Now, I'm kind of taking a little bit of a shift, right? And instead of doing a complete pharmacology overview, and last year we did a very extensive discussion just on inflammatory bowel disease, I've been challenged and given the grand charge, is what I should say, in just talking more about an update in IBD. So we're gonna do a 2024 IBD pharmacology update. Here are my disclosures. And our goals, of course, for this section to identify differentiating features of inflammatory bowel disease. So just do a quick overview, I know we really haven't discussed that during the last two days. Provide an update on new IBD pharmacological treatments, because they are changing, right? They're moving fast. Discuss the integration of biosimilars, and of course, explore updates on IBD safety. With that, here's a brief of IBD, right? We understand it's an inflammatory bowel disease and consisting of two subtypes. We have Crohn's disease and ulcerative colitis, right? Most recent studies estimate anywhere between 1.6 and 3.1 million Americans suffer from IBD. Approximately two to 28% of patients have another family member with IBD, and families frequently share the same pattern of disease. I found that a very interesting statistic, I wanted to bring that up. The diagnosis is usually made in the second and fourth decades of life, and is also noted to increase in the sixth decade. Even though I must tell you in my clinical practice, I am seeing IBD diagnosed more and more in our more mature population, or I would have to say elderly population, more than I've ever seen in the past. And IBD remains a significant cost to the US health system. So let's talk a little bit about differentiating features between Crohn's disease and ulcerative colitis. So then you can see here on the slide, there's a difference between location, inflammatory patterns, symptoms, and of course, extraintestinal manifestations. And the reason I bring this up is because this actually really does help guide some of our management tools, and in helping deciding what is the right therapy, right? We know that there are some therapies that are approved for Crohn's disease, and some that are approved for ulcerative colitis. So in Crohn's disease, remember, this is an inflammatory disease that occurs from the mouth to the anus, the entire GI tract. The terminal ileum is the most common location, as we just talked about. Rectal sparing, which means that the rectum is usually not involved, but this does not, and again, there's a differentiation between rectal sparing and perianal involvement. Usually there is perianal involvement when it comes to Crohn's disease, or can be perianal involvement, forgive me. With that being said, we recognize that Crohn's disease has patchy pattern of disease, as you can see by the image over here on the left-hand side of the screen, right? There's patchy or skipped lesions that we can see. Our common symptoms are usually right lower quadrant pain, weight loss, fatigue, diarrhea, malnutrition in our pediatric patients. And of course, they may have bloody stools, but they also may not. And we look at complications, these definitely differ between the two disease processes, between abscess, fistula, stricture, and of course, obstruction. We're going to save extra intestinal manifestations till the end. But how about ulcerative colitis, right? We know that this is isolated just to the colon. We always know that there is rectal involvement, and it's very uncommon to have any perianal involvement. So if you see perianal involvement, I usually shift my diagnosis over to Crohn's disease. When we look, of course, at the inflammatory pattern of ulcerative colitis, it's continuous, circumferential, right? Usually starts in the distal rectum and works its way proximally, right? So think about that when you're thinking about where the disease lives. Location is important. The number one or kind of most common symptoms, of course, usually hematochesia, right? Bloody stools, increase in bowel frequency, urgency, and left lower quadrant pain, along with tinnitus. So you can see there's a little, there's definitely a difference in symptoms. And again, think about where that disease lives, and of course, how it manifests. We think about complications, toxic megacolon, hemorrhage, and of course, perforation. What about extra intestinal manifestations? Now, what I want to point out here is that the extra intestinal manifestations that are listed can occur in either forms of inflammatory bowel disease, right? So they don't always have to be mutually exclusive, but they're categorized according to higher incidence of higher prevalence in each disease state. So for Crohn's disease, we've got erythema nodosum, iritis, uveitis, arthritis, or aptus ulcers. Again, I usually always ask to look inside their mouth. But how about ulcerative colitis, pyoderma gangrenosum, primary sclerosing cholangitis, which I know we had a great lecture on earlier today as well. All right, with that, let's talk about the guiding principles in IBD management. With that, we talk about risk stratification. So how do we decide which patients, of course, are at higher risk for progression of disease? And first and foremost, we look at that high risk progression. So those patients who are over the age of 40, who have extensive anatomic involvement, that they have a male score of three, that they have deep ulcers, low albumin, that they have, of course, an elevated CRP or SED rate, and of course, hospitalization. And the reason I just want to point out more of the high risk stratification is because we want to know how we manage, of course, our moderate to severe patients. We recognize that they're at lower risk for progression. These are the patients, of course, that we can watch. And of course, still need to be treated. But again, we want to talk more about rapid progression here. So we talk about disease activity. And I think some of the hot topics is how do we determine if a patient has mild, moderate to severe, or fulminant disease? And I think that this is a great table that really will help us as providers determine where does our patient actually fall into disease activity index? And I believe that this would, I would