Dr. Jordan Axelrad (NYU Grossman School of Medicine): My goal of this section that will then be followed by Jami, is really to give a nice overview of the more novel treatments that are currently available for our patients. To give a nice overview of what is available, and then, of course, how Jami and I are thinking about therapy selection.

Advanced Therapies in IBD

This is just a brief table describing all of the FDA-approved advanced therapies that we have for our patients and then which IBD subtype, Crohn's or ulcerative colitis, are they approved in.

Many of these you are all very familiar with. Today, we are going to be focusing on some of the more novel therapies, including selective IL-23 inhibitors, which include mirikizumab, risankizumab and guselkumab, all three of which are approved in Crohn's and ulcerative colitis. Then we will be focusing a bit on some of the small molecules and including JAK inhibitors and S1P receptor agonists.

Of note, I am going to be focusing on Crohn's disease, where only upadacitinib is approved. There is no approvals for the other JAK inhibitors or the S1P receptor agonists in Crohn's disease.

Long-term Outcomes in Crohn’s Disease

First, let us dive into the long-term outcomes in Crohn's disease. Now that we have these novel therapies available, what is really important for patients is that what durable impact they can get over time. So what do we know?

IM-UNITI LTE: SC Ustekinumab Long-term Outcomes in CD

Just thinking about a therapy that many of our patients are already on, although in the setting of more of the novel IL-23 agents, we are not doing as many new starts of ustekinumab anymore. Certainly many patients have been doing well on ustekinumab for many years.

This is a study looking at long-term outcomes over five years in patients with and without prior anti-TNF therapy exposure. That is what these curves are on the right are demonstrating are patients without prior anti-TNF exposure on the top hand curve. The bottom is with prior anti-TNF exposure.

You can see across the doses that were studied, and again, I will just mention that the blue bar is the dose that we use in IBD 90 milligrams Q8 weeks, is that for patients who achieved meaningful clinical remission, that was generally maintained over five years of follow-up. There was a little bit of attrition, but generally it was well maintained.

GRAVITI: Guselkumab in Moderate to Severe CD—Response by Previous Treatment at Wk 48

Focusing now on some of the more novel therapies. GRAVITI, which was the study of guselkumab in Crohn's disease, again, showing you data here stratified by outcomes by both bio-naive patients and those who had had prior exposure and tolerance to biologics for both clinical remission and endoscopic response. I will say that, as Jami and I tend to focus on more of the objective outcomes, so I like endoscopic response data.

What is really important here with GRAVITI, which again was the study of guselkumab in moderate to severe Crohn's disease, is that you can see that in patients who are bio-naive, there was not a major distinguishing outcome based on the maintenance dose that was used. Guselkumab is approved in both the 100 milligram Q8 week dose in maintenance or 200 milligrams Q4.

Most of us in practice use Q4. However, you could see that in those who are bio-naive, which is generally where we are using this therapy, there was not a major difference in endoscopic or clinical outcomes. Where we start to see some of that difference in maintenance dosing is in those who had prior or inadequate response to biologics in the past.

Here is where that 200 milligram Q4 dose really makes a more meaningful impact. You can see here a placebo rate of zero. That 200 Q4 dose is something that most of us are reaching for in practice, bio-naive or not, but the real statistical benefit here are in folks who have had prior or inadequate exposure to biologics.

GRAVITI: Guselkumab in Moderate to Severe CD—Corticosteroid-Free Remission and Safety

Again, still staying in guselkumab, looking at clinical remission and also 90-day corticosteroid-free clinical remission. We could see again that guselkumab was superior to placebo numerically better at the higher maintenance and shorter frequency at that at 200 Q4.

Importantly, when we looked at therapy discontinuations, you could see here that very few patients in the guselkumab 200 milligram Q4 dose discontinued therapy, about 4% compared to nearly a quarter to a third in those who were placebo-exposed patients. Again, that is common that we see across trials is that therapy discontinuations are more common in placebo because patients really need drug, and you want to see that durability in the therapy exposed groups, again, only 4% discontinuing therapy in the treatment exposed group at the 200 Q4.

