and certolizumab pegol is approved for Crohn's disease only. We have a couple of anti-integrin therapies, including natalizumab and vedolizumab, but you'll recall that we no longer use natalizumab because it blocks both alpha 4 beta 1 integrin and alpha 4 beta 7 integrin and is associated with progressive multifocal leukoencephalopathy. Therefore, we use vedolizumab, which is specific for alpha 4 beta 7 integrin. We also have IL-23 antagonists, which include, historically, ustekinumab, which blocks both interleukin 12 and 23 and, more recently, risankizumab, which specifically blocks IL-23.

We also have JAK inhibitors, which are oral agents, which started with tofacitinib, which is a pan-JAK inhibitor, approved in ulcerative colitis and upadacitinib (UPA), which is JAK1 selective, approved now for both Crohn's disease and ulcerative colitis. And finally, we have an S1P receptor modulator ozanimod, which is approved for ulcerative colitis.

Dr Charabaty: Thank you, Bruce. With that excellent overview, let's start with the UC case. We have a 36-year-old woman with mild to moderate UC that is still symptomatic despite oral and rectal mesalamine. She reports three to four loose bowel movements per day with blood streaks and occasional urgency. Her hemoglobin is 11, albumin 3.8. Her fecal calprotectin is elevated at 300 and a flex six shows a Mayo 2 endoscopic score. She has no extraintestinal manifestation. And in terms of social history, despite her symptoms, she is still able to go to work, but she has limited her work travels.

She has 2 kids, age 10 and 6. Bruce, in this patient, we have different option, different next step after partial or no response to mesalamine. We can move to ozanimod (OZA), vedolizumab, ustekinumab, or an anti-TNF. The question is, I'd love to hear your thoughts about this patient and what her treatment options are. But mainly, how do you assess her risk and benefit of every one of these therapies and how do you decide what is the best next treatment for her specifically?

Dr Sands: Yes. Well, this woman, although she is said to have mild-to-moderate ulcerative colitis, she's now flaring the despite being on maximal therapy with mesalamine. Historically, we might've tried corticosteroids, but increasingly, we're turning toward more advanced therapies. The way we would choose a therapy for a patient like this would really be an evaluation of their disease severity, as well as activity. We'll talk in a moment about the differences between measuring severity and activity.

We'd also taken to account the presence or absence of extraintestinal manifestations or any other associated conditions, such as psoriasis, and other comorbidities, such as malignancy or risk of infection. We also want to take into account what the patient has in mind for themselves: What are their goals? What are their preferences for method of delivery of the medication? And maybe they plan on starting a family or continuing to have more children.

We also need to consider the safety of any choice that we make and the need for combination therapy with immune modulators, which is really a feature of the anti-TNFs. We have to take into account prior treatment failures and successes. A word or two about measuring ulcerative colitis activity as compared to severity. We all think of disease activity as really a snapshot in time. How is your patient today? Cross-sectionally, it's a measure of symptoms, both gastrointestinal and extraintestinal symptoms.

We might measure biomarkers of inflammation, such as CRP or fecal calprotectin, and we would look at endoscopic findings, but that's how the patient is in the here and now. But we also have to look at the history of the disease, which also has an effect on the prognosis over the long term. This really has to do with prior flare behavior and the disease course since they've been diagnosed.

And then, we need to take into account whether the patient has risk factors for a bad outcome, specifically for colectomy. In younger patients, patients with more extensive colitis, those with deeper ulcers or more severe endoscopic activity, those who have been exposed to steroids, and especially if they're steroid-dependent, those with a history of hospitalization, have high biomarkers of inflammation, or with infection with C. diff or CMV; all those patients are at greatly increased risk for colectomy.

We need to consider that UC is a progressive disease, and it's not just this moment in time that we need to account for. Aline, I think your patient was started on ozanimod. Why did you choose this agent? And then could you review some of the top-line efficacy and safety data from the phase 3 trials for this drug?

Dr Charabaty: Thank you, Bruce. Like you said, there are many factors that play into the decision of what is the next best treatment in our patient, and obviously shared decision-making is key. The HEA clinical care pathway for the treatment of UC was actually developed before ozanimod was approved for UC and before the FDA required that the use of JAK inhibitor be restricted to patients who had previously been exposed to anti-TNF.

