Dr. Sands offers first and second-line choices of medication for the treatment of Ulcerative Colitis.
um I'm Rebecca Metro. I uh work with Dr Khanna Jetty at scripts and the IBD department and I am excited to introduce our next speaker. DR Bruce Sands who um is the doctor Burl be cone crone professor of medicine at Mount Sinai, which he is an expert in IBD management and has earned an international reputation for his care of patients with complex and our factory disease. Um and he's going to be speaking to us on positioning therapies for all sort of colitis. Thank you very much Doctor Metro and thank you for inviting me to participate in this meeting. Um I've been given what is an increasingly difficult task of talking about how to position different therapies for the treatment of all sort of colitis. And every time we add a new kind of treatment it gets a little bit more complicated. Here are my disclosures and you know what I'm going to try to do in this talk is we've together what the societies have recommended what the evidence shows but hopefully the societies have paid attention to and I think they have and and also just sort of how you actually put it together in practice because what I'm going to end up saying is that the choice of therapies as much as we would like to follow algorithms of care. Um basically there are some algorithms that you can follow but for the most part a lot of therapies individualized. So we'll start with induction permission in biologic naive patients with moderate to severe all sort of colitis. And here the recommendations of the societies are for anti TNF therapy influx model. Um Ahmad golimumab vandalism ab or tofu Sydney at least when when this was created where all possible therapies to face it and is bracketed for the reasons that bill showed you given the black box warning. That puts it as targeted really for use in patients who have failed anti TNF S. T. G guidelines. Also acknowledged the role of predniSONE is an inductive therapy for moderate to severe disease or for more moderate disease be decimated. Mm X. So the A C A G A N A C G agree that there's no inductive role for pureeing monotherapy or from methotrexate. Uh there have been studies of induction therapy of methotrexate and you see and they were not positive. So I don't recommend you use methotrexate monotherapy for all sort of colitis. And the idea also makes a statement that inflicts map or vandalism ab have better efficacy and inducing inducing remission compared to Adeline mab or golimumab. But there's no opinion about to facilitate due to lack of data. But again, for bio naive patients it's a moot point anyhow and the stated that inflicts map should be combined without appearing for induction of remission, which is a point worth discussing maybe later in the panel discussion that may depend quite a bit on your approach to therapy. How much you believe in a proactive drug monitoring and its ability to prevent anti drug antibodies to inflict some ab as opposed to trying to do that with combination therapy. So the A. J. Suggests the early use of biologic agents either with or without. You know modulator therapy or top Senate. We'll put that aside rather than gradual step up after failure of five municipal slates. And this is an older paradigm of treatment and if we're talking about mild moderate and severe disease activity and we should distinguish between activity and severity with activity being the snapshot, it's how the patient is doing today as opposed to severity overall, which is really the whole movie. It's not a snapshot, it's the whole history of the patient leading up to now and those are different concepts. But in the old days we would just look at the patient and say your disease activity is mild, moderate severe. We'd start at the bottom and work our way up. And of course there are still patients for whom you know solicits maybe good inductive therapy and good maintenance therapy. But if we take a treat to target approach to therapy and we really want to induce healing of the mucosa and ulcerative colitis which we certainly can do with the agents we have Now um you find that really Optimistically 35% of patients actually do achieve durable mucosal healing with five men to solicit plates with corticosteroids. Of course we all know that they're not safe for long term use. They're also not effective for long term use. Um It's really dubious how many patients actually do well on amino salicylic. It's after requiring corticosteroids. We know that's a turning point in their care that really warrants, demonstrates more disease activity and warrants of better therapy. The older way would be Thile pairings and certainly that is still an option. Although we are increasingly concerned about their toxicities or vegetable is a mob and we should add to this. Used to kinda map which is also a steroid sparing agent. And then stepping up in disease activity. We have the full gamut of things and add on cyclosporin, which still has potentially a role for some patients. Um but really is probably as effective as inflicts Ahmad in that setting for patients who have not already experienced inflicts math and ultimately, of course, there's always surgery. So it is also worthwhile. And the A g a long ago acknowledged this in their uh 2015 decision tool that actually Bill sanborn helped to create um trying to weigh the risk for collect me for the patient. And it's essentially the patients with extensive colitis who have deep ulceration, those who have extent extra intestinal manifestations and recover use of stories who are at high risk and the ones with more limited extensive disease and milder colitis obviously are at lower risk. So you can march up, those are definitely more severe patients from the get go if they have extensive colitis or deep ulceration don't don't reach for five minutes, solicit lights That just probably doesn't make sense at all. Well, we can start talking about the evidence and here one of my co speakers did sing was really instrumental in doing network meta analyses that are the basis of some of these comparisons because for the most part we do not have direct head to head comparisons of any of these agents with the exception of one study, the varsity study that I'll show you later. Um and if we look at different outcomes, we can look at clinical remission. The evidence shows that inflicts map and vandalism ab are fairly close in their ability to achieve clinical remission followed by Tokyo City Nib fell by the injectable anti TNF saddle. Um A big hole in the map. Clinical remission is not enough. It does of course incorporate mucosal healing. And you see, but if you really want to look