Introduction: The Clinical Burden of CD

Dr David Choi (University of Chicago): I want to first talk about the clinical burdens of Crohn's disease and what this may look like in the course of a patient's care for Crohn's disease.

[00:06:17]

Inflammatory Bowel Disease Prevalence in the US

Inflammatory bowel disease is currently thought to affect about 2.4 million people in the United States. When we think about inflammatory bowel disease, this is not an autoimmune condition, from the standpoint that the cells are specifically attacking the intestinal walls or the gastrointestinal tract. But this is an immune-mediated inflammatory disease, which means through a complex tapestry of genetic considerations, environmental factors, other kinds of things that we think about in terms of risk factors, all culminate into a hyper-immune response, where the immune system is hyperactive in the bowel tract. That, ultimately, causes collateral damage to the gastrointestinal tract.

The inflammatory bowel disease is really an umbrella term for 2 separate conditions. We have Crohn's disease as well as ulcerative colitis. Ulcerative colitis only affects the colon, while Crohn's disease can occur anywhere from the mouth to the anus, and can affect any part of the gastrointestinal tract. Diabetes, dyslipidemia. We know that a lot of times, especially with hypertension, diabetes, dyslipidemia, they tend to be asymptomatic.

There are not real symptoms associated with the disease earlier on. As a result, that is some of the differences. But when it comes to Crohn's disease, there can be severe symptoms that patients present with.

[00:07:39]

Symptom Impact in CD: Severity of Common IBD Symptoms Reported by Patients With CD

Here is a survey done amongst patients with Crohn's disease. They were asked what were se of the common IBD symptoms. One thing I do want to note is sometimes these symptoms do vary on the phenotype of the Crohn's disease, meaning where the Crohn's disease affects the gastrointestinal tract can really change the symptoms that patients report. However, as a whole, patients reported that tiredness, exhaustion, and fatigue was one of the number 1 symptoms reported. That could come from anemia due to blood loss. It could be due to nutritional deficiencies because patients cannot actually absorb nutrition very well through the small bowel, through inflammation.

Some of the other ones are anxiety, low mood, depression, rectal urgency, meaning patients have to immediately find a restroom because the urgency requires them to immediately have a bowel movement, that requires finding a nearby bathroom as urgently as possible. Bloating, abdominal pain, cramping, needing to use a toilet soon after eating, diarrhea, constipation, nausea, vomiting were some of the common signs and symptoms that patients with Crohn's disease reported.

As you can imagine, this can cause significant impairment to quality of life. When you think about day-to-day activities and the ability to go to work, go to school, be able to go to social gatherings, things along those lines. Significant impairment of quality of life is something that we see in patients with inflammatory bowel disease.

[00:09:04]

CD Symptoms With the Greatest Impacts on QoL: Patient and Physician Perspectives

What are the symptoms that have the greatest impact on the quality of life? The follow-up question here specifically looked at both patient and physician perspectives. Patients are in orange. Physicians are in blue. What you find, there are very common symptoms that really impact the patient's quality of life.

The first one is rectal urgency. Once again, that is that the patient immediately needs to use the restroom, immediately needs to find a restroom, scrambling to find a restroom. Sometimes has to pull over from the side of the highway to a rest stop to try and find a restroom because of the urgency. Abdominal pain, fatigue, diarrhea, needing to use a toilet soon after eating, as well as weight loss, have all been identified as important symptoms that really impact a patient's quality of life, and thinking about the day-to-day considerations there.

[00:09:54]

Patient and Physician Perspectives: Disease-Related Goals for Therapy

When we think about treating Crohn's disease, one of the questions is, what are some of our disease-related goals? What do we care the most about when treating our patients with Crohn's disease?

Here is what you will find is the number one improvement. The goals of therapy is to improve that quality of life. Improving quality of life is equal to both physicians as well as patients, to once again making sure that this is a goal of therapy that we are aiming for.

The second one is preventing disease progression, where long-standing Crohn's disease that constant inflammation, damage, repair can lead to significant complications for a patient with Crohn's disease. Those are examples of strictures, obstructions, fistulas, abscesses, development of perianal disease. Those complications are things that we are trying to avoid in our patients with Crohn's disease by getting them into remission earlier to help prevent those complications from forming.

[00:10:45]

Patient Perspective Video: My CD Treatment Journey- Suboptimal Initial Therapy

Go over a patient's journey that really taught us about what happens with suboptimal initial therapy. I wanted to introduce Emily Bennett and her story.

[00:10:56]

Patient Perspective Video

Emily Bennett: Hi, my name is Emily Bennett. I have been living with Crohn's disease for the last 20 years or so. I was diagnosed in 2005 when I was 19. I was lucky enough that I had a relatively straightforward approach to my diagnosis. I lived with symptoms for about 6 months before I was able to see a specialist, have some imaging done, and they determined ultimately, yes, this person has Crohn's.

Because of that, because I was lucky enough to get a diagnosis relatively quickly as opposed to some other people that unfortunately suffer from Crohn's disease and related intestinal inflammation, I was able to really begin my path on treatment.

Unfortunately, the first provider that I worked with was much more conservative in their treatment approach, which I absolutely understand. But for somebody like me who is living with pretty severe life-impacting symptoms, unfortunately, it meant that I got stuck in a loop of trying a treatment, the treatment not controlling my symptoms. I would have this large burst of inflammation and its related symptoms, and then I would have to go onto a pretty powerful drug like a steroid, which, as most people know, prednisone is a not very fun drug to take and be on, because the side effect is pretty intense.

Unfortunately, I was stuck in this loop for a while. I eventually transitioned away from that provider and found somebody who really was able to meet me where I was at, in my treatment, in my symptoms, and in my disease. They were able to get me onto a TNF blocker. Because of that, I was able to bring my disease under control. I was able to start making plans, living a life, planning my wedding, important things like that, which was really valuable for me.

[00:13:33]

Selective IL-23 Inhibition in CD: Key Evidence

Dr Bincy Abraham (Houston Methodist Academic Institute): All right. You have got to at least see an initial patient perspective of her journey. I will now introduce you to the interleukin-23 inhibition in Crohn's disease. A key evidence that we are using it today.

[00:13:44]

IL-12/IL-23: Agent Specificity

I am not sure how many of you are pharmacists, immunologists. Hopefully not only in the business side of things. To go into a little bit of biology or chemistry or the stuff that maybe we try to pass through in college, just to get to our next step in our lives here.

We have used interleukin-12/23 inhibition. Ustekinumab was our first and really only drug in Crohn's disease that affected this pathway. It is a great drug. We still use it to this day. It blocks both cytokines interleukin-12 and 23 in treating Crohn's disease.

Now, we have now 3 new biologics listed here, risankizumab, guselkumab, and mirikizumab that is approved for Crohn's disease in the United States. These specifically only block interleukin-23 in the sense that they are blocking this p19molecule, the receptors that actually contributes to the IL-23 cytokine activity. Interestingly, I will talk a little bit about guselkumab. It has an additional factor. It blocks CD64, which is a component that is found on monocyte. Actually, when it is triggered, will make more IL-23. There is a dual pathway of it treating inflammation as well.

