Drs. Dulai, Sandborn, Sands, and Singh answer questions from course participants.
we are now going to get started with our panel discussion with Dr Singh Dr SAnborn, Dr sands and Dr july um And um let's start with our first question for Dr SAnborn um do we know how you can have failure patients with would do with uh Rosen Kazoo mob Bruce? Maybe. I'm not sure if you were close to that there. What so the primary analysis population, which is what we looked at during my presentation, excluded all those patients. There were some patients may be as many as 10% of the trial that we're allowed to have uh received and failed. Used to kenya mob. It just wasn't part of the primary analysis population. I don't think it's been an abstract yet. I feel like I've seen the data and there was some benefit but I just can't quite recall it. So we will know something about that in a limited group of patients but we don't know yet burst, you know anything more than after. No, nothing more than what you said. Great, thank you. Um Another question um we have many of our patients are getting um older or younger patients are getting older and we have more and more older patients and many of us are finding that it's difficult to get some of the injection based therapies on patients on Medicare such as used to kinda map which you know in both of the talks earlier that was positioned, you know very highly and these older patients um do you have any tips or tricks or anything? Um you know Dr Sanger Dr Sands on how you're able to get that for these patients. Yes. We we seem to be able to give it in the setting of giving the injection in our infusion center in the hospital. Actually that seems to be a workaround for most patients. And I don't know if that's particular to new york. I doubt it because it's uh we're talking about federal insurance, I don't know what it's like in California but that's our work around and how how you does it Bruce. Well so we're giving the subcutaneous dozing but they're giving it in hospital administering it rather than self administration. It means they have to make the trip in. But at least it pays for it. It's a it's a similar thing here. I mean we uh doesn't make a lot of sense but they come in for injections to get here. They're always Medicare rules are changing. We're right now relying on certain extensions from Medicaid and it's always a guilty and at the top as to when they may start covering used to kidnap injections for these patients so far there is a bit of a gap but that's like extends to the end of september I believe or sometimes yeah. I've tried to get a couple of patients to do injections at the infusion center but even that with their particular coverage was was not um was not doable but it's a it's a big um gap because they're not really not able to get any of the injectable medications for that population. Um Another question either to doctor saying or dr sands. Um there's been a lot of talk recently about the H. L. A. D. QA one oh five genetic marker as uh increasing the risk of anti drug antibodies with anti TNF. How are you incorporating that into your clinical practice these days? Um If at all yeah I would say at this point uh dabbling with it to understand how best to use it. If I look at the data um what I see is maybe it would be useful in persuading a patient to have combination therapy if you have one or two leal's that are positive. Um it's very persuasive that they're at high risk for anti drug antibodies. And so that may be the extra wage or tool that will help me persuade a patient that they really should do that because a lot of patients don't like the idea of being onto immune suppressing medications on the flip side. The negative predictive value. In other words, if you don't have any of the risk of leal's for developing anti drug antibodies and I should be clear, we're talking about two anti TNF that were studied inflicts map and gadolinium ab not about the other biologics um it's you know, there is still some effect but Um it's still there is some effect protective effect of combination immunotherapy and so it's not 100% that if you're negative you're not going to develop anti drug antibodies so you have to discuss this and it's a kind of a sophisticated discussion to have with patients that is not that easy for them to understand. So I guess I'm just sort of playing with it at this point. I'd be interested to hear would sit or bill or parent beer are doing. I I have a similar approach. I haven't actually use it for any patient. I bring it up for discussion but I'm still trying to figure out what is the best scenario to use it. And because the evidence clearly suggests that combination therapy tends to work better. And for most patients right? And just to highlight what Bruce said, you know, if you do continuous therapy with federalism ever used to kim you bob. I have never in clinical practice seen a positive antibody with those drugs and I don't think it occurs in more than 1% of patients. If you do a drug holiday, you might get 5%. But it's really low on the other hand, you know, it's a real problem with anti TNF and personal view is that most patients would be better off with an anti TNF if they if they're really refusing and you think they're super high risk and you know, then I can see trying to pull it out of the hat, like like Bruce said and try to show them the data. But you yeah, I tend to agree. I think for somebody where they're high risk enough that you want to think about using combination therapy you should probably just use combination therapy. Uh The few times I've used the test so far has been people where they're not very sick, they've been escalated to anti TNF therapy and they have other reasons why it may be risky to use the immuno modulator and then it's a bit of both convincing them that they need it and were convincing myself that they may not need it if they're negative and that it might be reasonable to try mono therapy. But I think the majority of people escalating into tm therapy are going to get combination therapy one or the other. But I would