just refer back to it. So it's something that you can utilize. I use a modified male score in my own clinic. And again, my patients are aware of what that is as well. And again, I think that this kind of gives you a guidance as to where do we need to work in our treatment paradigm, but also if you're in a fulminant, if you have a patient with fulminant disease, this patient needs to be managed quicker, right? And what about risk stratification for Crohn's disease, right? So again, we look at our low risk, again, were they diagnosed over 30? Do they have limited anatomic involvement? No evidence of perianal disease, superficial ulcers, no surgeries, and no, that phenotype of course is not suggestive of stricturing or penetrating behavior. And how about high risk of progression? Again, under the age of 30 diagnosis, extensive anatomic involvement. So if it's terminal ileum and up, or if they have terminal ileum, colonic, perianal, that's what we're talking about. Do they have perianal and severe rectal disease, deep alterations, prior surgical resection, and of course, stricturing and or penetrating behavior. We talk about Crohn's disease activity index, how is it usually evaluated? And again, this is the score that's utilized when we look at some of the studies, I think it's important to recognize what does, what is that made of? Again, this is a great reference to have as well. So look at Crohn's disease activity index, number of liquid stools for a total of seven days, abdominal pain, generalized wellbeing, do they have extra intestinal complications? Are they using, of course, any type of Imodium or antidiarrheal agents? Do they have abdominal MAF? Any decrease in their hemoglobin? And then of course, any deviation of weight. And you can look here with that Crohn's disease activity index scores, of course, helps you determine do they have moderate to mild disease, moderate to severe, or do they have fulminant disease? And again, these fulminant patients, of course, need more aggressive type of therapeutic response. With that, treatment, of course, is important early on in disease. And this, of course, is one of my most favorite slides, and I had to, of course, put it in. So what we're looking here is digestive damage, right? And of course, inflammatory activity. And this is in a perceived Crohn's patient specifically. But as you can see over time, we see there's an increase with that inflammatory activity and digestive damage that occurs. And we can see that very early in the disease is our window of opportunity, of course, to intervene, so that when we look at the right-hand side, right, we can see here that we hopefully change the outcome or change the course of this disease by preventing the complications of abscess and fistula surgery and even stricture. Now, there are similar principles hypothesized in UC, but again, not totally clear. But again, the idea here is getting to that window of opportunity. I think back in the day, even when I was starting in practice, it was always like make a patient earn their medication, right, they had to like move up the chain, they had to fail things. We recognize that that is not the reason, that is not the way, sorry, that we should be monitoring our patients. We know that early in treatment is important because we want to, of course, change the course of this disease. All right, so 2024 pharmacology updates. And you can see here, look at our toolbox, right? Jeez, it's like almost overflowing at this point in time. I remember back in the day, I can only take about two tools out, right? Now we've got this toolbox, it's getting filled up, there's more and more tools, and we've got so many to choose from, which I think actually is relatively exciting. And just for the merits of this presentation, we are only going to be talking about the updates, so the newer therapies, or if there are new indications as well. With all of this, so IL-23, right? That's kind of our newer class. So IL-23 is a part of the inflammatory cascade. It amplifies the T helper 17 cells, which then leads to a release, of course, of interleukin-17. Interleukin-17 is involved in recruiting neutrophils to the mucosa, subsequently then resulting in inflammation, and of course, tissue damage. So our most newest, and of course, 2024 update, our first interleukin IL-23 that was approved for the induction and maintenance of alterative colitis in adults. Our induction is 300 milligrams IV at weeks zero, four, and eight. Maintenance dose are 200 milligrams sub-Q, and by the way, these are two 100 milligram pens that are given at week 12, and then every four weeks after that. As mentioned before, we talked about the importance of IL-23. So what is mirakizumab, and how does the mechanism of action? The monoclonal antibody that selectively binds the P19 subunit of IL-23 cytokines, and inhibits its interaction with the IL-23 receptor. Then, of course, inhibits the release of those pro-inflammatory cytokines, and of course, the chemokines, right? So, turns it off before it gets to the intestine. Side effects are very common of our other IL-23s that we've seen as well, URI, arthralgia, rash, headache, injection site reaction, and herpes viral infection as well. Prior to starting therapy, this is what you need, right? CBC, LFTs, I still do hepatitis B and TB screening for all of my patients. During therapy, I wanna make note that LFTs should be checked during induction at least up to 24 weeks post, and then I always do routine labs of CBC and LFTs and renal function every six months, and I do an annual TB quantifier and goals. How about our considerations for this? Of course, low risk of infection and malignancy, even though I do show you a slide, of course, I have some selected safety information here. Low immunogenicity rate, should be used as model therapy, no drug interactions, and of course, they're the half-life of 9.3 days. So, let's look at the studies, and I think this is important. As advanced practice providers, we should know what these studies are that led to, of course, the efficacy, and of course, approval. So, this is called LUCENT-1. This is the induction study for ulcerative colitis, right? So, our baseline patients here, just so you know, the median male score, and we kind of reviewed a little bit of that earlier, was seven, so these are moderate to severe patients. 