GALAXI 2/3 and GRAVITI LTEs: Guselkumab Long-term Outcomes in CD

Looking at both GALAXI and GRAVITI, so remembering that GRAVITI was the study of subcutaneous guselkumab induction and maintenance in Crohn's disease. GALAXI was the infusion induction followed by subcutaneous maintenance. This is looking at those long-term outcomes.

Again, across doses, what we are demonstrating here in clinical remission and endoscopic response is that for patients who achieve these meaningful outcomes, that tends to be maintained over follow up. Here we are seeing data up to week 96.

Again, similar to what we have seen with ustekinumab over five years. Now what we are seeing with our IL-23 agents, at least guselkumab here, up to week 96, that maintenance of responses is maintained for both clinical remission and endoscopic response. We see that across doses, again, with the caveats that higher dose 200 Q4 is something that most of us are using in practice and in some of our sicker patients, more advanced therapy exposed, we have better outcomes in that group.

VIVID-1: Mirikizumab in Moderate to Severe CD—Composite Endpoint Primary Efficacy

Turning to one of our other IL-23 inhibitors, mirikizumab. This is data from VIVID-1, which was a study of mirikizumab in moderate to severe Crohn's disease. This also was an active comparator study, where ustekinumab was an active arm. Here, you could see that mirikizumab met all the endpoints. As demonstrated here on the right, I am showing you patient-reported outcome remission at week 12. Then also remission and response at week 52.

You can see that mirikizumab-exposed patients far superior to placebo for achieving these outcomes. Again, looking at endoscopic response on the right is something that we care quite a bit about. Pretty wide delta with placebo, again, demonstrating the utility of mirikizumab in patients with Crohn's disease at week 52.

VIVID-1: Mirikizumab in Moderate to Severe CD—Response by Failure to Biologic Therapies at Wk 52

As I mentioned, this was an active comparator study. Again, as was GALAXI in Crohn's disease for guselkumab. Here in VIVID, mirikizumab, which had an active comparator, ustekinumab. Here I am showing you clinical remission at week 52 and then endoscopic response at week 52, on the right, you can see mirikizumab versus ustekinumab.

What is important here is that with the overall population, in particular, for those who had no prior advanced therapy exposure, there was very little clinical difference between ustekinumab and mirikizumab, although both were statistically much better than placebo.

What is important here is that there was numerically better outcomes and statistically better outcomes, at least for clinical remission, for those who had prior failure of advanced therapies biologics who received mirikizumab compared to ustekinumab.

Here is where you start to see that benefit of the IL-23 agents compared to ustekinumab that at least for clinical remission at week 52, mirikizumab is performing significantly better than ustekinumab. Again, that is really important, or at least numerically better than ustekinumab. We are going to review some of the data that this carries forward with the IL-23 class.

VIVID-1: Mirikizumab in Moderate to Severe CD—Corticosteroid-Free Remission and Safety

Again, looking a little bit deeper into mirikizumab. This is safety and corticosteroid-free remission. As expected, mirikizumab superior to placebo. As far as therapy discontinuations for adverse events, much higher in placebo groups compared to active mirikizumab or ustekinumab.

VIVID-2 OLE: Mirikizumab Long-term Outcomes in CD

Looking at more open-label, long-term outcomes. Again, these are data of mirikizumab looking up to week 152. Of course, what is not just important is how patients do over the first couple of weeks of a study, but how they do long-term. As expected, patients who achieve early remission maintain that remission over time up to 152 weeks, with the majority of patients maintaining CDAI remission and corticosteroid-free CDAI remission. So really important Crohn's disease data.

FORTIFY: Risankizumab in Moderate to Severe CD

Turning to FORTIFY, which was the study of risankizumab in moderate to severe Crohn's. We just went over guselkumab, then mirikizumab. Now we are turning to risankizumab in Crohn's disease, our third IL-23 inhibitor.

Here I am showing you clinical remission at week 52 and endoscopic response at week 52, similar to the other studies I showed you. Again, across therapy exposures, risankizumab was superior to placebo for all the outcomes, specifically endoscopic response. I just want to note some of the high placebo rates here. Keep in mind that this was a rerandomization study so that there may have been risankizumab-exposed patients in induction, who then were randomized to placebo for maintenance, and they would be captured in the placebo arm here. That may explain some of that higher placebo rate.

Regardless, we see statistical significance of risankizumab compared to placebo across these important outcomes, again, most important being endoscopic response in my view.