just add one more, one more viewpoint from Mount Sinai where I work with Marla Dubinsky who has a very interesting predictive model that helps you act more accurately dose inflicts mab early on and essentially what she finds when you apply this model. Um It's a farm co kinetic model and achieve adequate dose levels And you maintain them with inflicts mab you see very low rates of occurrence of anti antibodies to inflict mab. So a lot of what we're doing with immune combination immune therapy with inflicts mob is suppression of antibodies but you might be able to achieve the same thing if you adequately dosed with the anti TNF from the beginning and continuously it's just that that's hard to do right now. And of course inadvertent holidays happen all the time sometimes because of patients in my experience more often because of insurers and gaps and insurance. Yeah. And along those lines, can you comment on the use of an immuno modulator with feudalism? Abhor used to kinda map where there is such a low risk of antibody development. Do you use it for combination therapy or in in other circumstances? Yes. Well you know, I think the best evidence shows that there is no added benefit of combination therapy with federalism. Aber used to King mob. That being said if this is my last weapon in my arsenal and the patient has developed antibodies against every prior agent that they've used, I probably will still do combination therapy out of desperation and also maybe the whatever modest benefit of synergy with the other medication would be. So, you know, that's not evidence based, it's just instinct. I think in all honesty I kind of get to the same place for the different logic. I'm pretty persuaded you don't need it for immunogenicity even in those patients. But um I'd be interested the rest of you if you have the same anecdote. You know when, when you're getting to the point where patients have failed most or especially all of the available agents and you're getting into um uh combination biologics and things. I usually will stick um in immuno modulator in there and I can think of patients with Crohn's of the pouch where I've had them on. So used to kenya mob And as a 500 methotrexate and then for some reason you withdraw them suppressive than they worsen and you put it back on and they do better. So there do seem to be these anecdotes that you stumble into out of desperation where in of one treatment trials it makes a difference. I can't explain it, but anecdotally I have the same anecdote in a pouch patient as well. So I believe this is an occurrence and it goes to show you that we do not understand everything with every patient. And uh dr sanborn, you briefly mentioned uh this, but this is obviously off label. But at what point in your care of these patients are you considering combination biologic or small molecule biologic therapy? And what are, what are the one, you know, the combinations that you would recommend And for how long we should probably all weigh in on this because this is an evolving area that not much, not that much is written about sid and carol beer and I co authored a paper with the University of Calgary where we looked at the experience of the two centers in Crohn's Disease and in my logic there has been, I've done much less dual biologic therapy and all sort of colitis than Crohn's because there still is surgery as we were reminded this morning. And I, you know, you're getting um far a field from evidence based practice when you do dual biologics and so I still, I don't like to be pushed into dual biologics and those sort of colitis, although, you know, given the evolving experience experience in Crohn's that maybe I'm being a little unreasonable about that, but in Crohn's disease, you know, it's it's primarily been patient to fail all the individual drugs and then um the way that I've thought about it is that metal is a mob is both very safe and also got restricted as I sit and Bruce made the point used to kenya mob is remarkably safe but it is a systemic agent. And so if you mix it with an anti TNF, you know, I just theoretically, my intuition which may or may not be right is that you can see more side effects. So I think we we've had the most experience with mixing vandalism ab with either an anti TNF or with um used to kenya mob and a little bit less experience with mixing and anti TNF and used to kinda map together. But we did have a little bit of that and sometimes you want a particular attribute of of the that combination of drugs that federalism, I'm just just gonna to offer. Um and you know what we saw actually was that as many as 40% or so patients got into remission over a year, and that you know, third or so uh could get into substantial endoscopic improvement or remission. So it was a pretty meaningful uh observation will effect the other subgroup of patients as patients that like say you're cruising along and you're about has done right with um better losing mab, but you've got enclosing spondylitis and maybe your bowel didn't do great with the TNF blocker, but you know, they went off the TNF blocker, they went into battle is um they went into remission but they're backwards. Uh well, adding a TNF blocker, there can be good, you know, you and there's there's just a variety if your metal is um avenue significant pharmacologic condition, psoriasis scleroderma or something. A TNF blocker or used to kenya mob could be really good in that setting. So I think we've and then, you know, other arthritis, we have some experience with giving Sort of five mg, arthritis dose of the toughest city, Never you or the r a dose of you pattison ev with veto. Again, to cover kind of arthritis. So it would be good to hear what the other folks are doing, but that's how I sort of thought about it. Yeah, my my experience has been really just a smattering because first of all we have to admit honestly in my experience the only way I've been able to do this and get an insured to pay for it is in those situations you mentioned where there is a separate immunological condition where there's a separate indication