57% were biologic and JAK-naive, 41% had prior biologic failure, 3% had JAK failure, and 2% were exposed, but maybe not considered a failure to a biologic or a JAK. What we see here, of course, is that induction therapy, we had clinical remission in 24% versus 13% in our placebo arm, and clinical response, just so that we all know, is a two or more point reduction and a 30% decrease in their baseline rectal bleeding sub-score, right? So, that's, of course, what we wanted to see. What we can see here on the bottom, of course, is the percentage of patients who ended up having remission of symptoms, and again, the definition of remission of symptoms was a decrease in their stool frequency sub-score of zero or a sub-score of one, and of course, their rectal bleeding sub-score of zero. Now, we all know Mirakizumab has come out with this bowel urgency, so what I also wanted to point out in the bottom right-hand side of the slide is, of course, a change in bowel urgency, and again, we're looking for a range of bowel urgency of zero or one, and that, of course, is what they were looking for when it comes to improvement as well. So, how about their maintenance study? Because we want to make sure it doesn't work, but does it continue to work, right? So, we clearly see here is our clinical remission, and again, that should be a Mayo score of zero or one, just so you know, and again, we can see here almost 50%, 49.9% of patients been in clinical remission versus 25% are placebo-armed. What I do want to point out is that in the Mirakizumab trials is that they met all of their secondary, the endpoints, the five major secondary endpoints, as you can see listed as well. We did not, I did not break down all between the bio-naive and the bio-failure patients. That would be a, we'd need a whole day in order to complete all of those things, so I just wanted to point out some of the, I think the importance, and again, that change in bowel urgency, as we also thought from that induction study, you can see was also evident during our maintenance trial as well. These are just some selected safety outcomes. The reason I pulled this out, this was in the DeHanes article, and really, you know, our first slide really showed the most common ones. These are very rare, and again, the opportunistic infection only occurred in 1.3% of patients, and of cancer, only at 0.3. So, again, with this, we know that there was a very small number of patients who were treated with Mirakizumab who actually had any kind of opportunist infection or even cancer, and again, there's more data to come with Lucent 3 that's, you know, that is already published in regards to efficacy and safety that goes out over two years' time. So, what about our small molecules, right? Because, again, we've got our tiny but mighty small molecules as well. So, what happened in 2024? We had a new approval of Atrazimod, right? So, just to, again, review, our S1P receptor modulators decreased lymphocytes from leaving the lymph nodes, subsequently decreasing circulating lymphocytes, resulting in a decrease of inflammation. We have Atrazimod, which is used for the induction and maintenance of moderate to severe ulcerative colitis. Okay, so now we've got two drugs with ulcerative colitis indication. So, our dosing, of course, two milligrams once a day, and there's no titration dose. It's two milligrams once a day, you start right there. The mechanism of action behind, of course, our Atrazimod is that the S1P receptor modulator that binds to S1P receptors one, four, and five, right? So, it's a little bit different because it binds differently on some of those receptor modulators. So, it blocks the capacity of the lymphocytes to aggress from the lymph nodes, reducing the number of lymphocytes, of course, in peripheral blood, resulting in reduction, of course, of lymphocyte migration into the intestine. And again, this is more blocking receptors one, four, and five. Our side effects you can see over on the left-hand side, there is a transient dose-dependent bradycardia, which can happen early on. And again, we see our serious infections, including hypertension, macular edema, bradyarrhythmia, AV conduction delays as well. So, what do we need prior to starting this therapy? And this is where we take a second here, right? So, with that being said, prior to starting therapy, we need to have a CBC and LFTs at baseline, must have a baseline EKG. When it comes to skin exam and eye exam, it says, according to guidelines, that it should be done before or shortly after starting therapy for all patients, all right? So, those things need to happen. CBC, LFTs, baseline EKG, baseline skin exam or eye exam shortly before or starting therapy, right? So, just so that we have that listed. There also needs to be documentation of immunity to varicella zoster virus, and that needs to be done either by checking that antibody. So, during therapy, of course, routine labs, every three to six months, a CBC and a CMP is what I look for as well. Now, remember, that might be a decrease in that overall lymphocyte count. I recently had a primary doctor who kept checking a CBC on a patient who was on an F1P and kept rechecking because the lymphocyte count was low. Finally, I had to send her a personal message that said, stop checking that, please. So, these are things we need to be important and talk to our primary care providers as well. Considerations that should be avoided in pregnancy. Again, contraindicated in prior cardiac history in the last six months. So, Mobitz type 2, second or third degree AV block, sick sinus syndrome, or sinoatrial block, unless the patient has a functioning pacemaker. And again, should not be used in patients with uncontrolled sleep apnea. There is no food interactions with this F1P, just keep that in mind, but there are drug interactions. One thing I want to point out is the half-life for this is 30 hours, which of course is about one week, right, if you're going to talk about like a washout for this medication. And the atrazumab study state is usually reached within seven days. The reason I point