[00:15:11]

          IL-12 and IL-23 Pathways

Why are we considering targeting p19 and being more specific for IL-23? Why cannot we block IL-12 and 23? Because more cytokines block, maybe less inflammation. However, what we found is that if you look at the graphic here, all the red are the cytokines and the immune cells have been involved in causing inflammation in Crohn's disease. You have macrophages, dendritic cells, mast cells. They are all producing different cytokines, lymphocytes. IL-23 is in the red. TNF-alpha we know is in the red. These all contribute to inflammation.

You see IL-12 it is there, but it is not really doing anything. It is not necessarily causing inflammation per se. You are actually blocking a cytokine that you do not really need to block. Theoretically, while not blocking a cytokine that is not really needed to be blocked, maybe you can improve safety in these patients. Maybe with more targeted IL-23 blockade, we can be even more specific and be potentially even more efficacious in treating our Crohn's patients. That is the theory behind this IL-23 blockade.

It is great theoretically, but what does that really mean in clinical practice, and the evidence out there? I will talk briefly about that as well.

[00:16:26]

Selective IL-23 Inhibitor for Moderate to Severe CD

Knowing that we have different IL-23 inhibitors for treatment of mild to severe Crohn's disease, all of them have been approved as one as of last week, actually, for Crohn's disease. The rizankizumab, mirikizumab, and guselkumab was approved last week for Crohn's disease. All of them have been approved for ulcerative colitis as well. These block immunoglobulins that block the IL-23 receptors, but specifically guselkumab also blocks CD64, monocytes that actually make more IL-23.

Now, half-life is a bit different for these, but essentially within all less than a month. They are not staying in the system that long. That is just the generic half-life. The biologic active half-life may actually be even a bit longer, as you can see from our placebo trials. I will show you in a bit.

Dosing can vary. But before we would prescribe these medicines, always do our precautions before starting a biologic, making sure they are negative for TB. I check it annually in all my patients, check routine labs, blood counts, liver enzymes, routine stuff. Make sure they are appropriately vaccinated. Age-appropriate vaccines and immunosuppressive vaccines. For my younger patients, actually my 18- to 40-year-olds, I make sure that they get their shingles vaccination, pneumonia vaccinations done even before they are age 40 to prevent all those things, any of these immunosuppressive medications.

Then dosing. Pretty much all of them, you can do 3 IV induction doses and then move on to maintenance SC. But the nice thing about guselkumab, based on our studies, the Crohn's approval just allows us now for induction SC dosing without having to put our patients through IV, which makes it convenient for them. We have the ASTRO study. We will not talk about it in this session, but for ulcerative colitis, it also shows benefit in SC induction for UC patients. That, hopefully, will get approved in November of this year by the FDA as well, but all maintenance will be SC dosing.

We have some options for SC dosing for guselkumab as well. I will briefly talk about the data that supports this as well.

[00:18:40]

Risankizumab in Moderate to Severe CD (SEQUENCE): Primary Efficacy

Let us start with risankizumab. Actually, the SEQUENCE study was our first head-to-head IL-23 study. This actually was an open-label, so patients knew which drug they were getting. But it was still randomized for them to get either risankizumab or ustekinumab, or IL-12/23 inhibitor.

Here, that theoretical talk about, well, one, do we need to really block IL-12? Here, we are actually seeing that risankizumab patients on that, actually, had a higher percentage of patients achieving clinical remission, 59% compared to only 40% of ustekinumab. Endoscopic remission was achieved in 32% on risankizumab, only 16% on ustekinumab. We are actually demonstrating that blocking IL-23 is actually even better in a head-to-head study over ustekinumab.

[00:19:31]

Risankizumab in Moderate to Severe CD (SEQUENCE): Glucocorticoid-Free Remission and Safety

Then we compare both steroid-free endoscopic remission and steroid-free clinical remission at one-year mark. Again, you see that a higher percentage of patients on risankizumab achieved this over ustekinumab.

Now, when you look at safety, and remember I talked about theoretical safety depending on these things, actually, adverse events were very similar between both of these medications. We already knew using ustekinumab in practice for 10 plus years. I was even part of the clinical trials. I have had some patients on it, even in the Phase II trial, we know it is a safe drug, but if we can be potentially even safer, that is great. But interestingly, we had more patients actually discontinue on ustekinumab treatment during the trial, not necessarily because of safety issues, because of lack of efficacy, which makes sense.

[00:20:22]

Risankizumab: Sustained Benefits

Now, with risankizumab was great. You saw the one-year data, but actually, we had even the original study that compared it to a placebo, FORTIFY trial. We looked at one-year maintenance, and we saw more than 60% of our patients achieving clinical remission based on our CDI activity index score, stool frequency, abdominal pain remission, endoscopic response, and remission, meaning complete healing. That is in the 360-mg dosing, getting close to 80%. I have never seen this in any of my clinical trials of these medications in past in my career, being an IBD specialist. Deep remission and the endoscopic scoring, also healing, which is our score that we use when we do the scopes, the colonoscopies to look for healing, measuring each segment, the ileum, the right colon, left colon, rectosigmoid, et cetera, as well. Huge benefits here.

(00:21:20)

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

Now, moving on to another IL-23, mirikizumab, in their registrational trial, VIVID-1. It was a double-blinded Phase III randomized trial. We had the mirikizumab arm and the placebo arm, and we looked at patients who failed conventional therapy or one or more biologics as well. We looked at a composite endpoint, looking at patient-reported outcome remission, which is required by the FDA, and clinical remission data. That was one of the endpoints, but we also looked at patient-reported outcomes in response and endoscopic response as well. Here you can see 45% of patients on mirikizumab achieved this clinical remission, and 38%, almost close to 40% on the mirikizumab, also achieved endoscopic response as well with patient-reported outcome response.

Great drug. Of course, comparing it to placebo, I am still trying to figure out why even 9% of our patients are healing endoscopically. I can understand clinically feeling better, but I do not know. I sometimes wish I had a placebo clinic, sprinkle some dust, and then magically, 9% of my patients heal up too. No worrying about getting insurance approval for sprinkling magic dust. But unfortunately, that does not happen all the time. 9% is actually pretty pathetic compared to 60% healing, et cetera.

(00:22:41)

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

Now, if you look at patients getting on these medicines, depending on what they have been on previously, because that has been my biggest challenge. All of our centers were referral centers. We are not seeing that patient in the video who just got diagnosed. They have been seen by their general GI doctors, put on different medications, and then maybe they responded. I never see them, but a lot of them do not respond, or they fail, or only have a partial response. They come in saying I failed this medicine, that medicine.

Now, I only have 1 more medicine to give you. I guess, we have to give this a try. In the trial, we looked at patients who previously failed different biologic therapies and those that have not failed. Actually, if you look at the data here in this VIVID trial, we had the mirikizumab arm, rizankizumab arm. Generally, we are not seeing a huge difference, except that numerically, you are seeing a higher percentage of patients achieving clinical remission and endoscopic response if they are on mirikizumab compared to ustekinumab.

Perhaps this also could be related to mirikizumab as not a greater superior agent per se than ustekinumab. Hard to say because this was also in a trial. But interestingly, we are seeing in general, if you are coming in biologic naive, regardless of what medicine you are on, you have a better chance of getting into remission and responding endoscopically compared to if you failed other agents.

