Chapters Transcript Video IBD Breakout: Safety of Novel IBD Therapies: What and Where to Look For IBD Breakout Session: Safety of Novel IBD Therapies: What and Where to Look For *Not Eligible for CME Credit Great, good morning, everybody. Uh And thank you for coming. I'm leading today's breakout session on the safety of novel I V D therapies. What and where to look for? I'm not sure that makes sense in English. But um but you'll understand my talk uh as we go through this uh next 20 minutes. So my disclosures are here. Um Today, we are going to uh by the end of the presentation. Um Have you understand the history of I B D therapeutics and their safety uh summarize and I will summarize the data on the safety of uh several classes of new I B D medications including S one P agonists, selective Jack inhibitors and anti P 19 antibodies that are either here or are coming soon for the treatment of ulcerative colitis and Crohns disease. So, uh I thought it would be nice to have a certain perspective about the safety of uh therapies through the ages. Uh So, you know, the discovery of ulcerative colitis uh happened in uh or the description happened in 18 75. Um and as opposed to Crohn's uh uh Bel Crone, putting his own name on the disease, um Ulysses colitis did not put his name on the disease. It was actually two English guys named Wilks and, and Moxin who described ulcerative colitis in 18 75. And so, for many years to treat these diseases, we had sulfonamides and antibiotics and corticosteroids were only added to the arsenal in the fifties. Uh Thys actually came out in the late sixties but their description for use in Crohn's disease uh was in a seminal paper published in 1980. Uh and so for the first gosh, 100 years or so of treating inflammatory bowel disease. This is what we had, we had steroids and opines. But uh as of 1998 in flux mab came on the market followed by Adalimumab and several other anti T F biologics. And then we had a gap of 16 years until we had anti adhesion molecules. And then very quickly, we've had several classes of I B D therapeutics uh that have arrived on our shores uh in the last uh 20 years or so. So, uh in terms of looking at the safety of these drugs, uh you know, in terms of uh their use in inflammatory bowel disease, uh they have been uh uh moving from uh completely untargeted uh oral medications to very well targeted uh biologic medications delivered through intravenously or uh subcutaneously or now, uh via small molecule therapy, uh delivered orally. And so, when you think of the nonspecific of these drugs, they come with uh very important safety concerns. Uh Obviously, we know the side effects associated with corticosteroids, uh in terms of uh their effects on blood pressure and cataracts and blood glucose and uh osteoporosis and uh and mood changes and all the rest. And then we had thys, you know, for the next 28 years. Uh And with that came uh hepatotoxic and uh and bone marrow suppression and idiopathic uh you know, incidents of pancreatitis um and other problems. Um anti T F S has been associated with opportunistic infection. Um And there's been some controversy about whether they uh or to the degree with which they contribute to uh uh lymphoma and A T cell lymphoma. Um But the, the closer that we get to current day, the more targeted our therapies have become and hopefully the more safe uh as uh both the FDA demands it, uh patients demand it and drug companies have an eye towards safety. So, in terms of our armament, uh you can see the, the most recent drugs uh that have been approved and I'll even discuss drugs that are on their way. Um And so, uh this is an uh a rather dated slide now as uh as we have uh risen Kuma approved for the treatment of Crohn's disease. Uh And we have uh Zana mod uh available for ulcer of lettuce. Um relatively soon, we'll have two or three new drugs approved uh in the coming year. So first, I want to discuss uh the safety of Ozan mod. So, Zana mod uh is an oral small molecule. It is a sphingosine one phosphate uh agonist. Uh And the way it works is that sphingosine one phosphate is a, is a sugar molecule that uh its uh gradient uh is relied on by lymphocytes to track uh to regional lymph nodes uh through the uh uh through the lymphatics. Uh And when you block the action of uh or the recognition of S one P by uh gut lymphocytes, it locks these lymphocytes into the regional lymph nodes and prevents their uh egress. Uh And so that's how it prevents uh their effect or action on the gut. Um because they're locked into these regional lymph nodes. Um and uh and concurrently, you see a drop in the peripheral lymphocyte count. Um And uh and with this therapy, uh it can be very effective uh in a group of patients with moderate to severely active ulcerative colitis. So, uh this therapy uh has been shown to uh allow for significant mucosal healing with decreases in fetal calprotectin and c reactive protein uh in various clinical trials. Um But when we look at uh the safety margin, uh when compared to placebo, uh in terms of their induction uh induction studies and, and maintenance studies, it seems that uh the risks of many of these side effects are comparable to that uh with placebo, with the exception of uh nasopharyngitis. Uh um But you can see that uh those patients who encountered serious infections was uh was pretty comparable between Ozan mod and Placebo in