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Using IL-23s in Crohn's Disease
169 Plays2 years ago
Dr. Chris Ma speaks with Dr. Brian Feagan and Dr. Allen Lim about the role of IL-23 inhibitors in the management of Crohn's disease.
This episode of Science for the Real World is part of Canadian IBD Today, an open access scientific journal for the gastroenterology community.
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Transcript
Introduction to Science for the Real World
00:00:02
Speaker
Welcome to Science for the Real World, Conversations with Canadian Clinicians. This episode, part of Canadian IBD today, is about IL-23s and Crohn's disease and is sponsored by Adv.
Meet the Experts: Dr. Chris Ma, Dr. Brian Fagan, and Dr. Alan Lim
00:00:18
Speaker
Our moderator, Dr. Chris Ma, is joined by Dr. Brian Fagan and Dr. Alan Lim.
00:00:29
Speaker
Hello, everyone. My name is Chris
Role of IL-23 in Crohn's Treatment
00:00:31
Speaker
Ma. I'm a gastroenterologist at the University of Calgary. Tonight, I'm thrilled to be joined by two leaders in the IBD community in Canada to talk about the role of IL-23 inhibition for the treatment of Crohn's disease. I'm thrilled to welcome Dr. Brian Fagan, Professor of Medicine at Western University and Senior Scientific Director at Alimentiv.
00:00:55
Speaker
as well as Dr. Alan Lim, who's a gastroenterologist and expert clinical trialist at the University of Alberta. So it's really a pleasure to have you guys on the podcast tonight. We'll get started with the first question right away. And Brian, this first question's for you.
00:01:13
Speaker
It's
Historical and Modern Crohn's Treatments
00:01:14
Speaker
more of a historical perspective on treatment for Crohn's disease. Before the early 2000s, we really only had steroids and immunomodulators. Then for the better part of a decade, we really just had anti-TNF therapy. Now in 2023, we have more modern monoclonal therapies. How has that changed the risk-benefit profile versus pre-biologic and versus the anti-TNF days of Crohn's disease management?
00:01:44
Speaker
Well, Chris, I'm not surprised you asked me that question being the elderly statesman to Alan and you are children and wouldn't remember the pre-biologic era. Certainly, when all we had were immunosuppressives and corticosteroids, it was pretty dismal for many patients. And certainly, infliximab and natalumimab made an enormous change. And we all saw patients that would have ended up with disastrous results without those drugs.
00:02:11
Speaker
Those agents had their limitations, specifically their specific immune suppressives, and are associated with increased risk of serious infection.
Evolution of Treatments and Drug Monitoring
00:02:22
Speaker
So really, things began to change with the development of Vettilizumab, first as a specific agent, just affecting the gut, and Ustikinemab, and then subsequently the IL-23s, where these agents unexpectedly had very low rates of serious side effects.
00:02:43
Speaker
The other point I would underscore is that infliximab, particularly as a drug, was highly immunogenic and was under-dosed. We really got the dosing wrong. And that led to the whole concept of therapeutic drug monitoring.
00:02:59
Speaker
And I would just make the point that as we evolve into the modern era with the newer agents, that both reactive TDM and certainly proactive TDM are going to play a lesser role in our management strategies.
00:03:14
Speaker
Yeah, we've been really lucky, certainly in recent years, in terms of safety profile of our monoclonal therapies. I think it's really made a big difference in clinical practice. Alan, you're a very experienced clinical trialist. You're probably
Real-World Experience with Rizakizumab
00:03:28
Speaker
one of the highest enrolling sites in the world for the Riz and Kizmab Phase III program. How does what Brian described in terms of risk benefit for new therapies and new molecules, how does that align with your real world experience?
00:03:41
Speaker
Thanks, Chris. I think that my real world experience with Rizakizumab really aligns quite closely with the trial data. When I look at the patients that I enrolled, which is probably 30 to 40 of them, about 40 to 50 percent of them actually achieve substantial clinical remission response by one year or even week 12. You know, their abdominal pain scores, their stool frequency scores were a lot better.
00:04:08
Speaker
In terms of risks, we always worry about infection risks or side effects. Aside from my patients all getting COVID-19 at some point in the clinical trial because it was during the pandemic, I really didn't see any infection risks other than the odd bout of food poisoning, cold or flu. And I think one of my patients was hospitalized for a broken leg from a work accident.
00:04:29
Speaker
Yeah, that's really reassuring, actually, and really highlights, you know, the reality of living through 2019 to 2023, at least to present day. Brian,
Targeting IL-23 vs. IL-12 & IL-23 Combined
00:04:40
Speaker
you know, I think when we think about IL-23 targeted therapies, you know, a lot of our colleagues ask this question, which is how can you block just, you know, one molecule in IL-23 and how can that actually be more effective
00:04:55
Speaker
in blocking both IL-12 and IL-23, and it's from an immunological perspective, why would specific targeting of IL-23 be potentially better? And before you answer that, the second part of the question is, you know, do we have data to support that either in inflammatory bowel disease or in other indications?
00:05:17
Speaker
I think we've learned a lot on the evolution of this pathway. It started with Oostokinumab where we thought we were blocking IL-12 and because of the sharing of the P40 subunit between IL-12 and 23, we were blocking both the TH1 and TH17 pathways.