[00:24:09]

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

Now, if you look at steroid-free remission, again, mirikizumab compared to placebo, almost half your patients as early as Week 12. That means 3 IV induction doses. They are just starting their SC maintenance, already achieving clinical response based on the patient-reported outcome at Week 12. Those that reported this ended up achieving steroid-free remission by one year.

If you look at safety, the fantastic thing is that if you look at the placebo discontinuation rates and incidence rates of adverse events, it is actually either comparable to the drug arm or, in fact, the placebo rates were actually for adverse events, or discontinuation was actually higher. This actually made my life so much easier in clinic, because when I talked about putting somebody with moderate to severe Crohn's disease on biologic therapies, their main concern was it is too scary of a drug. I do not know, I am going to get sick, I am going to get cancer, I am going to get this. I do not want to be on it, but they would rather suffer from their disease, risk surgery, risk being in the hospital, than getting on these medications.

But now I can tell them, if you are worried about this, I have a couple of great drugs here. If you are not on this, you are more likely to have infections, being in the hospital, surgeries, et cetera. We actually have proven it in a randomized clinical double-blinded trial, that you end up having more adverse events getting on placebo, meaning they are not getting their disease under control compared to being on the drug. You actually end up being healthier because your immune system is functioning better. You are actually more of a normal human than getting sick at every single exposure, enteric infections left and right as well.

When I tell them that, I feel like my patients' eyes light up, and going, really? This is actually a safe drug. Yes, that is what I have been telling you. You should be on this medication.

[00:26:06]

Mirikizumab in Moderate to Severe CD (VIVID-1): Impact on Quality of Life and Work Productivity

The other part of this is, I guess, David actually talked to you about all the side effects of the disease, the complications, the stuff that the patients suffer from, the pain, the frequency, the urgency, the bleeding, the anemia, the fatigue, all of this stuff, but all of this is actually contributing to poor quality of life. Patients do not come in telling me they are going to see the GI doctor, telling me I am just miserable. I do not feel good. I think I am depressed. They tell me I am having pain and diarrhea. I have to ask how their quality of life is. They do not tell me, you know what? I did not go on a trip last week because I was having a bit of urgency. They will tell me about their bowel urgency part, but do not tell me about all the life stuff that they missed.

You can see that it is important to look at quality of life measures in any chronic disease mind you but especially, of course, in Crohn's disease. We actually reported that in a lot of these clinical trials, where in the mirikizumab trial, you can see that there were significant improvements across pretty much all these aspects of quality-of-life measurements.

Specifically, my patients and I am concerned about and employers should be concerned about is presenteeism. It is one thing to say I am calling in sick. I cannot make it to work. A lot of our patients are coming into work, but every 5 minutes running to the bathroom because their disease is out of control, but they do not want to call in sick too many times because they might lose their job. That is a big issue in our IBD patients, because otherwise, on the outside, they look completely healthy. They do not look like they are sick. They may look tired, perhaps, but they are having issues in the bathroom. If you see them in the bathroom every 5 minutes, and you are there too because you ate something bad last night, whatever, that is the only time you will know. That is a big issue.

If we can avoid that or minimize presenteeism along with absenteeism and everything else, huge win. Not only for the patient, but for us and society, and healthcare, and general care as well.

[00:28:15]

Guselkumab in Moderate to Severe CD (GRAVITI): Primary Efficacy

Now, going to GRAVITI, which was the guselkumab registrational trial. This was a double-blinded, randomized controlled trial that got this medicine approved. Again, we see 56% clinical remission rates, 41% endoscopic response rates in these patients. Compared to placebo in here, it is 21%, that magic dust of 21% feeling better and healing up as well.

[00:28:41]

Guselkumab in Moderate to Severe CD (GRAVITI): Response by Previous Treatment at WK 48

If you, again, compare the results to bionaive vs intolerant to biologics, this is what I want to focus a little bit on the dosing here. When FDA approved the medication for maintenance, we have the option of 100 mg every 8 weeks SC, or 200 mg every 4 weeks SC. It is not a double-dosing. It is a quadruple difference in dosing here. The question is, well, if you are looking at the patients, who would I prescribe the 100 every 8 weeks to vs the 200 every 4 weeks to? We have an answer here. I am not showing all the detailed information and other data, but key here is that if you are bionaive, more on the moderate side, more moderate of the SES, the endoscopic scoring, they tend to do well on the 100 every-8-week dosing.

But if I have a patient who has been on multiple biologics, they had severe inflammation or high endoscopic score, I am putting them on the 200 every 4-week dosing because the data actually looks much better on those more severe patients. The patients actually failed multiple agents before. That is how I clinically make that decision.

Now, there have been arguments. I think if I talk to all my other IBD colleagues across the US, they will say I just start with everyone on 200 Q4, then I do not have to worry about changing dosing later or getting it re-approved later, et cetera. Some will say I will do 100 every 8. It is convenient for the patient. If they do not respond, then I will move them up.

I am more the middle person where if they are more on the moderate side and first biologic, I will start them 100 every 8 weeks for convenience. The data look good. But if they are on the severe side, if they have failed multiple agents, I am starting them on 200 every 4. Why am I waiting? I have the best data there for those patients.

(00:30:30)

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

Steroid-free remission. Again, you are seeing again slightly higher numerically on the 200 every-4-week dosing, but still significantly higher, about 60%, 65% here of steroid-free remission rates as early as 90 days.

Safety. Again, same component of all the IL-23, same scene that we are seeing here. Generally, lower incidence rates of adverse events with the actual drug compared to placebo. Placebo patients had more adverse events throughout the trial. If you looked at discontinuation, a quarter of your placebo patients discontinued prior to finishing that study, but then those placebo patients moved on to guselkumab during that open-label option. 11% only discontinued.

The highest patients who stayed on the drug were actually the ones who were on the 200-mg arm. Again, showing the benefit of the higher dosing in this patient group.

(00:31:29)

Guselkumab: Additional Patient-Reported Outcomes

Additional reported outcomes such as abdominal pain, stool frequency, and the IBD questionnaire remission. Overall, you are seeing the 100- and 200-mg maintenance dosing better than placebo. In some cases, numerically a little bit higher with the 200-mg maintenance dosing.

Now, you are all experts on IL-23 inhibitors and the safety and efficacy profile, so let us see how you do on the post-test.

[00:32:02]

Posttest 1

After receiving an anti-TNF biologic for 7 years, a patient is having diminished response. Switching to a selective IL-23 inhibitor has been prescribed, but the patient wants to know more about these medicines. What is the best results from the clinical trials for these patients who received selective IL-23 inhibitor after failure on at least one other type of biologic therapy?

I know a lot of you answered previously. Is it correct or not, let us see.

Awesome. You guys were paying attention. I love it. I did not have much to explain. You are already experts anyway. Wonderful. You are absolutely right. With these IL-23 inhibitor agents, one of the highest levels of remission rates I have seen in all of our clinical trials. It is actually amazing to have this option for our patients.