deeply at the level of mucosal healing, the most objective outcome. Uh then you see that influx map is just edging out slightly Vettel is a mob uh and superior. The toughest in and golimumab as well as to a dilemma mob. And all of these are better than placebo. Um There's no significant difference between all these agents uh in maintaining remission. Generally. The thing that you induce remission with is the thing that you maintain your mission with. But you really cannot compare these agents for maintenance very easily because there are different trial designs, different durations of therapy? different populations um different designs of treat straight through or treating responders and maintenance. So what about induction information? And the patient is already an anti TNF experienced patient who has moderate to severe you see both the A. C. G. And the E. G. A. Recognized tofu Sydney before Vettel is mob. They should also recognize used to kinda mob. And um basically you see the data behind that uh in the bottom with Vettel is a mob and Tofu said Nib uh you know being compared and it looks really that tough. A Sydney is superior uh with with regard to the TNF experienced patients. So really the best positioning for Vettel is mob in uh patients with all sort of colitis would be as a first line biologic therapy. That's not to say that patients won't respond if they have failed. Anti TNF. And I'll show you some data in a bit. Now. Bill mentioned already that toughest said Nib is sort of in a penalty box because the black box warning and of course this was extended not just to the 10 mg, the adidas, but also the five mg dose. This comes from data from rheumatoid arthritis patients were 50 years or older who had one or more cardiovascular risk factors. Most of whom if not all were on methotrexate which may also affect venous thrombosis, embolism risk and pe risk risk of lung cancer maybe slightly increased in this population. Um But unfortunately they've sort of applied this black box warning to patients with you see and if you look directly at patients with you see it's hard to actually discern These risks in our population. Still it applies both now to the five mg twice daily and the 10 mg twice daily dose. So maintenance of remission after successful induction with an anti TNF federalism. Alberto facade nib the same agent will also be used as a maintenance agent except for steroids. Um The A. J. Makes no recommendation in favour of or against using biologic monotherapy or to facilitate rather than monotherapy by appearing mono therapy for maintenance of remission. There's a gap of knowledge there but the says after storied induction of remission maintenance without appearance is better than no treatment at all. But these days probably not the most modern choice and probably not as safe as things like that. It was never used to kinda map um the A G A N A C. G. Agree methotrexate should not be used for maintenance of remission and there's data directly for that. But as I said at the beginning I don't think of treatment choices algorithmic. I think there are many individual scenarios that could lead you to choose one or more drugs over another patient is newly diagnosed who's on the moderate survive side of severity may have a little bit more time. Maybe you don't need to reach immediately for an anti TNF. Maybe they're your first biologics might be Vettel is a mob or used to kenya mob and we can talk in a moment about whether that should. Also we should also include Ozan Ahmad which I think also would be reasonable patients felling the Salomon have a broad array of choices but again um it's entirely possible to use the newer, safer biologics or Ozan Ahmad patients fell in corticosteroids much the same patients filling immuno suppressive who are steroid dependent again the same but the patient who's hospitalized and filming ivy corticosteroids by and large those patients are going to be getting inflicts mob so they're going to get the ivy anti TNF or they're going to get cyclosporin but most people are really not doing that. So there are individual patient factors that could drive the choices of therapy and moderate to severe you see and these include age safer agents who would probably include dental is mob and I would probably adhere. You used to kidnap which seems to be quite safe even though it's blocking I'll 12 and 23 you would think those are very important cytokines for immunity and they are but in practice we don't see excesses of infections. We don't see excess of cancer. So I think the safety profiles of vandalism had been used to kenya matter really quite similar for patients with the significant cancer history or lymphoma Vettel is a map is probably a great choice in pregnancy. We can use vandalism ab most likely anti TNF is a thigh print and increasingly we also have evidence for use to kinda map but we wouldn't use tough assignment by choice started responsive, mild to moderate disease. You know, it's still a cheap option to use the thigh appearing. But increasingly we do not for those who have extra intestinal manifestations like arthritis than the choices might skew toward anti TNF tougher Sydney after anti TNF failure or used to k map previous anti TNF failure. Um that is largely going to be tough as Sydney or used to kenya mob patients with psoriasis, especially if it's a complication of anti TNF use Mr kingdom. That will be a great choice. And as I said for impatience it's gonna be either inflicts map for cyclists porn and these days you might consider following up the cycle. Sporn with Vettel is a mob rather than with a dye appearing. So let's look at some of the data and if we look directly then after prior use event, anti TNF in this case inflicts a mob Abdulemam app is actually decreased in its efficacy. Um still it does work but the efficacy is somewhat lower that Elizabeth's efficacy is decreased as well in anti TNF exposed patients that's not to say that there are not some patients who will respond and if you don't have other choices or their reasons not to choose other agents you see on the right hand side that there are anti TNF exposed patients who do still respond will achieve clinical remission, although at very low rates that are not statistically significant clinical response and even mucosal healing. If you look at the level of symptomatic response. Actually, the TNF antagonists exposed patients in the short term of six weeks of treatment don't really look very different from placebo, But possibly with longer term treatment, you may see this. So in these cases, if I'm using vandalism AB I will probably extend the treatment to 14 weeks if I have the time before I'll give