for a different biologic therapy and for the most part it's been, as you said, used to come every bottle is mob in combination with something else. Occasionally it's been gasol command map for me and I have you know, there have been some patients who have responded. It's a tiny experience. I think what we really would like to get to those who is rational combinations, not just combinations of convenience of what we have at hand. And there will be a price to pay if we keep piling on one immulogic mechanism on top of another. For the most part, I'm not talking about gut restricted things like metal is a map where there's probably less of the safety price. But you can look at the experience in R. A. Where they combined Tanner Cept with Anakin Row which is an one receptor antagonist and saw kind of prohibitive infection risk. Similarly, I don't know if anyone has tried this but I wouldn't try combining for example uh Tofas inaba jak inhibitor with the TNF inhibitor because they're completely non overlapping immunologically so I would expect you to have profound immune suppression and a price to pay What I'd really love to see our combinations that reach mechanistic lee in other directions such as improving barrier function or restoring the dis biotic microbiome that we know is common in all IBD patients, the problem is we just don't have those kinds of agents yet. But when we do then we might really have very rational combinations of therapy that are multi targeted might be synergistic and yet still very safe. Thank you. Um And then another question um can you share maybe dr dolittle you? Could you could start with this one. Can you share in practice if you're de prescribing five essays in Crohn's disease And select you see patients um for you see patients in clinical remission on an immuno modulator. Um And the five S. A. Do you recommend stopping the five S. A. Um and you stop the five S. E. Immediately or taper it off? How do you handle those patients? Yeah. So I do deep prescribe five S. A. Is quite a bit I think. Um in Crohn's disease for sure. And you see um for patients who are essentially escalating from five essay to uh immuno modulators and or biologics um I will usually give them a couple of months on the new therapy to allow them to get into remission and make sure they're in a sort of deep state of remission and then pull off the five A. Say you just don't want to wonder uh if you're sort of de escalation of the amount of the five essays resulting in the lack of sort of that final amount of efficacy. Um So I I do de escalate a fair amount in ultra colitis as well. Once they're in endoscopic remission at clinical and endoscopic remission. Mhm. Great. Um Although uh we're not seeing anti body developments uh still uh this person has seen multiple patients have a good response with uh realism ab and then a loss of response. Um Any reason why that's happening. Dr sands. Do you wanna take this one? Well, you could say this is the case, not just for Vettel is um a but for all of our treatments there is a great predictable rate of loss of response. It varies by treatment to some degree. Uh And I would suggest that actually the loss of response with Vettel is a map and used to kiss. Remember maybe not as high as what we see with the anti TNF. Maybe in part because we don't see nearly as much immunogenicity with those newer agents. But yet we still see probably mechanistic lee something else is happening. We're suppressing the inflammation in one way, Whatever it is that is triggering the inflammation is uh you know, there's a Darwinian evolution, evolutionary. Uh There's evolution of the immune response to work around what what you're doing to it. And that's another argument for multi pronged treatment approach addressing different mechanisms of action. Thank you. Um And dr sing. Um why don't you just uh you briefly talked about using your destiny need um in the mild Crohn's disease patients. Can you comment on just the use of your destiny and I. VB in general and maybe also include the uh um X. Form when you use that and all sort of colitis. Yes. So you're destined for christmas disease buddhist and generally would be using for somebody who's mild to model is symptomatic with a disease that's largely limited to the terminal ilium. In some part of the right conferences that liliuokalani disease for patients who are more severe, more sicker, more severe symptoms. I discussed with them that predniSONE is probably going to get them into symptomatic control quicker. Although it may come at a higher risk of side effects. Uh patient preferences waited there, try to experience with predniSONE often dictates what their preferences but for somebody with more mild to moderate symptoms I would use. But S. And P. For initial induction generally do a taper over 8 to 10 weeks. Um And then if it's somebody who has mild moderate from disease will otherwise I'm not worried about getting into trouble with disease complications or has rather mild superficial patty disease. I may hold off on any long term therapy. Alternatively you could conceivably go use something like vandalism have in that instance. But that's a discussion that you have with patients and evaluate their preferences in contrast for ulcerative colitis, similar approach for ulcerative colitis patients. Um I will preferably use your status or Bds and M. M. X. For those patients, especially those in more distant disease. Mhm. In that instance if their symptoms are moderate and they're afraid of side effects of predniSONE, I would use something like you said is on the other hand, if their symptoms are more prominent, I would tend to push them towards trying predniSONE to try to get into a symptom control quicker. Um And then at the same time trying to make other treatment decisions with regard to long term management of these patients. A few tricks of the trade with buddhist Sinead. So for illegal released you destiny. It reliably releases in the terminal ilium and the right colon and not the left colon. And so it didn't work well in crowns colitis. And with