[00:33:08]

          Posttest 1: Rationale

We saw that in the Phase III trial SEQUENCE, VIVID-1, GRAVITI for the risankizumab, the mirikizumab, and the guselkumab data, 51%, 60% achieved clinical remission.

[00:33:21]

Medication Options for CD: Biologic Agents

I talked specifically about the IL-23 inhibitors, but sometimes we may need to consider how to choose. We have lots of options: anti-TNFs, alpha4beta7 integrin inhibitors. We also have JAK inhibitors as well for treating Crohn's disease.

[00:33:40]

Medication Options for IBD

How do we choose? We have the conventional therapy. We reserve it really for the mild disease patients and sometimes to moderate, but we have really been staying away from it because 6-MP is a type. It really has not been proven to be better than the biologic therapies. Plus, we have to monitor labs every 3 months. If their liver enzymes go up, then we have to readjust their dosing.

I do not know how many of you guys are here in Texas, but we have a big problem. Everything is bigger in Texas. Our meals are bigger in Texas. My patients are bigger in Texas. My livers are bigger in Texas. I am still trying to sort out who has metabolic associated fatty liver disease vs drug-related enzyme elevation to alcohol, to everything else. I am tired of monitoring these patients vs the newer agents monitor severe disease. I joke with that. I am never tired of taking care of my patients. That is my life, but I am tired of monitoring labs every 3 months. If it is abnormal, I have to recheck it again and tell my patients, come on, eat better, diet, exercise, lose weight, stop drinking all that alcohol. It is not great for you anyway. Let me recheck your labs. Let me dose adjust, et cetera.

But with the newer agents, actually, it is so much easier. The safety is so much better. I am less worried about monitoring all those labs, the routine stuff that we have to do anyway. But in general, we have all these options. In Crohn's, we only have upadacitinib as our small molecule, but all the others we keep in that moderate to severe category.

[00:35:14]

AGA 2021 Guidelines: Recommendations for Moderate to Severe CD

Based on AGA guidelines, recommendations for moderate to severe Crohn's, biologic drug monotherapy is actually recommended over thiopurine monotherapy for induction of remission because we know they work better. Early introduction of a biologic, either with or without an immunomodulator, is suggested rather than delaying their use until failure, because again, the key is do not step up therapy. If the moderate to severe patient starting with mild agents, do not do that because you are just delaying their disease and making those newer medications less efficacious because they are already getting fibrotic disease, needing surgery, et cetera.

In patients that have Crohn's and active perianal fistulas, I did not even talk about the complex Crohn's patients. You really need to be using biologic agents early, actually in combination with antibiotics to calm down the inflammation. Then just a biologic drug alone. In some cases, we needed anti-TNF with immunomodulators to really aggressively treat them. Otherwise, they were going in and out of operating rooms, seeing colorectal surgery, and then messing up with biologics and trying to adjust them over time.

[00:36:20]

General Considerations for Choosing Therapy in Moderate to Severe CD

Because we have all these options, how do we choose therapy? We have to look into multiple aspects, not just one aspect of it. This is the art of medicine. We look at patient's preference. They prefer IV vs SC. Do they have Medicare? We have to consider IV options vs SC options for them because of the pharmacy benefit arm, et cetera. What is the efficacy between the agents?

We are coexisting conditions, which I will talk about in 1 more slide here. Do I need to continue these medicines in combination with immunomodulators? Are they going to get pregnant anytime soon? I am going to avoid the JAK inhibitors in those patients. They have fistula disease. Really get them on anti-TNFs first before, because we have the best evidence for fistulizing disease for the anti-TNFs.

[00:37:08]

Applying Evidence in Practice: Situation-Specific Recommendations

Specifically, if I have a patient with Crohn's disease and they have another condition such as multiple sclerosis, I am going to avoid anti-TNFs on them. Consider agents that could potentially treat both diseases. They have CHF, lupus, infections. Really avoiding the anti-TNF category.

I talked about pregnancy, avoiding upadacitinib. I feel safe using all the other biological window. We do not have a lot of data because we know IgG placental physiology. They failed prior agents. You want to consider using the newer agents and then go into upadacitinib, but we have great data. If your anti-TNF fail, upadacitinib works well. But we also have data that IL-23 inhibitors work as well.

[00:37:52]

Reflect and Connect: How can selective IL-23 inhibitors promote higher rates of disease remission among patients with CD?

Here, if you have a few minutes to reflect about how selective IL-23 inhibitors promote higher rates of disease remission among patients with Crohn's disease. The next 5 minutes, if you want to put in any thoughts, comments, questions in your iPad, or if you have something you want to ask, feel free to do so.

One question came up here of, what are helpful non-pharmacological therapies for completed Crohn's disease? Is it completed or complex Crohn's? Not really a lot of great non-pharmacological therapies, unfortunately, because not a lot of things have been able to study in our complex patients. What we do know is that the Mediterranean diet is something that we recommend, because that is something that has been studied compared to the simple carbohydrate diet, which is actually a bit more complex to do and a really limited diet, but the Mediterranean diet has been shown to help with symptoms of Crohn's patients. Can I say it helps cure them or heal their lining? Most probably not. But if it can help their symptoms and improve their quality of life, I do recommend that.

Any other thoughts or comments, or questions? Just adding to non-pharmacological stuff. Things like acupuncture has been tested. Helps with symptoms but does not help with healing. Probiotics have been tested, but probiotics play really no role in Crohn's disease either.

Any other thoughts? How will you compare mirikizumab with guselkumab? That is a good question. We unfortunately do not have head-to-head trials between the 3 IL-23 inhibitors. Time will tell. Real-world evidence data will come through. But at this point, I have zero evidence to say that one is better than the other, especially with guselkumab, even though theoretically it blocks the CD64, but we do not know what that means clinically at this time.

Any support programs to help patients with medication costs? Yes. All 3 of those companies, along with all the other biologic companies, do have patient support programs to help with copay costs, and to help bridge them, a bridge program to get started on drug for free while we are getting the insurance approval and all of that. They do that because I think from a physician's perspective, what I hate and I am suffering with my patients, is that we know a drug that is going to work for them, or we suspect it will work for them. We just cannot get the drug on time in the middle of all of this.

They are taking time off work. They are coming in and out of the emergency rooms. They are getting hospitalized. That delay in getting their therapy just messes up their life, their employer's life, everybody else's lives, their kids' lives, family. If we can get them the drug as soon as possible, when I clinically feel it is indicated to get them on the drug while we are sorting out the insurance, it is a huge thing. I need all of your help to get these medicines approved faster so the patients can heal better, so then we are actually reducing all the health care costs down the line, hospitalization, surgeries, multiple visits, et cetera as well.

Does my practice look like clinical trials? For the most part, yes. I do not know where to go with this. Again, my practice is a lot of complex patients have failed multiple agents. In a sense, I do not get to choose. I do not get the patients that never been exposed to biologics. I get the ones that have been exposed to multiple things. I am getting the shortlist of, I only have this or this option left to go for you. I am more in that boat, but other than that, pretty much practice what I preach. I think we probably have to stop right now. You can always ask me questions later after this is over. Thank you.