this out is because you're talking about family planning, right? If you, this therapy of course should be avoided in pregnancy, but if someone is on it and they decide that they wish to get pregnant or need to change a therapy, right, we know that the actual, you know, washout is probably closer to one week compared to the other S1P, which again is closer to three months, by the way. All right. So, of course, here's Elevate. This is the atrazumab induction and maintenance in patients with moderate to severe active ulcerative colitis. And what I want to point out is that this study is a little bit different than the ones that we had seen, right, it's a treat through study design. So patients with active ulcerative colitis got atrazumab two milligrams, you know, they got it during their induction. And then of course, maintenance period, which is unlike some of the other studies that we've seen versus placebo. There's a second Elevate UC, which again is just more induction. And for the purposes of today's discussion, we're just going to look at Elevate UC. With that being said, here's our data, right? And this is kind of what we want to see. Did our patients with moderate to severe ulcerative colitis, did they achieve these endpoints? At week 12, we see that 27% did meet that endpoint of clinical remission versus 7.4 in our placebo arm. And again, at maintenance, 32% met that endpoint versus 6.7. And to point out, to be fair and balanced, the baseline male score, of course, was anywhere between five to nine. And of course, 37% of these patients were prior biologic or JAK exposed. What I'd like to point out here, though, is a little bit different than looking at all of those study endpoints, is that looking specifically at symptomatic remission, this is what our patients want to know. And I actually found this information a little bit more resonant to what I think I do in clinical practice. So we saw that there was symptomatic remission as early as week two, right? As early as week two. And then this, of course, then continued through that full 48 weeks of the trial. So again, atrazumab was associated with significantly higher rates of symptomatic response, versus placebo at all time points from two weeks on. Because again, when we put these patients on medication, we know that they want to feel better. The other thing I'd like to point out with our atrazumab patients, they did include patients that had proctitis. That was about, they capped it at 15%, but those patients were looked at. How about safety? Because I think that this is the most important question that we have about these S1Ps, right? Specifically, are they safe? So what I want to point out here too, is that we really see, in regards to our Elevate UC and our Elevate UC12, you can see here that even when we look at adverse events, serious adverse events, these drugs are considered safe, right? And I would tell you that they are considered safe. You just have to be comfortable in using them and talking to your patients about them. We look at serious infections over to the right-hand side, right? We definitely, we talked about why patients need to be vaccinated for shingles. We want to make sure that that happens as well. And of course we do see these cardiac, the bradycardia, but I want to point out 1%, right? In that Elevate UC in the treatment group, right? It was only 1%. So kind of keep that in mind, because I think sometimes, you know, this category of drug is sometimes looked over just because of the thought of the safety. So what about our other small molecules, our JAKs, right? So let's take a look at our JAK inhibitors. With that being said, right, we know that JAK inhibitors inhibits inflammation by blocking the JAK-STAT pathway, which is dependent on signaling and production of inflammatory cytokines. And the reason I bring this one up is because we have UFDA-SENENIB or RENVO, right? Which was approved for Crohn's disease. And so now we have an oral agent that's approved for both alternative colitis and Crohn's disease. I've highlighted this here, I made it dark for you because Crohn's disease induction is 45 milligrams for 12 weeks. That's different than our UC indication, right? So we've got 12, so we've got a total of 12 weeks time versus eight weeks time. Our maintenance can be 30 milligrams or 15 milligrams once a day. I will tell you that 30 milligrams may be considered for patients who are more refractory, have extensive disease. So I'll be honest with you, right? Most of these patients have to have an intolerance or an inadequate response to TNF. They must actually, in order to get this drug, to have it approved. So I would say, and again, in my clinical practice, I keep them on the 30 milligrams until I know that they're in some deep remission before I even consider going to 15. Just to be honest with you, that's what I do. All right, so again, the mechanism of action, it's an oral small molecule. So with this specifically, UFDA-SENENIB has a selective and more predominant inhibitory influence on JAK1 relative to JAK2, 3, and even the TIK2 subtypes. It's preferential to JAK1, but to be, you know, upon, you know, knowing how this drug works, remember there may be spillover into the other JAKs as well. And with preferential, you know, JAK1 kind of signaling, there is a thought that could it be safer compared to a PANJAK that we're used to, okay? Our side effects, of course, upper respiratory infection, increased creatinine kinase, right? Acne, which can happen. And again, it's usually dose dependent. So the higher the dose, sometimes these patients get more acne. I recently heard Millie Long speak on this, and she said a clindamycin wash is actually a topical clindamycin wash, actually really helps with acne. Neutropenia, elevated LFTs, and rash. And of course, we definitely see the black box warning of serious infections, malignancy, mace, and of course, thrombosis, which we can talk about too. Prior to starting therapy, these patients must have a CBC, LFTs, and a lipid profile. I still believe in doing hepatitis B pregnancy tests, and of course, TB testing on all of my patients. And I do a risk screening for thrombosis, right? Are they over the age of 60? Do they have any