Overall, the AGA recommends using a biologic or small molecule in a patient with moderate to severe disease, or, like you described, the patient with a high colectomy risk, but also actually in a patient with mild disease that does not respond to mesalamine, biologic and small molecules are indicated. We will see in the next few slides that ozanimod is actually very effective in bio-I UC. I would definitely consider it in a patient with mild or moderate disease who had no response or partial response to mesalamine, like our patients.

In this particular patient, the GI symptoms were only moderately affecting her quality of life and daily life. She had no extraintestinal manifestation, so we had the opportunity to choose a drug that has mainly a luminal effect with a good safety profile and a reasonable time for onset of action. Finally, ozanimod is an oral formulation, which is really convenient for a working mom or any patients who need to travel for work and prefers not to take time away from work and family for infusions.

Now, let's take a look at the ozanimod data together. These are the results of the phase 3 trial of ozanimod as induction therapy in moderate-to-severe active UC. These are patients that did not respond to mesalamine or steroids before getting enrolled in the OZA trial. Patients either received oral ozanimod hydrochloride at a dose of one milligram, which is equivalent to 0.92 milligram of ozanimod, or placebo once a day. Clinical remission was significantly higher among patients who received ozanimod than among those who received placebo, 18% on OZA versus 6% on placebo.

Also, all other secondary endpoints were significantly improved with ozanimod compared to placebo, including clinical response at 47% compared to 25%, as well as endoscopic improvement and mucosal healing. Now, if we look at patient response by prior anti-TNF exposure, the anti-TNF-naive group had actually a higher incidence of clinical remission at week 10—a higher clinical response, a higher endoscopic remission and mucosal healing compared to those that were previously exposed to anti-TNF.

For instance, clinical remission in bio-naive patients was 22% versus 10% in anti-TNF-exposed patient. Clinical response was 52% in bio-naive patients compared to 37% in anti-TNF exposed group. In terms of maintenance, patients on ozanimod had a significantly higher clinical response and clinical remission rate at week 52 compared to the placebo group. Two important endpoints here that I would like to highlight: Steroid-free remission rate was 31% in the OZA group compared to 16% of patients on placebo.

The maintenance of remission that was defined as remission at week 52 in the subgroup of patients who were in remission at week 10 was 52% on OZA versus 29% on placebo. If your patient did well at the end of 10-week induction, they had a high chance to remain well at the end of a year on maintenance ozanimod. In terms of side effects with ozanimod in clinical trials, the most common ones were an increase in liver enzymes, ALT. We saw that in 6% of patients, and a drop in lymphocyte count and lymphopenia in 6% to 9% of patients.

Bruce, I'm going to turn to you again and ask you to highlight for us what are some of the safety considerations we have to think about when starting a patient on ozanimod?

Dr Sands: Sure. Well, as you've outlined, ozanimod is a highly effective therapy, but there are some things that people need to know before they start a patient on it. First, you need to initiate laboratory monitoring both before treatment as well as during treatment. To begin with, this includes a complete blood count with differential and a complete metabolic profile. Because there can be hypertension, you need to monitor blood pressure a bit during treatment, and it's recommended that all patients get an EKG at baseline. This is because there can be bradycardia in some patients.

Some patients may be prone to macular edema, particularly if they have a history of uveitis or prior macular edema. Those patients, not all patients, would require ophthalmic evaluation by fundoscopy. And then, if a patient has a history of lung disease, they might consider getting spirometry. It's also important to note that there is an increased risk of herpes zoster with ozanimod; and therefore, it would be important to check for varicella zoster immunoglobulin. And if the patient is negative for that, initiate a vaccination with varicella zoster more than 30 days prior, preferably.

There are a number of potential contraindications to the use of ozanimod. For example, if the patient has had a prior history of myocardial infarction or unstable angina stroke, TIA, or decompensated heart failure that has required hospitalization or has been class 3 or 4, particularly in the last 6 months, that would be a fairly strong contraindication. Also, I noted the effect of ozanimod on cardiac conduction.

The presence of Mobitz Type II second-degree or third-degree AV block or sick sinus syndrome or sinoatrial block is a contraindication, unless the patient has a functioning pacemaker. Patients with severe untreated sleep apnea should avoid using ozanimod and concomitant use of a monoamine oxidase inhibitor is a fairly strong contraindication. You should always check for drug-drug interactions of ozanimod and other drugs the patient may be on. Aline, do you have any final thoughts on ozanimod?