[00:42:17]

Contemporary Treatment Outcomes and Healthcare Utilization in Moderate to Severe CD

Dr Sheena Crosby (Mayo Clinic): Great talk, guys. Really great information. Thanks for sharing that. During my part of this presentation, I wanted to share with you the contemporary treatment outcomes and health care utilization in moderate to severe Crohn's disease.

[00:42:31]

Estimating the Cost of IBD

The economic burden is very exorbitant with our patients who have Crohn's disease. For instance, patients who have Crohn's disease can experience an annual direct cost of up to $12,000 annually, specific in this specific study. Direct costs, specifically can be hospitalization, surgeries, as well as medication costs. Even ostomy supplies and seeing other healthcare specialists such as rheumatologists, dermatologists, because with our patients, we recommend at least an annual skin check every year due to their higher risk of skin cancers, and even seeing behavioral specialists, and even pharmacists like myself for extra counseling and education about these medications, and to have a conversation about shared-decision making when it comes to what medications will they try out of the recommendations that our providers think will work best for them.

Indirect costs is also something to really consider. As Dr Abraham had mentioned, presenteeism is a real issue in regards to our patients. Are scared to miss work, and they may run out of PTO. They show up, but they may not be at their best self to really work at their best capacity. They may have a reduced capacity of having to run to the bathroom often, missing certain meetings, or just not being fully present.

One in 6 patients report a cost-related medication nonadherence, which is something to really consider too.

[00:44:08]

Financial Toxicity in IBD

Financial toxicity is basically the combination of financial burden and financial distress that affects our patients with inflammatory bowel disease. Risk factors that really increase financial toxicity are lower education levels, lower income, lack of insurance, food insecurities, and having less medical-related savings. They experience financial hardships, and they have higher healthcare costs. With that, they had the worst 5-year health-related IBD-specific quality of life. It is very important that we address the morbidity that is associated with the decrease in quality of life and every aspect of our patients' lives.

[00:44:49]

Economic Impact of Crohn’s Disease Flares

In this specific 2019 National Health and Wellness US survey, Dr Choi had briefly touched upon this, that these patients who had Crohn's disease but were not being treated for it. They were broken up into different subgroups: infrequent, intermediate, and those who had frequent flares.

Two-thirds of these patients actually were the ones that had intermediate or frequent flares out of the group of patients who actually self-reported that they had mild disease, which is really interesting. Very important to consider how much healthcare utilization is even reported with these patients who think they have mild disease but may not actually have, may have more severe disease.

[00:45:37]

Direct Costs of CD Flares: Healthcare Utilization

In this same analysis, you can see here that as you move towards more increased risk of flares or increased frequency of flares, you use more healthcare utilization, so more increased visits to the gastroenterologist, more frequent ER visits, and more risk of being hospitalized.

[00:46:00]

Indirect Costs of CD Flares: Work Impairment

Indirect costs are also increased, so the total work productivity is impaired. Presenteeism, which we briefly touched upon, was both statistically significant in affecting our patients, especially those who had more of an intermediate or increased severity of flares.

Important to note here, specifically in this study, how important it is to get our patients into remission who have Crohn's disease, as well as ulcerative colitis in general. But specifically for these patients in this specific study, patients who were in Crohn's disease remission had as high as 50%, had lower health care resource utilization, and also had at least one less health care visit per year compared to those who were not in remission.

[00:46:18]

CD Remission Impact on Healthcare Resource Utilization

Important to note here that, specifically on the right-hand side, those who were not in remission had a 50% or higher chance of needing a surgery within those 12 months. Very important to get our patients into clinical remission, as well as endoscopic remission.

[00:47:12]

Posttest 2

Posttest 2 question. Your organization is trying to decide whether incorporating another biologic for Crohn's disease into its formulary, to provide more patient options, could provide direct economic benefit. Which of the following would provide the most accurate data for the decision?

Correct. Compared with patients in remission, patients not in remission are about twice as likely to undergo surgery over the course of one year.

[00:48:01]

          Posttest 2: Rationale

That was according to the Adelphi Real World IBD Disease Specific Program data.

[00:48:09]

Indicators of Suboptimal Biologic Therapy for CD

This is also a very interesting information that was found in regards to indicators of suboptimal biologic therapy for Crohn's disease. It is very common with our patients that when we start them off at standard therapy or standard FDA-approved therapy, that they have a high rate of having suboptimal therapy, either having a loss of response primarily and not responding to the medication in the beginning, or they may respond to it initially, but then may lose response over time.

It is very common for us to optimize medication to get ahead of those symptoms and get ahead of healing so that we can avoid, A, not being able to fully optimize the drug that they are completely on, because we do have limited resources in regards to medications that we have for treatment. As Dr Choi and Dr Abraham said, with our patient population, oftentimes when they come to our centers, they have tried multiple different agents. The amount of options that we have can be pretty limited.

But suboptimal biologic therapy often leads to dose adjustments. Either that could be a dose frequency change, where we can narrow the frequency compared to the standard recommended maintenance therapy; therapeutic augmentation, which means that we can add additional drugs to that specific therapy, whether it be certain immunomodulators like Thiopurine, 6-mercaptopurine, or even methotrexate, as well as even steroids, which we will go into in just a little bit. Therapy changes as well as discontinuation of the drug.

This specific retrospective analysis does show that our patients have a higher rate of suboptimal biologic therapy issues.

If you see on this left-hand side of this table, you can see as high as 91% of patients in this specific study had at least one indicator of suboptimal therapy that we mentioned. That was as of 36 months after starting a biologic therapy. After that, about 62% of those who were at 36 months had a risk of discontinuation, and about 50% of those patients at 36 months had a risk of augmentation, and having to add another medication in addition to those biologic therapies.

[00:50:38]

Patients with Suboptimal Therapy May Rely on Corticosteroid Use

Suboptimal therapy can also lead to steroid use, as I briefly mentioned. Do not get me wrong, steroid use when used short-term, especially in someone who is in a flare, is very important, especially if we need to get their symptoms under control and we need to hopefully avoid having them to be admitted to the ER or into the hospital, and having further complications from that standpoint.

But we do not want to solely rely on steroid use long-term because that can increase the risk of many different adverse effects, not only increased risk of opportunistic infections, osteoporosis and bone loss, even adrenal axis suppression, insomnia, which can also affect their quality of life and work productivity, and even blood sugar issues, blood sugar elevation, blood pressure elevation, cataracts, glaucoma. It runs the gamut. Weight gain.

Ideally, we want to get our patients started on an advanced therapy, such as a biologic or small molecule, and help spare having to use a steroid long term.

[00:51:46]

Anti-TNF Therapies Are Commonly Used for CD

Anti-TNF therapy, such as infliximab and adalimumab, are commonly used for Crohn's disease, and they have been around for many years. They have improved treatment of IBD, and approximately 60% of our patients with IBD experience a rapid disease remission, high rate of mucosal healing, and improved quality of life. But up to 40% of our patients with IBD did not respond to anti-TNF induction therapy in clinical trials. Approximately 50% of those patients have a primary response, but then may lose response eventually later on. They are secondary non-responders.