FORTIFY: Risankizumab in Moderate to Severe CD Long-term Efficacy

Looking at more long-term outcomes at week 52, again, we see that risankizumab is superior to placebo. On some of the specific outcomes, we start to see a little bit of a distinguishing outcomes as far as which dose was used in maintenance, remembering that risankizumab is approved at both the 360 and 180 milligram Q8 week dose. Most of us in clinical practice, again, similar to how we approach guselkumab are reaching for that higher dose, that 360 dose.

You can see on certain outcomes like endoscopic remission, a simple endoscopic score of zero to two, so much tighter endoscopic control. We see that risankizumab at that higher dose may have some benefits numerically compared to the other dose, 180 Q8. Again, most of us reaching for that higher dose.

SEQUENCE OLE: Risankizumab Long-term Outcomes in CD

Turning to SEQUENCE, which was another active comparator trial. We already mentioned that in GALAXI, we saw an active comparator guselkumab to ustekinumab. In VIVID, we saw an active comparator of mirikizumab to ustekinumab. Now in SEQUENCE, this was an active comparator risankizumab to ustekinumab. Essentially all the IL-23s were attempting and have demonstrated significant, if not numerically superiority to ustekinumab.

What is important from the take-home here is that, again, in open-label outcomes, up to week 100, patients who achieve meaningful remission have that maintained over time. Here we are looking at clinical remission and then clinical remission that is also corticosteroid-free. That is maintained over time in patients who achieve these. So a pretty good long-term control.

U-ENDURE OLE: Upadacitinib Long-term Outcomes in CD

Before I turn it over to Jami, I just want to touch on upadacitinib. Remember, the only small molecule, JAK-1 selective inhibitor approved in Crohn's disease. These are our long-term outcomes looking at week 48. As anticipated, you can see that those who achieve clinical remission have that maintained over time. Also important to note that both doses here in maintenance, the 30 milligram upadacitinib and 15 milligram upadacitinib have that similar maintenance of remission over time. Again, most of us in clinical practice are reaching for that higher dose 30 milligrams.

You can see if they are able to achieve meaningful disease outcomes, they are maintained at whatever dose they are maintained on. Again, a little reassurance there.

Long-term Outcomes in Ulcerative Colitis

I am going to turn it over to Jami to talk about long-term outcomes in ulcerative colitis.

Dr. Jami Kinnucan (Mayo Clinic Florida): Great. Thanks, Jordan. That was a great overview of some of these newer therapies in Crohn's disease. You really gave the audience some very practical tips, many of which actually carry over into the ulcerative colitis space.

Let us shift to reviewing some of these similar therapies with additional ones, as well as long-term outcomes in patients with ulcerative colitis across our currently and newer approved therapies.

UNIFI LTE: Ustekinumab Long-term Outcomes in UC

I am going to start with the UNIFI long-term extension data. This is looking at IL-12/23 therapy with ustekinumab. This is following patients out almost four years. It is combining both those patients that are biologic-naive and those that have been biologic-exposed with just over half of them able to achieve corticosteroid-free clinical remission, which is a really important outcome that we care about but our patients also care about, because we can get many patients well on steroid therapy, but it is the importance that we can keep them off of steroid therapy.

If you take out those patients that had prior biologic exposure, you get nearly 70% achieving that endpoint towards the use of first ustekinumab early in treatment exposure patient. There are no new safety profile events, and anything that happened in this follow-up study was similar to that of the placebo arm.

QUASAR: Guselkumab in Moderate to Severe UC

I am going to shift us away from the IL-12/23 ustekinumab and move towards QUASAR, which evaluated the IL-23 therapy that you have already heard about from Jordan, guselkumab. This is looking at both 12-week outcomes, so induction outcomes, as well as week 44 outcomes for maintenance.

On the left here, you can see, and I think of things a little bit backward. You can see that overall symptom response in the bottom box, nearly three quarters of patients by week 12 were able to achieve improvement in their symptoms, and nearly a quarter were able to achieve clinical remission, absence of symptoms.

Following these patients out to week 44, we have three groups that we are going to be looking at here. We are going to be looking at placebo, which is actually a withdrawal group. Those patients that received induction guselkumab were now placed into a placebo group we randomized. We are seeing the potential impacts of getting exposure to induction guselkumab.