up on the treatment. So if the symptoms efficacy is not decreased and I should also qualify what I'm saying here. I'm really referring to the treatment effect size is not different regardless of whether you're TNF exposed or naive, but you clearly do see that the absolute efficacy is in fact decreased after anti TNF exposure. As is the case with all second line use of agents. And this is just another way of showing you the same data. But in a time course, essentially showing you that for the TNF failure patients which are the dotted lines, there's a frame shifting down of the rectal bleeding sub score trajectory but basically still showing you that there is efficacy among the anti TNF exposed patients. Similar to what you see with the TNF naive patients. Similarly used to kingdom abs efficacy is not decreased with regard to the treatment effect size in the bio failure patients as compared to the bio naive, making it a great choice for second line use after auntie tina failure. But again, there is a slight decrease in overall absolute efficacy. What about the use of anti TNF after vandalism ab Well, so this is a very reasonable question because if you're going to do as I suggested and consider using vandalism ab as a first line therapy, how do we know you're going to respond to an anti TNF? These data are open label and experiential I would say. But they clearly show that whether you use the anti TNF uh as a second line or first line use after Vettel is mob, the outcomes look quite similar. So I find these data reassuring. Now the only data for which we have a direct head to head comparison in a randomized controlled trial and ulcerative colitis between two biologics is the varsity study. So we don't have to rely on network meta analysis here. Although interestingly said Singh can tell you the network meta analysis showed a similar result but the reality is that google is mad is superior to a dilemma mob at least one. Anti TNF, especially for anti TNF naive populations. If you look at the anti TNF exposed or failed patients, you don't see a difference. But actually the efficacy is quite similar in that patient population to again, suggesting that this is a good choice as the first line biologic and similarly if we look at secondary outcomes like the castle Healing and we look similarly at anti TNF exposure or naive, you can see that most of the benefit is accrued in the anti TNF naive populations, comprising about 80% of the patients who were enrolled in this study. Now there was no difference between the rates of corticosteroid free remission in these patients. There are some peculiarities of how the study was done. It's not easy to explain this, but we can see that the mean change from baseline in the median oral corticosteroid dose was really quite similar between Vettel is mob a dilemma mob, which is I think reassuring. And finally, what about the time course historically we thought, well, anti TNF star the fastest thing that we have and in fact you can see that vandalism ab is just as fast as a dilemma map, if not faster in achieving clinical response and you can see this as early as week six and even you see the beginning of separation between madeleine Madeleine videos map Even as early as four weeks. So, but in the absence of head to head trials for all the different agents that we have. Can we get valuable information by other means, such as network meta analysis? Well, certainly we can. And this is an approach that said Singh has really spearheaded and done best of all of anyone in the field of IBD and you can do this for direct comparisons for induction of clinical mission in patients with prior TNF inhibitor exposure. Um And of course we do have the one direct comparison which is the vertical line joining addle. Um Ahmad and vandalism had to tie it all together in the network. And what comes out of this is that actually inflict some ab comes out best but Vettel is map is probably next. And then you see a smattering of all the other agents coming in behind for endoscopic improvement and for clinical remission. And if we look at the patients who had prior anti TNF exposure here, you see used to kinda map and tofu Sydney moving to the front of the line. But what about safety and that also has to color how you choose the therapy. And there's no question if you look at the data from the network meta analysis that the agents that stand out are really Vettel is a map and used to kinda map and so that should color the choice. And again, I think positions Federalism map and potentially used to can map as wonderful first line biologic agents. Now, what about Ozan mod Bill showed you the data. This is the study design very straightforward induction and re randomization of responders and maintenance and it won't delve too deeply in this because he already showed you the data except to comment that we have yet to see a lot of explanation of how the Oh no, I even about failure patients did during induction the bio naive patients did better. I'm not showing you these data but telling you about it. But over the longer term treatment there were many patients who actually if they responded and were re randomized to continue on maintenance, dozing actually did quite well. And here you see the prior TNF inhibitor versus no prior during induction at week 10 and you can see that no prior TNF inhibitor did better. But even if you look at clinical response it's still significant and it looks even better and I will actually be presenting the longer term data um later this year I just want to point out that no matter what agent you choose, it's important that you look for objective evidence of response. You want to see mucosal healing. This is achievable in ulcerative colitis. So if there's a rationale for tight monitoring and you see you actually can achieve it with the agents that we have and I advocate looking also of course monitoring with biomarkers such as fickle cow protecting in between. So in conclusion for patients with moderate to severe you see I would consider strongly individual patient characteristics and their disease severity, not just their disease activity In general influx map and Vettel is map are the best most effective first line choices but used to king mob. Adeline mapping goalie golimumab are also effective. Used to kind of have been tough to sit in a bar the best second line choices, but you really have to consider cost, convenience, safety and efficacy and balance that with what the patient wants and what their characteristics are. So I hope you haven't found that too confusing. It is still a bit of an art and not just a science and that's the fun of medicine in IBD. Thanks for listening.