[00:52:24]

Proposed Safety Hierarchy of FDA-Approved Biologic and Small Molecule Therapies

I often go through this triangle with my patients as I have a pharmacist consultation, to help them, A, try to start therapy, or B, let us consider other options, because we do have a lot of patients who are reluctant to start therapy as they read that package insert and they see all the different side effects. Having that pharmacist consultation is really helpful to help put those side effects into perspective.

When you look at this triangle, this is called the safety triangle of advanced therapies, and includes both small molecules and biologics. It is organized from, at the very top, our most safest classes of medication. Specifically, at the top rectangle there, you can see the anti-interleukins, which also include the medications that Dr Abraham had included. Then as you move down towards that triangle, you run into other options that, yes, work great, but they may have a higher risk of side effects, and may also need additional monitoring. Additional use of healthcare utilization.

As you get down to the bottom, that is where you have the steroids. That is more so a risk of chronic steroid use. Ideally, we want to get our patients on therapy, to get them into clinical and endoscopic remission, and help them maintain that.

Like was briefly mentioned earlier as well, is that we also have to consider different patient populations and why we may pick certain therapies for our patients as well. There may be patients who may have heart failure or moderate to severe heart failure. We may not be able to consider something like an anti-TNF agent. I have had patients who have had concomitant cancers that they are being treated for with chemotherapy, but also have active inflammatory bowel disease. We may need to choose something that is higher up in this triangle with less risk of side effects. That can be safer for them to also treat their inflammatory bowel disease, allow them to heal that, but also allow them to be treated for their active cancers. Those are just some different options.

Even with my patients who are older and maybe at higher risk of opportunistic infections, choosing one of these medications that are higher in this triangle, are great options for them. Definitely, it is nuanced in regards to how we pick medications. Hopefully, when we write those letters of medical necessity, it can help paint that picture of why we specifically need this drug compared to some other drug that is on formulary.

[00:55:06]

Reflect and Connect

Let us reflect and connect. How have you assessed the economic impacts of suboptimal Crohn's disease treatments in your healthcare population? Feel free to speak out loud, discuss amongst yourselves, or put it in the chat box. Any questions?

Speaker: When you say suboptimal, is there a way to mitigate against that by just starting out more aggressively, or a suboptimal? Meanwhile, I made the best clinical decision I could at the time I made it, but the patient just did not do as good as one would have hoped.

Dr Crosby: That is a great question. Absolutely. We have to start off with the standard dosing of what is FDA-approved dosing. A big roadblock that we run into is when we need to optimize therapy is, will it be covered? Oftentimes, we need to provide additional evidence-based literature to support the use of why we are optimizing, for instance, ustekinumab every 8 weeks to every 6 or every 4 weeks. I have been seeing a lot of denials with that as well. That can take a long time to get approved.

With some of my patients, it can take, after multiple appeals, sometimes up to a couple of months. When you think about a couple of months, that leaves that patient at risk of developing further issues in terms of flares and bleeding and nutrient deficiencies, and their disease progressing. Great question.

Speaker: [Inaudible].

Dr Crosby: Absolutely. Yes. Definitely. In my practice, we are in support of biosimilars. They are just as safe and just as effective. They are FDA-approved to be just as safe and as effective as the parent drug. If it is going to help with healthcare costs, both from the payer side as well as trickle down to the patient side, we are all for it. We just want to make sure we get our patients on therapy and stay on therapy. Great question. Anybody else? Okay.

[00:58:06]

Managed Care Strategies to Decrease Economic Impact and Disease Burden of Moderate to Severe CD

Dr Choi: Was there another question or comment? We are going to be pivoting the conversation now to talk about Managed Care Strategies to Decrease Economic Impact and Disease Burden of Moderate to Severe Crohn's Disease. Through this section, we will actually be talking a little bit about the questions that were in here. I am really excited to be able to answer some of those questions and talk a little bit deeper with that.

(00:58:29)

Patient Perspective Video: My CD Treatment Journey – Contending With Treatment Failure

Going back to our patient, let us talk about the patient's journey, about what to do with the treatment failure, and how to contend with that.

Emily Bennett: Unfortunately, as does happen sometimes, I developed a resistance to this TNF blocker, which was relatively unfortunate. It had served me well over the years. My provider and I had to begin searching for something else that would be different enough, but still be able to support me and control my symptoms.

Unfortunately, during this transitional period, it was a little difficult because I was also transitioning to a different insurance. Of course, as many people know, Crohn's treatments are pretty high class or schedule of drugs. They can be pretty difficult sometimes to find coverage for.

I, unfortunately, got locked in this who is on first, if you will, a back and forth between my insurance company, my doctor's office, trying to sort out things like prior authorizations and all the sort of paperwork that has to go into actually accessing your treatment.

Of course, for somebody like me who needs their drugs pretty consistently, I did not have a backup supply of these drugs. Even then, they were not helping me anymore. I was basically in this in-between period where I was not receiving treatment, and I was not exactly sure when my next treatment was going to come. It was pretty scary, pretty stressful. But luckily, I have a really wonderful provider. They held my hand through all of this. I was able to get access to my medication, get access to my treatment, and start building those properties back up within my system.

Now, I am back to living my life, back to enjoying a relatively normal. I will not say carefree life, but at least able to do all the things that I need to do without interruption from my disease. Overall, a relatively happy ending.

[01:01:08]

STRIDE-II: Dynamic Treat to Target

Dr Choi: All right. I think that really showcased the importance of staying on therapy, getting on the right therapy, as well as that quality of life that we talked about earlier.

One of the questions that came up pretty frequently is how do we know if a patient is on suboptimal therapy? Or how do we know when to call it quits with the therapy? When it comes to disease states like hypertension, diabetes, that is pretty well known. We have very clear blood pressure goals. We have very clear A1C goals. We start therapy. We repeat. If they are not controlled, we make treatment modifications. Repeat those again until the patients get to the target goal of A1c and blood pressure.

The same principles can be applied to inflammatory bowel disease. That is through something we call the STRIDE-II guidelines, which is the dynamic treat-to-target approach that we think about with patients with inflammatory bowel disease.

What that really means is when we have a patient with active disease, we will choose the right drug for the right patient and initiate that therapy for the patient. There is various targets that we are aiming for throughout this purpose. Once again, the ultimate goal is making sure that patients are in clinical endoscopic remission with a normal quality of life. But the targets we are aiming for are the immediate targets, the intermediate targets, and the long-term targets.

What the immediate target means is, is the patient responding to the medication? Symptomatically, are we seeing improvement with this therapy being added? The intermediate goal is, are the patient's symptoms now in remission? But can we use objective markers to ensure, yes, inflammation is improving? The 2 that we utilize in clinical practice is a C-reactive protein that measures how much inflammation is in the blood, but more importantly, a fecal calprotectin that measures how much inflammation is in their stool. Those are objective markers that can tell us, yes, the patient is, in fact, responding to therapy.

Once we get that, the long-term goal, once again, is that clinical endoscopic remission, as well as the improved or normalization of quality of life. If at any point, they are not hitting the target, we need to go back to the therapy and evaluate, is this the right therapy for the patient? Is this the right dose for the patient? Make the change and redo the treat-to-target approach. That is how we know if a patient is on a suboptimal therapy and if a therapy change needs to be made.