This treatment groups looked at both 100 and 200 milligrams. Overall, we are seeing meaningful clinical remission as well as endoscopic remission across advanced therapy exposed and naive patients, meeting both clinical outcomes for our patients but as well as some of these objective things that Jordan had talked about in terms of endoscopic remission.

QUASAR LTE: Guselkumab Long-term Outcomes in UC

Now we are going to follow this out to the QUASAR long-term extension data. We really were looking first at that first year, and now we are going to follow patients out two years. We see these sustained outcomes, including clinical remission, maintenance of clinical remission, which means that you achieved that response at week 44 and you were able to maintain that response, symptomatic remission, endoscopic improvement as well as normalization.

Then another endpoint that you are going to start to hear more about, which is histologic endoscopic remission, or HEMI. As we expected, there were no new safety concerns when we followed these patients out. Efficacy looks good. Durability is great, and safety remains strong.

LUCENT-1/2: Mirikizumab in Moderate to Severe UC

I am going to shift us to another IL-23 therapy used in ulcerative colitis, mirikizumab, through the LUCENT-1 and 2 clinical trial program. This assessed induction outcomes at week 12, achieving clinical remission in nearly a quarter of our patients and endoscopic remission in over 30%, as well as HEMI in a similar group.

Further, the LUCENT-2 now follows these patients out to week 40. There is high rates of clinical, endoscopic and HEMI outcomes in these patients as well. You can see that on the right.

LUCENT-3 OLE: Mirikizumab Long-term Outcomes in UC

When we look forward to LUCENT-3, which is now the long-term extension data for mirikizumab, exposing patients with moderate to severe ulcerative colitis, this is actually the longest term follow-up that we have in this class, at least in ulcerative colitis patients.

We have high rates of clinical remission, high rates of symptomatic remission, endo/histologic remission, disease clearance, which actually means not only did they meet endo/histologic remission, but they also had symptomatic remission. That was in up to 50% of patients.

Any treatment-emergent adverse events were considered mild to moderate in less than 5% with serious adverse events. There were no surprises in terms of this follow-up and what we would expect from this IL-23 class.

INSPIRE and COMMAND: Risankizumab in Moderate to Severe UC

I am going to shift us to our last IL-23. Last but not least, in ulcerative colitis, finishing out with risankizumab in the INSPIRE induction trial, with over 20% of these patients achieving clinical remission. Slightly higher in those patients who had never been exposed to an advanced therapy, really just highlight how important it is to select effective therapy early in the treatment course.

The COMMAND maintenance trial showed both doses, 180 and 360. Again, in clinical practice, most of us are using 360 because many of us in a referral center are taking care of patients that might be a little bit sicker than what we might see in the clinical trial programs.

These doses both met clinical remission, clinical response and endoscopic improvement in the maintenance follow-up.

COMMAND OLE: Risankizumab Long-term Outcomes in UC

Similarly, following these patients out in the open-label extension, which you can see here on this next slide, we see stable efficacy rates across clinical remission, clinical response, endoscopic improvement, and that again, the important endpoint of corticosteroid-free clinical remission in up to 82% of patients. They were able to remain off steroids as we follow these patients out, which means that they are calling the office less, they are feeling well, they have great quality of life.

U-ACHIEVE Substudy 3: Upadacitinib in Moderate to Severe UC—Long-term Outcomes

I am going to shift this now to small molecule. Similarly to Jordan, we are going to talk about the use of JAK inhibitors, upadacitinib. Mainly focusing on upadacitinib because it was the most recently approved JAK inhibitor.

This is looking at the U-ACHIEVE subset 3 for moderate to severe ulcerative colitis. So we are not looking at the main clinical trial program, but really this longer term outcomes program.

We can see focusing on week 52 outcomes in the clinical trial program, we see clinical remission rates nearly 60% across all groups. Biologic naive as well as those with single or multiple advanced therapy. I usually like not use the word advanced because it suggests that we should be stepping up to it, but more of effective therapy or other advanced therapies, unfortunately, is what we are using. There is a significantly high delta from placebo across each of these endpoints.