just as said said, you could try him. Mx off label for Crohn's colitis in that setting. But so ilium and right colon disease. Of course the natural history of those patients is to get operated and many of them have had operation. So if you have the, you know, not just the ascending colon, but if you have and elio trans verse. And especially in elio descending aurelio sigmoid Aurilia. Rectal anastomosis actually wouldn't want the mm XP destiny because it will probably just blast through and the the right colon becomes the left colon becomes the right colon in the in the surgical reception setting. And so will you release be decimated for Ilya rectal sigmoid Ilias descending is a great therapy um it releases perfectly for a pouch. So if you have both crowns of the pouch but also pouch itis. So Bruce, you'll probably remember there was a study way back when in Argentina where they looked at do destination enemas versus which were not available in the US but were available there versus Metro night is all I think for pouch itis and ups and it worked great. So that's my for pouch itis as opposed to CNN's of the pouch. My second line therapy after antibiotics is actually earlier release be decimated. Um, and then from a safety, you know, we say that you shouldn't use uh steroids for maintenance, but you decimated, I think has a little bit of caveat on that. So first of all, when we did The, we did a pooled analysis of all the distant, ideally released maintenance studies in Crohn's disease. And what we saw was the median time to relapse on Placebo was 90 days, and the median time to relapse on drug was 270 days. So it was a pretty big difference. If you look at the proportions of patients who were in remission on drug and placebo, they were statistically significant through three months. Just about there at Six months and and less at 12 months. And so if you read the label, it actually indicates maintenance for three months and it was sort of based on those cross sectional data. But then on the safety standpoint you get very little steroid side effects. It's not to say that it never happens. But it was remarkably unusual with the six mg dose. And in fact, there was, there was a bone safety study done in the Netherlands years ago where they randomized, you could never do this today. This must have been done in the nineties, early two thousands. They randomized patients for two years of therapy with predniSONE uh 20 mg A day and then you could adjust up or down to control symptoms versus destiny and you could just up or down. So after two years, The average dose of predniSONE was 20 and the average dose of medicine, it was about seven, which means there was a fair amount of nine as well as some six and three and zero. And they looked at bone density and fracture and the bone density dropped in the chronic predniSONE patients and there was no difference over two years and An average of seven mg a day with my destiny. So I often will use medicine. Need sort of chronically for patients that don't want to go to a biologic in the mild to moderate patient. In some cases where I'm not going to give them about appearing because I don't think they work and they have toxicity. I might just give them six mg would be decimated and I sometimes we'll add it in on top of the train wreck patients. So you have patients with the biologic and if I appearing And they still got some disease and symptoms and put six mg would be destined in there. So I don't know if you guys have any other tricks but I think that drug is a great drug. I certainly do use it. I I have to say that I don't have many patients on chronic buddhist need but but I do have some and as you say, it's all it's just sort of the balancing of what what what one of the risks and benefits of the alternatives available to the patient. There are some circumstances where it makes a lot of sense. Thank you. Um And then going back to uh the escalation, maybe uh doctor you can grab this one to um when or if do you withdraw immuno modulators wants patients achieve remission on combination therapy. Yeah, that's a tough one. I try not to um for many, many reasons but I think so if the question of de escalating the immune modulator comes up, I tend to walk the patient through really just the risks of it, the disease. Relapse considerations around it. If there's still consideration for wanting to move forward. You want to see at least a good 2 to 3 years of deep remission. Uh normal biomarkers. Endoscopic permission and hopefully ideally histological permission and that they've been doing really, really, really well. Um And at that point, you know, you can have a frank discussion with them about the risk of withdrawing it and the risk of immunogenicity. I will say that recently I had this come up once and I ordered the risk commune tests they actually um for the antibody and it came back positive and the patient said okay we'll just stay on the combination therapy long term because I don't want to lose the benefit of achieved from the Remicade them on. So that's sort of one opportunity that you might think about using that test in there both to convince them to stay on it and or sort of see if it's possible. But this is definitely an area where we need some dedicated sort of clinical studies and clinical trials to understand you know who we might be able to deescalate combination therapy on. Um And think about some of the proactive monitoring abuse you talked about to try to avoid the immunogenicity risk which is a big concern first. Your colleague john fred column bell if you were here I think would have a very different view of that. What's the sort of spectrum of approaching de escalation in Mount Sinai? Uh Probably as many approaches as there are providers but you know based on the data from story um guess jean fred is very optimistic person and would say that half the patients do get away with it for about three years. Of course three years is not a lifetime and there are some predictors of who's going to relapse. Uh you know I think it's okay. Uh you know there are some patients for