We follow, as our guidelines, the treat-to-target approach. If you go to all the GI conferences, you will hear everyone talking about the treat-to-target approach, to making sure, once again, we are getting our patients into remission.

[01:03:36]

          CALM Trial

Does the treat-to-target approach work? Does this use of biomarkers actually improve outcomes? The answer is yes.

This is the CALM trial, which is a prospective trial that was done, that specifically compared endoscopic and clinical remission or outcomes in patients with moderate to severe Crohn's disease. They were stratified into 2 groups. We had the tight control algorithm that used clinical symptoms, as well as biomarkers vs just normal clinical management.

When they compared the 2 groups, what they found was there was a profound benefit of using the tight control arm or using the biomarker-driven approach, showing that we were actually able to have higher rates of mucosal healing when we use this tight control treat-to-target approach, as well as steroid-free remission as well when we utilize this, once again, treat-to-target high tide control approach.

The clinical implications are, once again, using clinical symptoms with objective biomarkers, we can actually improve outcomes in patients with Crohn's disease and getting them into that long-term target of remission.

[01:04:35]

Goals and Timelines for Moderate to Severe CD

One of the questions that I think patients ask a lot, and this is something that we specifically talk to patients for a very long time, is what are we trying to accomplish? What are our goals? What are our timeline? What are our expectations?

Once again, our goals are 3. One, get you into clinical remission. Two, get you into endoscopic remission. Three, normalize your quality of life. Four, I should say, no steroids. Those are the 4 goals that we are aiming for, for our patients.

When we think about the clinical remission, the symptomatic improvement, I will say this varies on the drug. Some medications work faster than others. We have to tailor it to the medication. But as a whole, we will say about 3 to 6 months. Three to 6 months is an adequate amount of period for us to figure out are you responding to this medication symptomatically.

Biomarkers as well. Normalization, once again, of that C-reactive protein in the blood and the fecal calprotectin are absolutely key. At the University of Chicago for interleukin-23 patients, we actually will repeat a fecal calprotectin in CRP at the 12-week or 3-month mark, as well as the 6-month mark, because once again, our goal is to make sure that they are, in fact, going to that long-term remission.

Ultimately, endoscopic remission is our next important point. If their disease is beyond what gastronomists are able to do with endoscopy, we may rely on imaging as well. Those are CT, MRI as well as intestinal ultrasound. That is something we have been incorporating at the University of Chicago to, once again, reassess healing as well as remission.

The practical implications are, once again, we are going to use symptoms. We are going to use biomarkers. We are going to use endoscopy and imaging to make sure our patients are, in fact, going to the long-term treatment goal of clinical and endoscopic remission.

[01:06:19]

Support for Early Use of Biologic Therapies in CD

Now that we know the treat-to-target approach of how do we evaluate suboptimal use, how do we ensure patients are on the right track, the question becomes, and Dr Abraham talked about this earlier with the guidelines is, does timing of the advanced IBD therapy matter? Does timing matter? The answer is yes. When we look at a meta-analysis, that broke patients down into 2 groups, the early initiation, which is really less than or equal to 2 years from diagnosis, or the late group, which is greater than 2 years from diagnosis.

What we found was that the early use of biologic therapy was associated with significantly higher rates of clinical remission, lower relapse rates, higher mucosal healing rates. This really comes down to the fundamental understanding of a step-up therapy approach vs a top-down therapy approach.

Step-up therapy is asking patients to try conventional therapies first. They have to show that they failed it, and then you step up to the advanced IV therapies. While the top-down approach is the right drug for the right patient, and then making sure we are initiating that early.

A specific prospective longitudinal cohort at 34 US centers found that, once again, when comparing early vs late initiation, that the late initiation was associated with significantly higher rates of surgery. More patients needed surgery, and more patients had disease progression.

What that means are patients who start therapy later are at higher risk for lower rates of clinical remission, higher relapse rates, lower mucosal healing rates, higher surgery, higher risk for disease progression. So yes, timing of the advanced IV therapies is very important when we think about treating our patients with Crohn's disease.

[01:08:02]

Posttest 3

This brings us to our post-test question number 3. In patients with moderate to severe Crohn's disease, starting biologic greater than 2 years after diagnosis, compared with sooner after diagnosis, is associated with…

1. Higher relapse rates and similar rates of mucosal healing;
2. Higher relapse rates and higher risk of surgery;
3. Lower clinical remission rates and similar risk for surgery;
4. Lower clinical remission rates and similar rates of mucosal healing.

The correct answer here is B, higher relapse rates and higher risk for surgery. What we saw was based off the meta-analysis, as well as the prospective trials that really the late initiation of therapy has been associated with that higher relapse rate, higher risk for surgery, and just more disease progression as well.

[01:09:09]

Challenges of Treat to Target in IBD

We know that these therapies are effective. These are something that timing matters. We want to follow the treat-to-target approach to make sure we are optimally treating our patients to get them into that deep remission. What are some of the challenges and barriers we encounter on a day-to-day basis of getting the patients the care that they need?

There are many examples. We hear some of the 4 big ones. The first one is a lack of insurance coverage for advanced diabetes therapies. Second, due to the lack of coverage or sometimes the prior authorization process, there is an increased administrative burden due to prior authorizations. The increased need for clinical monitoring and patient follow-up, as well as personnel constraints, and not having the dedicated staff to, one, be able to navigate patients through this process, but 2, being able to actually follow the treat-to-target approach.

[01:09:55]

CD Treatment Delays: Associated Challenges

With that being said, we are going to delve into the first one that talks about the treatment delays associated with the current prior authorization process.

Here is a 2022 provider survey in which half the respondents reported that PAs are universally required with initiating a biologic therapy. More so, greater than 50% said that there needs to be further healthcare involvement of doing peer-to-peers, as well as written appeals, because of denials associated with the prior authorization process. The thing that is very important to see, though, is 97% reported increased PA-related burnout due to increased PA clinical burden.

What this leads to is treatment abandonment, not being able to pursue the therapies for patients, as well as just burnout from clinician of being able to use the therapies that are needed for a patient.

More so, when they did the survey in patients with IBD, what they found was over 50%, the majority of patients, once again, experienced problems accessing medication because of insurance. Going back to our patient, Emily, and her journey, we talked about how there was a gap in therapy, and the patient was scared of flaring, losing response, having progression, kind of things along those lines. Ultimately, that will lead to treatment abandonment, not adherence from patients as well. That leads to disease progression and complications from that standpoint.

[01:11:14]

What Contributes to Treatment Delay?

What contributes to treatment delay? There are a myriad of factors that were identified in studies. Some of the things they looked at were clinical, social, and financial barriers that specifically led to treatment delays. The median delay in initiating biologic therapy in the current literature is found to be about 20 days. It takes 20 days from being able to get our patients on therapy that they need.

Longer delays were observed for certain groups, such as Black patients, patients located greater than 50 miles away from a care center, as well as patients who require an appeal for their treatment, i.e., the prior authorization was denied. Those all specifically were factors that led to significantly increased delays. The type of payer and the route of administration were also found to influence rates of delay, showing that patients with commercial insurance actually were more likely to experience delays, as well as IV agents more likely to be associated with delays vs self-injections, as well as oral therapies.