cardiovascular risk factors? Have they ever had, you know, any kind of a DVT or PE in the past as well? And these are things that I do utilize before I make a decision on utilizing a JAK inhibitor. During therapy, you can see I'm a little bit more aggressive I think in checking labs. So I usually check labs at least four, eight, and 12. And again, then every three months thereafter, I don't do it as much every three months. I think I kind of spaced that out depending on my patients. With that being said, this again should be avoid in use in pregnancy. It's got a quick onset of action. There are studies from Marla Dubinsky that this drug can work as fast as 24 to 48 hours. We recognize that there is no apparent immunogenicity. And again, as I've already talked about, we've recommended vaccination with non-live herpes zoster vaccine. It is not recommended in use of combination of any other IBD therapy as of this time. And you should avoid grapefruit juice with it. So that's something that I had recently learned as well. So let's look, of course, at the studies when it comes to approval and looking at efficacy. So we have UXL, which is a mixed population of both biological failure and conventional therapies along with biologics. So 46%, just so you know, were biologic failures and 54 were bio-naive. So that's UXL. Now we look at the other one, UXC. These are all biofailure patients. So these patients had moderate to severe Crohn's disease using that Crohn's disease activity index score, which we talked about earlier. Just so we know endoscopic response, because you see that here is an end point, is defined as a decrease in what's called the simple endoscopic score for Crohn's disease. So patients who had evidence of ulcers, and these are graded upon severity and location, had to have a decrease of 50% from baseline in the induction trial in order to have an endoscopic response. What we clearly see here in our UXL and UXC trials is that, look at remissions. We're looking at remission at 12 weeks. 50% of this UXL trial met remission at 12 weeks versus 29% in our placebo arm. And again, this UXC, these are all biofailure patients, 39%, of course, in remission versus 21% in placebo arm. And you can also see endoscopic response, of course, much more robust in our treatment arm versus our placebo arm. And again, remember, this is 45 milligrams daily for a total of 12 weeks. That's why we're looking at 12 week data here. Now let's look at our safety outcomes. And clearly, we can see here number one side effect, and again, you can see our UPA under the 12 weeks, and of course, from UXC and UXL, that the number one side effect, of course, is nasopharyngitis on both sides. And you can definitely see acne is a bit higher, again, on that UXL, right? And again, remember, these are, and the UXC, sorry, because these are 45 milligrams, right? So this is a higher dose. So again, that acne is sometimes dose-dependent as well. But again, I think a lot of these other side effects are things that we are all very, very commonly see. So how about you endure? Now, you endure with the maintenance. If so, patients who had a clinical response to upazidinib were then randomly assigned in the you endure maintenance trial to receive either 15 milligrams, 30 milligrams, or placebo from a one-to-one-to-one ratio daily, and that equaled then a total of 52 weeks. So it was, again, it was 40 weeks in addition. So at week 52 at you endure, a higher percentage of patients had clinical remission with 15 milligrams, that was 37%. And then we looked at our 30 milligram arm, that was 47%, and our placebo arm was only 15%. With that being said, here's our safety outcome. Because again, I think our biggest question when we talk to our patients is safety. Are these drugs safe, right? And what we can clearly see here, again, we look at both our 30 milligram and our 15 milligram. Again, we see very common, you know, side effects and safety signals that are not actually outlandish, you know, compared to our placebo arm. So again, these are things that we want to know. Before I move on, I just wanted to add in here, when we talk about, you know, looking at, you know, the complications of Crohn's disease, and there are two separate post hoc analysis by Dr. Kallenbell and colleagues, looking at, of course, the patient population from you excel, you exceed, and you endure, right? So induction and maintenance, evaluating improvements in extraintestinal manifestations of Crohn's disease. So including all of those, so arthralgia, anemia, so on and so forth, along with fissure and fistula. What I'd like to point out, and again, these are, these are available, these are not, you know, nothing that I'm saying that's not visible yet. But the conclusion was that OOPA led to higher rates of external closure of fistula, resolution of drainage and healing of fissures, along with clinical remission and improvement in luminal Crohn's disease compared to placebo, and there was overall improvement, and again, these extraintestinal manifestations as well. So I think more to come, especially on the Crohn's disease element, and of course, OOPA. So how about new formulations and mode of delivery, right? And I'm going to start off with one that maybe, you know, we haven't seen just yet, but our TNF inhibitor. So we've got a new sub-Q formulation that's coming out. We expect it to be available, it was supposed to be available at the end of quarter two, so I'd expect it any time now. So infliximab is now going to be available in a sub-Q formulation. We already have one TNF, you know, that sub-Q formulation, but now we've got another, right? So infliximab, it's been approved for the maintenance of, and again, maintenance, okay? So let's be clear here, maintenance of moderate to severe Crohn's disease and ulcerative colitis. So that's both. So we're looking at induction, and induction will be IV still. IV of five milligrams per kilogram at week zero, two and six with a maintenance starting at week 10 of 120 milligrams sub-Q every two weeks. Now you can administer your sub-Q dose in place of the IV dose, and then every two weeks thereafter. We've already reviewed MOAs of TNF in the past. The side effects and lab monitoring are