Dr Charabaty: This data that we shared together, in my opinion, ozanimod is best used for moderate UC, also for mild UC not responding to mesalamine. It's not my preferred drug for severe ulcerative colitis unless there are specific circumstances for that. Ideally, I would use it in bio-naive patients. We saw there's a lower response rate in patients with prior anti-TNF use and with greater number of biologics used.

However, if you use it in a patient that was previously on anti-TNF, if they do respond to the induction dose, the maintenance response rate at week 52 is actually equivalent to those who were anti-TNF-naive. If there's no response at week 10, it's important to know that an additional 5 or 10 weeks of ozanimod can lead to 44% and 49% respectively in clinical response. If your patient is doing well, but not perfect, at the end of week 10, extend that induction dose, reassess after 5 to 10 weeks.

As a good long-term efficacy and safety, it should be avoided in pregnancy and in women planning pregnancy, and actually, contraceptives should be used up to three months after stopping ozanimod.

Dr Sands: What happened next with your patient?

Dr Charabaty: My patient actually did really well on ozanimod for several months, but then she developed a moderate-to-severe flare with six loose bloody bowel movement, increased urgency, and occasional stool incontinence. At this point, her hemoglobin had dropped to nine, her fecal calprotectin was elevated at 500. Her stools were negative for C. diff., and on colonoscopy, her disease had progressed to a Mayo endoscopic score of 3. We started her on infliximab. However, she did not tolerate azathioprine in combination with infliximab, so we had to stop azathioprine.

The patient did well on infliximab monotherapy for several months, but then lost response due to developing antibody to infliximab. She has now moderate-to-severe symptoms, has been unable to go to work and be present to her family. She now also reports joint pains in her knees and elbows. Again, it would be interesting to see now what is your thought, Bruce, on what would be the next option in this patient? Should we try a different anti-TNF? Should we move to a different mechanism of action, another biologic, vedolizumab, ustekinumab, or should we move to a JAK inhibitor?

Dr Sands: Yeah, it's a difficult decision. This patient had tried one TNF inhibitor, but rapidly lost response because of anti-drug antibodies. That is likely to happen with a second TNF inhibitor. Vedolizumab I don't think of as a very effective second-line agent in ulcerative colitis. Better used as a first-line agent. Ustekinumab would be a choice, but again, this is a busy working mom, so maybe a JAK inhibitor. Is that what you chose?

Dr Charabaty: Absolutely, and I agree with you. I think we think very similarly. We have somebody who has symptoms that are deeply impacting their life. They're having GI symptoms and joint pain. We need a drug that works fast, that works well for both the luminal disease and the joints, and absolutely an oral option would be very convenient for a mom of two who's also traveling for work. Yes, I think this is a great opportunity to use a JAK inhibitor to control the disease and the extraintestinal manifestation of the disease.

Bruce, we do have two JAK inhibitors now for UC: tofacitinib and upadacitinib. UPA was also recently approved for Crohn's disease, and we'll talk about that. We're going to focus on UPA as it's the newer one of the two, but I think it's important to look at them side by side. There are some differences and maybe you can walk us through this.

Dr Sands: Sure. Well, the older of the two is tofacitinib. We've been using that for a number of years, now. That's a pan-JAK inhibitor, but it primarily blocks both JAK1 and JAK3. You know that we have a standard induction dosing of 10 milligrams twice daily for at least 8 weeks and maintenance dosing of either 5 or 10 milligrams twice daily. Fortunately, there is also an extended-release version of the treatment induction dosing with 22 milligram once daily dose for 8 or more weeks and a maintenance once-daily 11 milligrams dose.

For upadacitinib, that primarily blocks JAK1, with possible benefits in terms of safety and efficacy. The formulations include a 45 milligram once-daily dose for eight weeks for ulcerative colitis, and for Crohn's disease, we would extend that to 12 weeks. The maintenance dosing could either be 15 milligrams once daily, or—for a patient who's had refractory, severe, or extensive disease—we might choose to maintain with 30 milligrams once daily. The data are very striking for induction with upadacitinib in moderate to severe UC.

We have 2 studies that looked at parallel populations, U-ACCOMPLISH and U-ACHIEVE studies, and they showed virtually the same thing. Nearly three-quarters of patients achieve clinical response by week eight. In fact, many patients achieve clinical response even far earlier than that. Clinical remission occurred in about a third of patients overall, and we saw substantial numbers of patients with endoscopic improvement, and even the combination of endoscopic improvement and histologic improvement that we call histo-endoscopic mucosal improvement.