[01:12:09]

Factors Associated With Delays in Starting Advanced IBD Therapies

This is a really interesting study that was published earlier this year, that specifically looked at factors associated with delays in starting advanced IBD therapies. This was a retrospective study at 2 large gastroenterology academic centers. I do want to note, one of those sites had a dedicated pharmacy team. The other did not.

What they actually found was they looked at patients who had no delays in initiation of therapy or had a delay. That was defined by 14 days or 2 weeks. Patients who could start therapy within 2 weeks, or patients took longer than 2 weeks to get started on therapy.

What they found was the majority of patients, all had delays in terms of starting therapy, and it was significantly delayed. These are important considerations because these delays, once again, can lead to treatment abandonment, because patients just give up hope of using these medications. The clinician team burns out. These delays can actually have profound impacts on it.

More importantly, when they looked at the predictors of delay, they actually found something very interesting. Having a dedicated pharmacy team actually led to less delays, improved access to these therapies, as well as intravenous delivery. IV ended up becoming a predictor of delay, as well as the type of insurance.

One thing you will see in the bottom right is when we look at the insurance delays, it really has to do with denials and appeals being the biggest contender for the delaying process.

[01:13:33]

Managed Care Strategies

When we think about these therapies, someone made this comment as well, we know that the advanced IBD therapies are very expensive. These are expensive medications. We are not a country of unlimited resources, so cost containment, cost effective use is definitely a consideration we need to take into place. However, the one thing I will say is when we think about the various payer management strategies that are being utilized, although in theory makes sense, leads to a significant burden on the care team as well as the patients, for gaining the therapies that they need.

I think with prior authorizations or step therapy, this is something we are all very aware of. But something that we think about is a lot of times, these go against the guideline recommendations. The requirement of doing step therapy or step-up therapy is against what we know with the literature of getting patients into remission faster, making sure that we are able to prevent those complications later on.

More recently, we have been encountering quantity limit issues, where it limits the dispensing of medication per year. Unfortunately, this has become a huge burden for us to actually keep patients on therapy because, in particular, the problem we have is we do not know what the quantity limits are. We only know at the time it dispensed. A patient is trying to go for a refill and also we get a message from the patient saying, “Hey, I am being told I cannot refill this medication”. At that point, we are urgently trying to submit a quantity limit prior authorization at that time, which then the insurance company sees the PA on file for the drug, tells us it is approved, that no quantity limit P is needed, then go back. The pharmacy then tells us the quantity limit P is needed. So we have to contact the insurance again to submit a quantity limit PA.

They get confused. We need to ask to a supervisor finally get one submitted. At that point, it has been 2 weeks. Patient has been missing their doses for about 2 weeks, and putting them at risk for flare. I think the quantity limits is something we are struggling with a little bit, especially over the past 1 to 2 years.

Re-authorization, once again, makes sense. You want to make sure patients are not on suboptimal therapy, that they are responding. But sometimes when we run into problems with re-authorization in terms of patients who do amazing, they are doing well on the drug, but it gets denied for a dosing reason or something, can lead to significant delays as well.

Split-fill is not something we really encountered in the IBD setting, as well as the clinical pathways as well.

[01:15:44]

Value-Based Care in Inflammatory Bowel Disease

Thinking about the cost containment strategies. Once again, we realize these are very expensive medications. We need to be mindful of costs in use. One of the pivots away is what about if we use some kind of value-based care in inflammatory bowel disease? What that means is the right drug, for the right patient, at the right time. From there, being able to do the shared-decision making, identifying the best and optimal therapy for the patient, where they will be adherent to that because of the route of administration, and doing the treat-to-target approach to making sure that we are, in fact, getting patients into remission.

If we were to transition away from necessarily cost containment strategies that is causing burden to the clinicians, to the patients, to a value-based care model, that is something that would be a potential solution to help the burnout.

[01:16:35]

Pharmacist Practice Model

One example I wanted to give is the pharmacist practice model we currently utilize at University of Chicago Medicine. We saw the barriers that currently exist in terms of getting the patients the therapies that they need. We have been using the pharmacy to help fill in the gaps, you could say. The way that it works is the IBD care team would place a referral. That referral will then notify our pharmacy team by going into a centralized intake queue where a pharmacy technician runs insurance benefits, make sure patients have active insurance. Run a test claim. See if a prior authorization is needed.

If it is, another pharmacy technician will submit that prior authorization on behalf of the provider team. Include chart notes. Answer the questions. If the prior authorization gets denied, our pharmacy team will handle the appeals process. We will do the letters of medical necessity on behalf of our providers. Once it is approved, the pharmacist will then make sure that all baseline labs are completed. We are doing comprehensive medication reconciliation. We are looking for drug interactions, make a recommendation for inappropriate drug use, things along those lines.

Once again, also providing comprehensive patient education, which means how do you take it? How do you store it? How do you administer it? What are some of the side effects to look out for? What are some of the concerns that may limit adherence to this medication? From there, the patient will actually enter a pharmacist direct to treat-to-target, where pharmacists will follow along, make sure that the patients are in fact, going towards that remission that we talked about.

[01:18:02]

Pharmacists Management Strategies for IBD

Beyond access to therapy, there are additional roles that pharmacists can have, once again, improving care for patients with IBD. This is reviewing the appropriate dosing, so making sure patients are adherent. We are monitoring the patient as well. That comprehensive education on therapeutic expectations. The number one question patients have is when should this start working and how do I know? At what point do we decide this is not working and we move on to the next drug? Those are some of the really important things to talk about.

Development of therapeutic pathways, assessing appropriateness for biosimilars, and switching patients over to biosimilars is an absolutely key role that pharmacy can play. Adverse event identification mitigation, IBD symptom assessments, as well as treatment, and making recommendations to the care team of making changes to therapy and things along those lines.

Ultimately, Dr Abraham was talking about this as well, assisting in financial assistance for drug acquisition. In particular, making sure our patients can afford these therapies, are very key. That is something that our pharmacy team takes on, on behalf of the provider, because we do not want patients to be nonadherent because of the cost of these medications.

This brings me to my last slide.

[01:19:12]

Improving Collaboration Across Stakeholders: Reducing Financial Toxicity for Patients

We talked about the clinical burdens of the current prior authorization process. Some of the prior management strategies that are in place, which once again, from a theoretical standpoint, makes sense. Cost containment, cost effectiveness is an important consideration. But is there a way to better improve this process that can decrease that 97% clinical burden, as well as the issues there?

What this means is engaging the healthcare team, the patient, and the provider to working together and having collaboration to really help our patients get the therapies that they need. Between the healthcare provider as well as the patient, that shared decision-making, including the patient in that journey, talking about potential barriers and things along those lines.

A direct line of communication between the healthcare team as well as the payer, to really going over what are the benefits? What are the risks of these therapies? Someone mentioned in the comments, are there ICER models available to look at cost effectiveness of these medications?

Maybe that is something we could collaborate on because that is something that would be helpful for us to know. It is just this collaboration of, can we figure out a better strategy of getting the patients the therapy that they need? Because at the end of the day, it really is about the right drug, for the right patient, at the right time.