exactly the same as they were if you were going to use IV TNF. So kind of keep that in mind. So let's look at a dosing schedule. What does that actually look like, right? And I think I'm a visual person, I like to look at this. So our IV induction dose, zero, two, six, and then if you wish, you can shift after four weeks to then going to subcutaneous dosing at week 10, and then do biweekly dosing thereafter that. What if a patient is on maintenance dosing, doesn't need induction? Well, you look at where they are on their maintenance schedule, and of course you can shift to where their next IV is supposed to be given, and then you start giving biweekly dosing. With that, let's look at some data here. This is looking at the effectiveness of switching from IV to subcutaneous infliximab in patients with inflammatory bowel disease. What we're looking at here, and I guess it's more of looking at, are patients going to relapse, or are they going to have any kind of adverse event if we switch them to subcutaneous, right? So this is 133 people with IBD who are in clinical remission, who were switched from an IV dose of infliximab to subcutaneous dose of 120 milligrams every other week. And when you look at the dark green quartile, of course it's five milligrams per kilogram standard dose, yellow is 10 milligrams per kilogram every eight weeks, orange is 10 milligrams per kilogram every six, and then red, of course, is 10 milligrams per kilogram every four. What we really see here is that there was a high relapse rate among patients who were receiving 10 milligrams per kilogram, especially that every four weeks. But in our patients who were at five milligrams per kilogram every eight weeks, that standard dose, even those 10 milligrams per kilogram every eight weeks, we saw that their actual relapse, they actually didn't have any. With that, what would that algorithm possibly look like to switch from IV to sub-Q? And again, this comes from clinical gastroenterology and HEP. Again, I think I might have some reluctancy on these 10 milligram per kilogram patients, but I think if there's a patient with I that was treated with infliximab and they were in remission, right? If they were in remission, again, one of the things I wanna talk to everybody about is before we're changing these patients, let's get some non-invasive markers. Let's make sure that they are in remission, right? If we can't scope them, can we do a fecal calprotectin? Can we do a CRP? Is that level, and they're saying less than 250. I'm a little, I like my level a little bit less than that, right? And we look at their last IV infusion. Are they on five migs, 10 migs every eight or 10 migs every six? Could we then switch them to 120? And according to, of course, that REMA switch, yeah, we possibly could without having to think. We know that there was effectiveness in switching those patients, right? More of those patients that were on the 10 milligrams per kilogram every four weeks, which you can see over on the left-hand side, those patients might need a higher dose. Again, that is completely off label. And again, I don't think, you know, ready for prime time, especially for a community-based provider like myself. But if they were on the five migs per kig every eight, 10 every eight or 10 every six, could we go to that sub-Q every 120 every other week? Possibly, yeah. And then again, what we really want to do is then check another, potentially check another level of their drug, which they're suggesting doing it at eight weeks and then continuing that 120 migs, 120 milligrams every other week. Now, I will tell you that, you know, if you're thinking about, you know, hey, are patients actually needing, you know, when we're looking at serum levels, I have some data to look at that, but the answer is yes. When they looked at serum levels, that overall average was not lower in patients who had IV infusion. In fact, some of the data actually suggests that average serum drug levels on the subcutaneous every other week dosing, it's actually slightly higher. The average, again, is slightly higher than our standard IV formulation that we've been given. So what about, you know, another new formulation? And again, we have our vetilizumab subcutaneous formulation and now it's again, maintenance, again, maintenance for moderate to severe ulcerative colitis in adults. So our induction is 300 milligrams IV at week zero and two. Our maintenance begins at week six. And again, this is 108 milligrams sub-Q and continues every two weeks thereafter. The patients can be switched from IV to sub-Q for patients with a clinical response beyond week six. And of course, you can also administer a sub-Q dose in place of an IV dose and then every two weeks thereafter. We already know the mechanism of action, I think, of our anti-integrins, but again, this is a good reminder. Again, it selectively inhibits, you know, GI inflammation. Again, just so that we know there's a little difference in that when we're talking to our patients too. Our side effects are exactly the same, except for the fact we do see some injection site reaction with this as well. But the overall incidence of serious infection is 1%. When we look at our lab monitoring and our considerations, they are exactly the same as what they are when it comes to IV medication. So I, again, visual person, I like to show this. So what's our recommended schedule that we can do? So for our IV maintenance, you know, we can go zero to six, that's your induction. And then when it comes to then the next IV, which would be, you know, our IV dosing, you know, then we can consider doing that just the way we're doing it. So you can see that first IV maintenance arm that goes across the top. How about this new subcutaneous one? We can see at week zero and two, IV, then followed at week six, you start that subcutaneous injection. Then again, every two weeks thereafter. But here's some other examples of how it can be incorporated. You can switch after three IV doses. You can switch after maintenance. So again, if that patient, again, has gotten another IV dose and then at that week eight, then you start giving the subcutaneous dosing again there. Or again, for patients who are maintained