The patients who responded in those programs were randomized to maintenance therapy and followed out to week 52. There were very high rates of corticosteroid-free clinical remission, about two-thirds of patients achieving that, nearly two-thirds achieving endoscopic improvement, and more than half maintaining clinical remission and HEMI. Of course, there are some side effects associated with upadacitinib as there are with all JAK inhibitors. There is a risk of herpes zoster.

There's a low risk of neutropenia, but this did occur. It's not as risky a thing as we used to see with azathioprine and thiopurines, and there can be largely asymptomatic CPK elevation that we do not worry very much about. There's some laboratory monitoring that is recommended for upadacitinib at baseline. You would like to check a CBC with differential, looking at lymphocyte counts, neutrophils, hemoglobin, also a CMP looking at liver enzymes. And then you might want to periodically check those.

I usually will repeat those every 3 or 4 months. It's important to remember that there can be an effect of increasing total cholesterol on therapy, and therefore, it's recommended that sometime around 12 weeks after initiating therapy that you check lipids at least once. I don't think that you have to keep repeating it if the lipids are normal. And if cholesterol is out of range and meets guidelines for treatment of hypercholesterolemia, you would initiate therapy for that.

It's important to remember that these are small molecule oral agents. The JAK inhibitors are all oral, and, therefore, they have convenient dosing. They're not immunogenic, unlike the anti-TNFs, and they have very reliable pharmacokinetics. They can work very rapidly. This is a little bit in contrast to ozanimod, which maybe has a slower onset of effect, but still is effective. Perhaps we can do a more rapid steroid taper or even avoid steroids altogether. This is a systemically effective therapy, so it can treat extraintestinal manifestations and arthritis.

We don't really recommend washout periods from biologics when you have a sick patient that needs treatment. But it's important to remember that the label in the United States requires prior treatment with anti-TNF inhibitors, so we position this as a second-line therapy. It's important to note that there's also a black box warning for thrombosis, major adverse cardiovascular events, malignancies, serious infections, and mortality. But these data come from rheumatoid arthritis populations with 1 or more risk factors for cardiovascular disease. In fact, in IBD studies, we have not actually observed an increased risk for thromboembolic events or major adverse cardiovascular events. Still, it is something we do need to discuss with our patients. As I mentioned, both LDL and HDL may increase. There's the possibility of drug interactions, particularly CYP3A4 inhibitors and inducers. Just as with ozanimod, we'd like to vaccinate for herpes zoster, although it can be done, if necessary, after starting therapy.

We don't have a whole lot of information about the safety in pregnancy. At this point in time, I don't routinely recommend its use in women planning to become pregnant or who are pregnant.

Dr Charabaty: Bruce, thank you for this excellent update on JAK inhibitor and UPA in UC. Now we're going to shift gears to Crohn's disease, and I believe you do have a case of Crohn's disease to share with us.

Dr Sands: I do. This is a 35-year-old man with a 7-year history of Crohn's disease of the terminal ileum in the entire colon except for sparing of the rectum. In that diagnosis, he was treated with prednisone and azathioprine, but at 6 months he had recurrent flare and he started infliximab. He did well actually for 6 years, but now he has recurrent flare symptoms despite having good trough levels of infliximab at 12.5 without detection of antibodies to infliximab.

An MRE confirms thickening and mucosal enhancement, as well as engorged vasa recta in the distal 25 centimeters of terminal ileum in the entire colon except for the rectum, but there's no fistula or stricture identified. Do you have any thoughts on this case? Would you follow the guidelines which were published before risankizumab and upadacitinib became available, or would you try one of these newer agents?

Dr Charabaty: Agree, Bruce. The AGA guidelines were developed before these drugs were available, these newer drugs were available to us. And, typically, what we see in the guidelines is that in patients with severe Crohn's disease, the recommendation is to use an anti-TNF or ustekinumab IL-12, IL-23 inhibitor. Your patient has severe Crohn's disease. Because of its high inflammatory burden, he has the colon being involved and extensive small bowel being involved.

This patient has lost response to infliximab, so typically I would have moved to ustekinumab. But now, like you said, we have two new players in Crohn's disease, IL-23 inhibitor with risankizumab and UPA is JAK inhibitor, who have shown really impressive efficacy in terms of clinical remission and endoscopic healing in Crohn's clinical trial. These are two excellent choices for this patient. I think the final answer will depend on the factors that you previously described, whether there are any associated condition, comorbidities, access to specific therapy, patient preference, and, of course, in a woman, if there's any pregnancy planning, we should stay away from JAK inhibitors at this point.