terms of uh how we follow patients and, and their safety uh on Ozan mod. Uh it's mandated to obtain uh a certain work up prior to prescribing Ozan mod. And that includes obtaining baseline uh lab testing, uh A CBC with total lymphocyte count. Um and we know that the total lymphocyte count will decrease after starting Zosia or Ozan mod and it will reach a stable level about 45%. Uh the value of baseline um at roughly three months after use. Um and it should stay there. Uh We also check liver function testing in Billy Ribbon because there can be uh a brief but uh slight increase uh in liver function tests and and Billy Rubin with the start of Zanon therapy in terms of obtaining a baseline. EKG really the concern is with uh those adults who have uh conduction problems uh in involving ventricular arrhythmias. So especially if they have a Mobi type two, uh second or third degree heart block or six sinus syndrome or an A B block. Uh you have to use these drugs uh with, with significant caution. Um uh And those patients may also qualify to have pacemakers placed and once they are placed, then Ozan can be used safely. Uh There's also an ophthalmologic exam recommended for those patients who have a history of macular edema U V IIS or diabetes melody. Um, because, uh, in rare cases, uh, these S one p uh have been shown to cause uh, macular Dema and those who are susceptible. Um, because of the safety concerns, uh, Ozan mod uh, has a titration schedule, uh, and the first blister pack that's supplied to patients, um, provides them with the appropriate uh, dosing. So, uh, what we recognize from the clinical trials is that those treatment, uh emergent adverse events are most likely to occur within the first three months of therapy. Um And uh so you can see that uh roughly 40% of patients who did encounter adverse events encountered them uh within the first few months of therapy. Um Beyond that, you can have a bit more uh confidence uh that, that this drug uh class will be safe uh for use in your patients. Um So, uh these patients noted improvements in their patient reported outcomes as early as week two with biomarker improvements. Um But also that most adverse events uh were similar between Xao and placebo. Um And those that occurred during induction tend to be transient. Um And uh when you look over the longer time periods, uh patients uh generally had fewer adverse events when on these drugs uh for a longer period of time. Um And so, uh obviously you have to obtain a baseline uh pretreatment work up. Uh And this is one of those drugs that does not require you to have uh the patient to have failed prior therapies uh in order to use it. Uh So, uh whereas the Jack inhibitors, for instance, um you can only use once patients have failed, for instance, anti canni biologics, speaking of which uh Toni uh was the first Jack inhibitor to market. Uh And uh the jacks sta pathway is targeted by this oral small molecule. Uh Jack is a uh is a transcription uh factor uh that uh that once blocked. Uh and, and by blocking the phosphorylation of stat, uh you have the, the blocking of uh of the transcription of our, of M R N A for certain important inflammatory cytokines um such as those listed here. So we all know uh about toy. Um and uh and the fact that it's relatively nonspecific for the three uh uh Jacks. Um and here's the clinical trial data, octave uh induction studies and the maintenance sustained studies showing the advantage of uh using Toni over placebo. But in terms of its uh safety concerns, um there have been black box warnings applied to uh Toni and these black box warnings were actually updated in 2021. So, the primary concerns with using these drugs are those of uh infections with herpes Oster uh and opportunistic infections. Um And now that uh that Shingrix uh has uh been approved uh for young adults, uh it should be provided to all of our I V E patients. Um and not only those who may need in the future, a Jack inhibitor. Um The other safety concerns that we have are for uh uh my myocardial infarction and stroke. Uh and for a thrombosis, uh those are the biggest safety concerns we have with using the Jack inhibitors. There does seem to be an increased risk risk of non hodgkin's lymphoma, uh as well as the nonmelanoma skin cancers as we have with several of our biologics and perhaps with solid tumors, we see uh increases in L D L and H D L in patients on these jack inhibitors. Um uh and uh those risks are associated not only with uh some of the uh increased doses that uh that centers like uh michigan have used in their hospitalized patients, but also some of the standard dosing uh the 10 mg doses and the five mg doses, um especially when compared to looking at the safety margins that we see with anti tina biologics. So I would ask you to use these drugs with caution in older adults and those with uh with a cardiac history or a history of V T E. Um uh But otherwise, it really should be reserved for those patients who failed other therapies. Um And so, uh in addition to standard monitoring tests, we do obtain lipid panels uh at baseline after uh to induction and then every six months uh thereafter. Um now we have several other Jack inhibitors uh that are either on the market or are soon to be released. Um And those include Nib and Phil Cob. Um These are more Jack one uh selective or specific. Uh And so uh one might think that their