again, then I would consider possibly changing them to sub-Q dosing as well. So what I want to point out here, again, looking at transitioning from IV to subcutaneous betelizumab in patients with inflammatory bowel disease, this is the travel list study. So again, we're looking at 178 adults with IVD treated with IV betelizumab. They were offered the option to transition to home-administered subcutaneous veto. So 124 of them decided, okay, let's do this. We looked at efficacy, safety, and satisfaction after 12 weeks. And if we look at the findings, of course, maintenance at baseline was maintained in 84% of the patients. What we saw is there was no change in disease activity looking at that 12 weeks. And overall patients thought it was well tolerated. There was some increase in injection site reactions. So 15% joint pain, rash, and headache. And again, these are pretty common as well, even in our side effect profile from our IV infusion. So what about a transitioned program? And I think this is almost good even for any of our patients. So patients are approached if they're at IV betelizumab by an IBD specialist. We provide them with information, do a shared decision-making. We look at a baseline review, right? Their CBC, I would actually suggest, yes, do a serum betelizumab concentration and a stool for fecal calprotectin. Where are they at before deciding to change them to subcutaneous? That first subcutaneous dose can be administered in place of a planned IV dose. And then, of course, this can be decided on how they acquire it. Of course, it's up to insurance, not really up to us. At week 12, could you, of course, then recheck lead test serum betelizumab level in a stool fecal calprotectin? My answer would probably be yes. And I want to be a little bit tighter on that as well. And just so you know, there is data that looks at the overall average, again, average serum concentration of betelizumab. And with that being said, that average ended up tending to be slightly higher than it was for our traditional IV. All right. Biosimilar briefing. Well, I think if we're going to talk about updates, we have to talk about biosimilars, but we will do it relatively quickly. Biosimilars, of course, are biologic products that are highly similar to what's called a reference product. So our reference product is our originator. Our biosimilar is, you know, exactly supposed to be a highly similar product to the reference. It's made of the same type of sources, administered the same way, have the same strength, dosage, and potential treatment and side effects as, of course, the reference product. With that being said, we have to be very certain that we even inform our patients that biosimilars are not generic. There are differences between the two. And for just elements of time, this is a slide that just tells you what are the difference between a biosimilar and a generic. But how about interchangeability, right? So just so you know, interchangeability allows the back and forth switching between biologics without adverse events or loss of efficacy and without provider input. This means that a patient, if a biologic has a interchangeable designation, it means it can be changed by a pharmacist without the provider knowing. So with that, though, for a biologic to, or biosimilar, I apologize, for a biosimilar to obtain interchangeability, they have to undergo studies that have three switches. Each switch has to cross the alternate product for at least two exposures with each drug, right? So, and the FDA requires evaluation of PK, PD, immunogenicity, and safety. Now, each state has the ability to govern this, but I will tell you to prevent substitutions, you can write on their dispenses written or brand medically necessary, and then prescriber and patient must be notified of any substitution. So what available biosimilars do we have? And I think that this might be a little bit surprising to some of you, but we definitely see that there is an overflow, right, of our biosimilars that we have in Humira, right? So Adalumumab biosimilars, we have a bunch. You can see here the approval dates on all of them. And I'm sure for those of us who treat our IBD population, we recognize that there is a large quantity. We've been familiar with biosimilars for infliximab for a long time, and you can see here those are on the left. But also just to point out, there is a biosimilar available for ustekinumab. It was actually approved in 2023. We don't expect it to be available probably till end of 2024 or beginning 2025. So when do we use biosimilars, right? When there's a non-medical switch, meaning the insurance mandated it, and the switch was due to cost, copay, or hospital institution. That's a non-medical switch. How about a medical switch? Well, it's introduced by us as the provider. So when we're starting a therapy, could we start them on a biosimilar? Absolutely. Could we use them for maintenance? Absolutely. Or is this a stabilized responder? But I would go back to that travel list kind of, when they were talking about moving the patients from IV to subcutaneous, I actually do check a drug level. And if it's a TNF agent, because those are what we have available now, I do check for antibody development as well, and also check for fecal calprotectin before I, if I am given a mandated switch, before going over to a biosimilar, just so that I can keep tabs on my patients, just to ensure if they're telling me that they have side effects, that I have measurable data from before use, and then after use of the biosimilar. So when not to use, is there a possibility of uncertainty? Do they have frequent insurance changes, hospitalizations? Are they in a flare? Don't change them, right? If they have a loss of response to the originator biologic, don't think if they didn't respond to, you know, infliximab or Remicade, right? If you change them over to the biosimilar, that they're going to have a response. They're not going to. So don't try and make that type of a change, right? That's not going to work. So again, we're talking either primary response or secondary response. If they've had an adverse reaction to the originator, or if they have anti-drug antibodies to the originator drug. And now