Endoscopic remission was defined as a Mayo endoscopic score of zero, means the absence of inflammation, and that was seen in 30% of patients. Again, this endpoint is holding across all prior treatment exposures.

Now, we know from the FDA label that we had to position this after anti-TNF, but there was that recent update that this could be left to the discretion of the prescribing provider. So if this is an appropriate therapy using it on-label, we update yourself on with FDA label shows.

U-ACTIVATE LTE: Upadacitinib Long-term Outcomes in UC

The U-ACTIVATE long-term extension study, we see further response beyond the initial clinical remission rates that we saw in the initial program with those achieve those outcomes at week 52 were able to maintain that remission at week 96. In particular, focusing on particular patient-reported outcomes of urgency and abdominal pain.

These are very important in terms of patients’ overall quality of life indicators. This is where we start to see some of those endpoints creeping into the clinical trial programs and long-term extension follow-up.

Most notable is the overall tolerance of therapy with serious adverse events noted as hepatic disorder, elevated liver enzymes and potential for serious infection. We do know that patients that start on JAK inhibitors should be vaccinated for the herpes zoster virus through the recombinant vaccination, and overall, some of the fear that came out of the surveillance data that was in upadacitinib in rheumatoid arthritis patients: MACE, VTE and malignancy were all very rare in this long-term extension.

So we can feel confident that this is an effective therapy to use in our patients with moderate to severe ulcerative colitis, but also that we did not see any short-term as well as long-term follow-up major safety concerns.

ELEVATE UC 12/52: Etrasimod in Moderate to Severe UC

Lastly, I am going to turn to the ELEVATE UC program, which is again another small molecule with etrasimod, looking at clinical remission, endoscopic remission and HEMI at week 12. We see high rates across that are on the left. Then looking at week 52, clinical remission up to 31%. It does not differentiate those that had had prior advanced treatment exposure.

ELEVATE UC OLE: Etrasimod Long-term Outcomes in UC

However, in the ELEVATE UC’s open-label extension out to two years, which you can see on this slide, it shows durable clinical response in those that entered into the long-term extension, symptomatic remission, which is the absence of symptoms, clinical remission and endoscopic improvement.

Clinical remission is a slightly stricter endpoint than symptomatic remission or response because it includes both symptomatic remission as well as endoscopic improvement. There was a serious adverse events less than 10% in these patients.

With that, I am going to hand it back to my colleague, Amy, for overall next steps and discussion.

Novel Subcutaneous Formulations in IBD

Amy Stewart: We are actually almost there, Jami. First, Dr. Axelrad is rather going to lead us through some novel subcutaneous formulations in IBD, and then we will get into some polling questions here.

Dr. Axelrad: Yes. I am going to take over and talk about some of our subcutaneous IBD therapies. You just heard about mirikizumab, risankizumab, guselkumab, upadacitinib, and then also the S1P receptor modulators, including etrasimod. Those are essentially all of our novel therapies.

Now let us dive a little bit deeper into the therapies that are subcutaneous. In addition, I just want to underscore all of the IL-23 inhibitors that were mentioned: mirikizumab, risankizumab, and guselkumab, are all subcutaneous and maintenance, but they are not all subcutaneous for induction.

LIBERTY-CD: SC Infliximab in Moderate to Severe CD

What are the formulations that we currently have that are available subcutaneous that is novel? Well, infliximab is now also available as a subcutaneous maintenance regimen.

These are the data from LIBERTY-Crohn's Disease, which is a study of subcutaneous infliximab in moderate to severe Crohn's disease. Really important useful data, as you can see that essentially for clinical remission, which was a CDAI of less than 150 and endoscopic remission here in the bottom right, again, that is the outcome that most of us really pay a lot of attention to because it is objective.

You can see that infliximab subcutaneous was superior to placebo for achieving these outcomes. Importantly, they also stratified these data, if you look on the bottom right here by those who had primarily small bowel disease, which is generally considered a much more difficult to treat group versus those who had colon-dominant disease, which we also think may be a little easier to treat in Crohn's disease. You could see that this was fairly effective across those disease distributions.

Again, LIBERTY-CD demonstrating the utility of a subcutaneous infliximab as maintenance therapy in Crohn's disease, something that really very useful to patients who do not want to maintain on long-term infusion therapy. Just to underscore, that is after infusion induction.