safety margin would be improved over uh the uh Tofacitinib which is less uh jack one specific. Um but we don't have uh quite yet the safety data to support this conclusion. Um And so, uh while Pacini is gaining in terms of its patient uh exposure, um it may be a little while until we have a better understanding of uh its safety and whether using a Jack one more selective inhibitor would provide for improved safety margins. Um And so these are the effects of uh Jack inhibitors uh on various uh processes including those in the immune system. Uh And uh and trying to discern why the Jack inhibitors are more likely to cause uh thrombosis uh is rather difficult. I could come up with a number of uh postulated uh reasons for this. Um But these are the way that the Jack inhibitors uh exert their effects. Um And as you can see, they have profound effects on the immune system uh and, and effector cells. So, uh you know, Toni uh has been approved now for several years. NIB was approved for ulcerative colitis last spring. Uh and forgot uh was uh this application was turned into the European uh medicines uh regulatory authorities uh for the use in adults with ulcerative colitis. Um And uh they are awaiting uh word on, on approval uh in Europe. Um So, here's some of the clinical trial data supporting the use of the Pacini and active ulcerative colitis showing you that uh that doses, uh induction doses of 45 mg uh were significantly more likely than placebo uh to allow for endoscopic improvement and histologic improvement. Uh And here again, is data showing that even extraintestinal manifestations are improved in those patients uh in the clinical trials who took nib and those include extraintestinal manifestations of uh both peripheral and axial arthropathies in terms of uh safety when looking at uh at the eight week induction trials. Uh And comparing uh the various distance of had toy to placebo, uh You can see that uh adverse events uh were relatively comparable. Um uh And that uh there were no uh there was no evidence of zoster encounter during this uh eight week uh trial period. Um no serious uh uh cardiovascular vaccine. Um And one reported case of V pe or and pulmonary embolism in a 65 year old former smoker um who was also on steroids and hospitalized on bed rest. Um So, uh you know, one might conclude that uh nib in terms of its safety margins is uh similar to placebo in very controlled clinical trial uh data. Uh And again, uh here is uh the uh uh a summary of all of the data with EPA seen in atop dermatitis and rheumatoid arthritis and in ulcerative colitis um showing you that uh rates of serious uh adverse events uh were similar uh if not less than that scene uh in placebo. OK. Moving on uh in terms of drug classes to uh I L 12, 23 antibodies. So we had Eakin Aab approved several years ago for the treatment of adults with ulcerative colitis. And I would remind you that the induction trials showed that intravenous dosing of tic Kuma uh led to a significant improvement uh in uh in terms of remission and ulcerative colitis over that uh scene with placebo and in the long term uh 44 week maintenance, uh trial data, again, there's uh nearly a doubling uh of uh uh of remission over that scene with placebo. Um But now uh we have newer family members to add to the uh group uh including E to Kuma. So Eina uh is a uh antibody directed against the P 40 subunit uh that's shared by both I L 12 and I L 23. Um But we recognize that there may be important uh roles uh for uh I L 23 in, in the immune system uh in terms of regulation. Um And so, uh the most recent drugs um are targeting P 19 which is uh which uh is present on, on the uh uh only on the I L 23 molecule. Um I'm sorry. So aisle 12 may have important regulatory uh uh responsibilities and by blocking aisle 23 that may uh more selectively block uh the T effector cells, the aisle 17 pathway. Uh And uh and so we have, we may have uh better safety margins um and see better efficacy in in antibodies that uh selectively block the pine subunit. Um uh And so I'll show you in a little bit why that may be. So, Risa um was approved uh this past summer for the treatment of uh adults with moderate to severely active Crohn's disease and its use in the treatment of ulcerative colitis uh is now under review by the FDA and I would imagine it will probably be approved within the next several months. Um uh Miri Kuma uh similarly uh has promising trial data uh in ulcerative colitis. Um And its application is also under FDA review and may have a similar timeline of approval as uh Risin Kuma for ulcerative colitis. So, we may have two P 19 antibodies available for the treatment of ulcerative colitis in adults uh within the next 3 to 4 months. So, uh here's the data supporting uh the use of meria uh both in induction uh and the 52 week data. So, in the left-hand panel, you can see the induction data in terms of clinical response, the uh the doses that provide uh uh a higher likelihood of remission when compared to placebo um in either in the biologic naive uh which is more profound or in those um who are biologic experienced. And then in the right hand panel, you can see the clinical trial data um as it pertains to those patients who were in the maintenance trials, again showing significant uh clinical remission uh at the 52 week time point in those patients who were on uh Meza uh and and this goes to show