last but not least, I think this is super important as providers, we have to avoid what's called the nocebo effect, right? So that's an incitement or worsening of symptoms produced by a negative expectation about a drug. The patient is now given a biosimilar, they're unhappy, they don't want it. And this isn't a direct result of a specific pharmacological action. It's just because of, you know, the patient's negative expectations because it's considered a biosimilar, right? So as clinicians, we have to do our best to avoid trailing the nocebo effect. So educate yourself and your patients about biosimilars, focus on positive effects, focus on, avoid focusing on the side effects, do avoid conflicting messages and employed shared decision-making. And I also do discuss how they came to be FDA approved. So we're gonna finish up here in just a minute. There are so many choices, which way to go, right? It becomes overall confusing. That overall toolbox is just overflowing at this point in time. And I think some of the biggest element is looking at IBD drug safety. So what we're seeing here, of course, is this is a review article that provided an update on safety synthesis of advanced IBG treatments, including new data on drugs that have newly emerged since previous safety reviews, as well as additional safety data on more established therapies. And this is, of course, a pyramid to, of course, look at the hierarchy of safety profiles for the various classes of therapy. I will tell you, I actually use this quite a lot. I talk to my patients about it. And when I'm providing educational lectures, I think that this is the best visual tool to look at, right? And we talk about, you know, again, safety. Look at where all of our real safety profile lives here, right? If we look at the bottom, our thiopurine with our, of course, our bottom is steroids, right? We all know that. But we have our thiopurine with our T-ring, thiopurine plus non-TNF and biologic, you know, on the next lineup, right? How about, you know, TNF or even TOFA? Again, and what I want to put on the side is that inadequate treatment is also considered an adverse event. We've got OOPA. And then, of course, at the top, we've got VEDO, OOSTA, right? Rizikizumab, Mirakizumab. And then, of course, we even have our F1Ps. So we've got ozanamide and atrazimide. So when we're considering, you know, our safety profile for a patient, and I think that this is also what we need to concede, if we look at all the safety data, look at your pyramid here, right? This still gives us a lot of options. But we also think two patient-specific considerations definitely influence our safety profile. This includes age, disease classification, phenotype, burden of disease, comorbidities, concomitant medications, and, of course, conception plan or family planning. So factors that lead us to the right treatment for the right patient. Efficacy, of course, our indication. Ulcerative colitis, Crohn's disease, right? Rapidity, durability, pharmacokinetics, right? And also combination versus monotherapy. Safety, of course, looking at infection, cancer, specific mechanism of action. How about individual characteristics, right? Even payer coverage in there. And, of course, disease characteristics. Extensive activity, behaviors, and, of course, those EIMs, which I think more data to come, especially when we're talking about UCA earlier. Now, this is not my slide, and forgive me for the kind of the blurriness of it. This was a slide that Millie Long presented at the Crohn's and Colitis Congress, and I have to tell you, it's probably one of my more favorite slides. But, you know, how do you pull it all together? How do you make a decision? And I think that this is a great just overall slide on what can we use for our patients with individual characteristics? And, again, these are not all inclusive, and, again, just some overall thoughts on how do we pull together all of these therapies, the newer therapies we have, this ginormous toolbox, and what makes us help those decisions. So I'm just gonna review a few. So a newly diagnosed man with moderate Crohn's disease with a personal history of lymphoma, right? So we're probably gonna avoid maybe a TNF in this patient, but we could use Vito, Usta, or RZA, right? Because these are all approved for Crohn's disease. What about a patient that's considering pregnancy or has a plan to start a family? So a young woman who's steroid-dependent, ulcerative colitis, planning to start a family. Actually, any biologic. Now, this doesn't include small molecule, right? Any biologic we can actually use in this patient. How about lifestyle considerations? So it's a businesswoman who travels often for work with Crohn's iliitis. And of course, the sub-Q Vito and Fliximab should actually be in italicis because they're both gonna be approved soon enough. So again, with that, we're thinking about someone who's moving around a lot, right? So someone who probably needs injectables, right? So we've got Adalumumab, Rizinkizumab, Ustekinumab. And of course, now we've got these newer formulations that, again, we know in Fliximab's already approved. We're just waiting for it to come out. And I know sub-Q Vito will be approved eventually as well, right? So again, how about all of these, this type of patient population and just pulling it together? And again, we have so many great tools. Nowadays, we just don't have one option for one patient type. But again, that shared decision-making is so important with our patients. So with that, our practice pearls, there are multiple new therapies that have improved for the treatment of IBD and many more in the future, as we all know. The safest treatment is often the treatment that effectively controls IBD and positioning decisions should really be patient-centered, include clinical characteristics and informed by decision-making and informed by shared decision-making. Whew, that was long. All right, everyone, thank you so much. I know Jill wants to get to some questions. I want to get to some questions. So we appreciate your patience.

inflammatory bowel disease

pharmacology

IL-23 inhibitors

small molecules

biosimilars

Crohn's disease

ulcerative colitis

safety considerations