VISIBLE 1: SC Vedolizumab in Moderate to Severe UC

Turning to another novel, subcutaneous therapy, vedolizumab. Again, this is the data from VISIBLE-1, which is a study of subcutaneous vedolizumab in moderate to severe ulcerative colitis. Again, this was a phase III trial that started with IV infusion vedolizumab induction. Patients were then transitioned over to subcutaneous vedolizumab maintenance.

Here we are seeing clinical remission at week 52 across all patients and then stratified by prior anti-TNF failures. Again, as you can see across drug was superior to placebo and there was even reasonable efficacy in those who had prior anti-TNF failure who were moved over to subcutaneous vedolizumab.

Important data, as again, another option for patients who do not want to maintain on long-term infusion with vedolizumab. This is a nice option for maintenance therapy as a subcutaneous therapy.

VISIBLE 2: SC Vedolizumab in Moderate to Severe CD

Turning to the Crohn's disease data for vedolizumab. This is VISIBLE-2, similar study structure, started with infusion vedolizumab for induction. Patients were then rolled over into subcutaneous maintenance or placebo.

Here you can see again across outcomes, there was general either numerically greater or statistically superior outcomes for subcutaneous vedolizumab compared to placebo at week 52. Again, a nice option for patients additionally with Crohn's disease who require vedolizumab and do not want to maintain on an infusion therapy.

The only new adverse event to note here was that, of course, this is a subcutaneous injection, so about 3% of patients had injection site reactions. Again, that is actually quite a small number for an injectable, but underscores that this is a nice option for patients who want a subcutaneous option.

GRAVITI: SC Guselkumab Induction and Maintenance in Moderate to Severe UC

We already talked about guselkumab in both Crohn's disease and ulcerative colitis. These are data from GRAVITI, which was a subcutaneous study of guselkumab maintenance. Basically they were induced with a subcutaneous formulation and then maintained on a subcutaneous formulation. This is a unique study where there is no infusion induction. It is actually subcutaneous induction followed by subcutaneous maintenance.

I already mentioned that most of us in practice are reaching for that 200 Q4 week maintenance. Here, as you can see on the bottom, these are the data stratified by BIO, JAK and S1P receptor modulator naive patients and those who were exposed for both clinical remission and endoscopic outcomes.

What is really important here again is that drug was superior to placebo, again underscoring the usefulness of this drug for subcutaneous formulation in maintenance. Again, this is being guselkumab.

ASTRO: SC Guselkumab Induction and Maintenance in Moderate to Severe CD

What about in Crohn's disease? Similar study. This was called ASTRO. Again, patients were randomized to subcutaneous induction followed then by subcutaneous maintenance. Just want to underscore that currently guselkumab is the only FDA-approved IL-23 that has subcutaneous induction and maintenance for patients with both Crohn's and ulcerative colitis. Again, these are the Crohn's disease data looking at week 24 and week 48 outcomes.

As anticipated, across exposures to guselkumab, superior to placebo. Of note, in that higher dose, shorter frequency, so that 200 Q4, we are seeing numerically better outcomes. Again, not so much statistically, but numerically better outcomes at that higher dose, particularly in those who are advanced therapy exposed or intolerant. Again, underscoring how we approach utilization of the doses.

Posttest 1

A post-test question before we move on to the next section. A 34-year-old man with ileal colonic Crohn's disease has secondary loss of response on adalimumab 40 milligrams every other week despite dose optimization and therapeutic drug monitoring.

Colonoscopy shows persistent deep ulcers in the TI and right colon. Fecal calprotectin is elevated at 1350. There is no perianal fistula, no abscess, no current infection. The patient shares that he would prefer infrequent dosing. Which treatment would you recommend for this patient?

1. Continue adalimumab with prednisone;
2. Switch to risankizumab;
3. Switch to ustekinumab; or
4. Switch to vedolizumab.

Pre-test we were really split. Almost a quarter of people chose each of the four answers. Now moving on to the post test, 62% of participants chose B, switch to risankizumab.

Posttest 1: Rationale

This patient has active Crohn's disease after TNF failure and SEQUENCE directly compared risankizumab to ustekinumab in patients with moderate to severe Crohn's disease who had failed anti-TNF therapy and supports that choice with the data that we talked through.