you that they were able to maintain remission, but in terms of its safety uh when compared to uh placebo, uh again, those patients who were on either the 50 mg or the 200 mg doses uh of Meria um had quite similar uh rates of adverse events uh to those in the placebo group. Uh and uh similar as serious adverse events. Uh that's for the uh uh both the induction and the maintenance uh dosing uh data you can see here um any clinical trial that stands the wintertime uh is gonna have adverse events that include things like nasopharyngitis uh and other upper respiratory tract infections. So, in terms of uh blocking I L 12 and, and 23 again, uh uh I L 12 may have important effects on interferon gamma uh and the generation of uh T H 17 cells. Um And so there may be uh an advantage to A P 19 antibody. Um uh We've had eakin aab available to treat uh moderate to severe ulcerative colitis. Uh Now, for quite a while, uh here's the data from uh the unity trials uh showing its advantage uh in terms of uh placebo uh patients enjoying remission uh and uh improvements in c reactive protein that persisted throughout their maintenance uh treatment. Um So now, uh in terms of getting uh beyond uh the aisle 12, uh 23 we're getting into uh looking at uh at the role of I L 23 in perpetuating T H 17 pro inflammatory responses uh as I showed you earlier. Um and that uh I L 23 is thought to be um responsible in uh in the uh in various aspects of the inflammatory cascade uh that are elicited by t effector cells um that make up the T H 17 pathway. Um The dosing of Risin kuma uh is 600 mg I V given at week 04 and eight. And then there's maintenance dosing uh given subcutaneously. Um This is uh the approved dosing for those patients with Crohn's disease. Again, in terms of uh safety monitoring, it's recommended to obtain liver enzymes and billy ribbons prior to initiating treatment. Uh And then following those uh over time, um and here's the clinical trial data that supports the use of uh Riza in patients with Crohn's disease. Um You can see that the I V induction doses in both the advanced and the motivate trials led to a significant improvement uh in terms of induction over that scene with placebo. Um and the maintenance trial uh had similar outcome where nearly half of patients um uh at 52 weeks were uh clinical responders when compared to those um who were exposed to placebo. Um And again, uh looking at endoscopic remission, significant uh deltas here between placebo and the active drug and here's the clinical remission over time showing you that patients may enjoy significant clinical uh response uh and remission um uh rather quickly over the 1st 12 weeks um of therapy. Um And again, here's the maintenance data uh showing uh that uh clinical remission is enjoyed by those who maintained uh risen Zais compared to those on placebo. So, in terms of safety, uh those uh on uh placebo and those on uh risen Kuma, uh the data looks very similar, those who uh had severe adverse events uh were comparable between those on placebo and those on active drug. Um And again, uh few patients had to actually discontinue their study drug. And here's the rates of infection uh and serious infection uh as well as patients uh who encountered uh adverse events like uh herpes zoster. But again, you can see that uh the safety margins are relatively similar between placebo uh and those patients who uh were exposed to Risa. Um in terms of the uh serious infections that were seen in both the induction trials. Um uh again, viral pharyngitis appendicitis. Um These things weren't necessarily attributable to being on RSID Kuma versus those on placebo who likely had adverse events related to ongoing disease activity. And here is the uh data as normalized uh to uh 100 patient years. Um And again, you can see that adverse events were quite similar when compared to placebo. Um, here we can see serious uh infections, herpes zoster. Um uh There was even one herpes Oster encountered in the, the placebo arm. And here are the uh serious infections encountered during the maintenance study. So, uh a couple of cases of heis uh and pneumonia, uh one peral abscess. Um And so again, the safety data looks quite similar. So in terms of therapies with these new mechanisms of action and multiple promising relatives on their way. Um uh you can see that the the safety data is is looking uh quite comparable in these clinical trials to that compared with placebo. Uh It's important to understand when trying to interpret post talk analysis that you can, can't compare these data across clinical trials. Um But the safety profile are relatively favorable, they are limited by small numbers of adverse events and shorter follow-up periods. And so, uh with post marketing surveillance um and increasing numbers of patients treated and patient years exposed, we will have a better understanding of patient safety uh with these new mechanisms of action. Um in terms of those patients who have more severe disease and intestine manifestations. Um We may need to use higher doses which may again uh provide additional safety concerns. Um And uh and we are still lacking a robust body of data on safety uh when it comes to these new mechanisms of action. Um but stay tuned. All right. Well, thank you so much for attending and uh enjoy the rest of the conference. Created by
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