whom it's not the last straw it's not the last thing in your toolbox and there are others for whom it is. Um I think, you know, if you talk to marla, she thinks everything can be done by just making sure that the levels are adequate from the beginning, that you don't have early image ethnicity and you keep adequate drug levels throughout the course of treatment. I think most of us are somewhere in between those two extremes and pick and choose. Another question for the panel is what are your opinions on biosimilars? Well, they're here, there's no question. They're here in a big way and whether we like them or not, they're here because initially in the first few years they entered the US market at least in new york, we saw very little push from insurers to use them. That is no longer the case. We're seeing a very vigorous push toward biosimilars and we have really no choice to do it. It's created a lot of work and a lot of concern among patients. But in fact, the data from europe are largely reassuring about switching from innovator uh inflicts map to biosimilar, inflicts maps of different sorts. Um and even switching back and forth to some degree, there are some reassuring data. So I basically tell my patients, you know, we can try to fight this, but for the most part we don't win. We don't have a compelling rationale not to switch and uh mostly I have to say our experiences they have done. Well, I would just say don't feel guilty about it. It's fine. This is not a battle I ever like to take on because I think intellectually it's perfect. They're interchangeable and I don't care. It's it's not something I want to fight, but it's really of consternation to patients who have been told from the beginning don't stop this. You know, and they view this as stopping one thing and starting a different thing. And what if it doesn't work? What if I lose response? So it raises an emotional response among patients? It's hard to address. What I like to say is do you feel comfortable switching one bottled water for another? I will drink bio somewhere water. That's exactly I just have one last question before we wrap up for the morning session. Um and maybe dr sands. You can start with it. Um The newest drug on the block Ozan Ahmad um you know, you briefly talked about where it might fit in the algorithm, but who are the patients that you're starting it on in your clinic these days? Well, I have to say that I have more experience at this point in the clinical trials than than I do in clinical practice in the clinical trials. Of course. Most of the patients were highly refractory patients and not all of them did well, but really have some impressive examples of some who did do very well. Um you know, the data show that the drug is a bit more effective as with all things in the more night biologic naive populations but there are subsets of patients. I'm not sure how they're defined really who do respond even if they're not even if they are bio experience. So at this point it's inevitable when a new drug is introduced. It's almost always given first in clinical practice to the patients who don't have other choices. That is obviously going to be the hardest test of a drug and lead you potentially to conclude that the drug is not as effective as we've seen in the clinical trials because this is an effective drug. Um So I think I try to offer it to patients even as an early therapeutic. Um Even in biologic naive patients and um it depends on the patient's some of them are very conservative and they're thinking say this is a new drug, don't want to start a new drug. Some of them really take to the convenience of an oral and that's the winning feature for them. And there's a new you know with with those enema. There's some new sort of check marks that we have to go through that we're not not used to EKGs potentially eye exams and that sort of thing. Um Are you how are you navigating that with your patients in a way that doesn't sort of scare them from uh from the drug. Yeah I don't think it's really that hard. You just need a you need an E. K. G. At baseline. It's not hard to look for conduction abnormalities. Even I can still do that after practicing solely gastroenterology and solely IBD for many years. It's not that hard. Um You know and the actual rate of occurrence in the clinical trials of conduction delays. Dinovo were pretty low because of the dose pack that's given. It's really quite easy with the blister pack. Um As far as the ocular toxicity. Yeah if the patient has a history of UV itis if they're diabetic they're you know they're already getting they should be getting eye exams. Uh So they just need another one at baseline and I don't find that to be terribly onerous either. Um The one thing that I would say is there are a lot of at least potential drug drug interactions. So it is worth checking that in your electronic health record against what else the patients on or have a pharmacist do that. Um I think the interactions with foods like red wine and terming uh containing things are maybe a little bit overstated. And probably not that concerning dr singer doctor. Do I do you have any clinical experience with it in your practice and very limited if any it's very new for me personally. So I would say not enough to comment and I don't have it. Like well asians really well generally well tolerated. You don't need an eye exam unless you have you the itis or diabetes. You just don't need it. And the E K. G. I'm not as sanguine as Bruce and I like to read EKGs, but the cardiologist doesn't for you. So all you need to do is be sure that you saw the report. You don't even need to recognize the conduction abnormality. You just need to recognize when the cardiologist, cardiologist writes it down that you have one. Um So it's really that's really simple. It's easier than getting a Quantum Fear on or Hepatitis B stuff. I mean it's just very simple Test and and watch for the full publication which is coming September 32, a prominent journal are getting EKGs for other medications or we should be at least that are used in general. G. So