Dr Sands: Well, that's great. I mean, Aline, there's so much information. Could you review some of the data on these newer agents?

Dr Charabaty: Yes. Let's start with the use of OPA and UPA in Crohn's disease. We have two phase 3 induction trials, U-EXCEL and U-EXCEED, that looked at patients with moderate to severe Crohn's disease and who were randomized to receive upadacitinib 45 milligrams or placebo for 12 weeks.

As you can see here, again, same as you've shown with UC, the results are really impressive in this induction trial for Crohn's disease. A significantly higher percentage of patients who received UPA at 45 milligrams compared to placebo had clinical remission. In U-EXCEL, that rate was 49% compared to 29% in the placebo group. In U-EXCEED, the rate of clinical remission in the UPA arm was 38.9% compared to 21% in the placebo group. At the same time, endoscopic response was also higher in the UPA treated groups.

Again, really impressive data. Now, patients who had a clinical response to 12 weeks of UPA induction were enrolled in the maintenance trial U-ENDURE and randomized to receive UPA at a dose of 15 milligrams or 30 milligrams or placebo. At week 52, we see here a higher percentage of patients, again, who had clinical remission on UPA. If they were on 15 milligrams, that remission rate was 37%.

On UPA 30 milligram, the remission rate was 47%, and this is compared to only 15% in the placebo group. We also had a higher percentage of patients who achieved endoscopic response on UPA. Here, again, you see a delta between the response in the UPA group and the placebo. That was very impressive.

Now, moving to risankizumab in Crohn's disease, we have two trials, ADVANCE and MOTIVATE, that looked at the efficacy of IV risankizumab at a dose of 600 milligrams or 1200 milligrams given at weeks 0, 4 and 8. The ADVANCE trial enrolled patient who were previously intolerant or had inadequate response to one or more biologics or to conventional therapy. MOTIVATE enrolled patients who were previously intolerant or had inadequate response to biologics only.

You can see here, again, that all endpoints at week 12 were met in both trials and with both doses of RISA. In ADVANCE, clinical remission rate was 45% with RISA given a 600 milligram dose and 42% with RISA given a 1200 milligram dose compared to placebo rates of 25%. Similar numbers we're seeing in the stool frequency and abdominal pain score clinical remission rate and endoscopic response rate were also quite impressive here, 40% with RISA 600 milligrams, 32% with RISA at 1200 milligrams versus only 12% with placebo.

The MOTIVATE trial also showed comparable results and efficacy with both dose of RISA. Now, in term of maintenance, patient who had a clinical response to RISA in the ADVANCE and MOTIVATE induction studies were included in the maintenance trial and randomized to sub-q risankizumab at a dose of 180 milligrams or 360 milligrams given every eight weeks or subcutaneous placebo. Again, we see a greater clinical remission and endoscopic response with the 360-milligrams of RISA compared to placebo.

Now, you're seeing a high placebo maintenance rate. Just remember that these patients who are now getting placebo maintenance actually had already received three induction doses of RISA previously and had responded to the RISA induction. Finally, in terms of safety data, the maintenance treatment was overall very well-tolerated. Adverse event rates were very similar among groups, and the most frequently reported adverse event in all treatment groups were worsening of Crohn's disease, nasopharyngitis, arthralgia, and headache. Bruce, any final thoughts on your case and where these newer agents fit into treatment of moderate to severe Crohn's disease?

Dr Sands: Yeah. I mean, this patient could easily have gotten either risankizumab or upadacitinib. I would tend to favor risankizumab only because of its superior safety profile, but both of these agents are highly effective as second line agents in advanced therapy.

Dr Charabaty: I agree. It's great to have the opportunity to have new effective therapies for our patients, especially those who did not respond to anti-TNF or had higher risk of anti-TNF. Anti-TNFs have traditionally been our preferred drug for very sick patients or patients with extensive disease. Now we have the opportunity to have two new mechanisms of action that are effective, that have a quick onset of action and have a great efficacy also for extraintestinal manifestation.

Bruce, I'd like to thank you again for joining me today, and thank you everyone for participating in this Medscape activity. Please continue on to answer the questions that follow and complete the evaluation.

This transcript has not been copyedited.