00:05:35
Speaker
And the concern was that ultimately that approach would result in severe immune suppression and just the opposite occurred. And with the advent of oostokinumab therapy and psoriasis, and we've had enormous experience with that over more than a decade now, it's apparent that this is quite safe. So one of the fundamental questions was why blocking 12 and 23 would be safe.
00:06:00
Speaker
It turns out that this relates to the fact that the 23 pathway is really fundamental to very specific inflammatory diseases, not all immune diseases. In fact, it's just the IBDs and the emphaticities, including angspond, psoriatic arthritis, and uveitis.
00:06:22
Speaker
blocking that pathway actually downregulating specifically has a tremendous beneficial effect. And remember, one of the risk factors for side effects is disease activity. So more effective directed therapies result in safer drugs. And then as far as the data from animal models and that, one really important observation is that the IL-23 knockout mouse is actually immune competent.
00:06:50
Speaker
So I think that kind of explains the situation. And then back to psoriasis regarding efficacy, we don't have the data yet from comparative trials of 1223 Oostokinumab versus the specific 23 inhibitors, but the data in psoriasis are in and it's quite clear that, as you alluded to, that the more specific targeting of 23 is a more effective strategy.
00:07:16
Speaker
And it's a tough question because why that is specifically at a molecular pathway level isn't known. There are some interesting observations, though, that I think help us. First off, it comes from the clinic, not the lab. But we know that our experiments with blocking IL-17, which is the effector cytokine of the Th17 pathway in patients with Crohn's disease, was actually very
00:07:43
Speaker
unsuccessful and unhelpful in that it appeared to increase the risk of certain infections, fungal infections specifically, and we know that IL-17 in the gut is protective and important for barrier function. In IBD, that may be a bad strategy because local production of IL-17 by T17 positive cells appears to be a protective mechanism, and there was no evidence of efficacy in that approach.
00:08:10
Speaker
And then conversely, in ankylosing spondulitis and psoriatic arthritis, we see a very interesting differential effect in that blockade of 23 is not effective in angspond where it is in psoriatic arthritis. And it may be an analogous situation to the gut in that local production of IL-17 by TH17 cells is important in angspond and can't be overcome by systemic blockade of 23 higher up in the pathway.
00:08:40
Speaker
So, you know, that's really taking into clinical observations and speculating back to the pathogenesis being common but different in these diseases.
00:08:51
Speaker
That's a great answer, Brian. It's no wonder I only ask you the hard questions. One of the things that you mentioned, I think, is a nice segue to this question for Alan.
Head-to-Head Studies of IL-23 Inhibitors
00:09:01
Speaker
Alan, Brian mentioned potential head-to-head studies. I know your sites involved in some of these studies in Crohn's disease can tell us a little bit about these, what mechanisms of action are being compared, and how those might influence our practice moving forward.
00:09:19
Speaker
So right now, one of the studies that we are involved in would be the sequence study. And in this study, they're comparing eusochismab, a P40 inhibitor versus rizochismab, which is a P19 subunit inhibitor. We don't have the data yet, but it's going to be interesting to see whether or not there's an inferiority or superiority bias based on this trial.
00:09:41
Speaker
Some of the other IL-23 trials have done comparator arms. For example, the Galaxy trial is comparing Galsakizumab versus Eustachizumab, as well as the Vivid study looking at Mirachizumab. They're comparing their drug against Eustachizumab as well. So I think we're going to be inundated with a lot of data comparing all these different molecules in the next year or so.
00:10:05
Speaker
It's a tremendous evolution. Even a couple years ago, we said we didn't have head-to-head trials in IBD, and now hopefully we'll have very clinically relevant answers from some of these big studies that you mentioned.
Advancements in Clinical Trials and Endpoints
00:10:17
Speaker
Brian, in terms of newer phase 3 trials that have been recently completed or that are ongoing,
00:10:23
Speaker
Could you talk a little bit about how those trials have evolved and how those endpoints have changed? And how does that influence your ability to compare even indirectly rates of mucosal healing in phase three programs?
00:10:38
Speaker
Well, if we start at ulcerative colitis trials, the FDA has shown a pretty important leadership here in that we've refined the definition of clinical remission in UC, getting rid of the physician global rating and insisting on a bleeding score of zero as a criterion for remission. And that's actually improved the specificity and lower placebo rates. So that that's been a positive development.
00:11:04
Speaker
The other aspect has been the implementation of central reading of endoscopy in both UC and CD trials. Again, that's helped control placebo rates and led us to improve quality in trials generally. So I think that's been a very positive development generally. Also in UC, histopathology is emerging as an important endpoint and it'll be interesting to watch this over the years.
00:11:32
Speaker
There's a lot of clinical resistance to using it for good reason. We don't have pathologists who really interpret biopsies in the way the trials are interpreting them. And so watch this space over the next five or 10 years because it's likely to be an important endpoint. In Crohn's disease, as usual, things are more complicated. And really the most important development is we've moved away from symptom-based endpoints.
00:11:58
Speaker
and qualifying patients with objective evidence of inflammation by endoscopy. And that's helped tremendously, again, controlling placebo rates, which has been the real thorn in our sides methodologically over the years that has really interfered with their ability to detect effective treatments. So the big thing has been, if you look at, for example, the most recent
00:12:23
Speaker
is in case you have studied or the opposite nip studies and crohn's disease we see endoscopic data that is not comparable to previous studies in the sense that very sophisticated central reading and there's been an emphasis on improving
00:12:41
Speaker
the methodology for incorporating objective measure of endoscopy, a 50% reduction in the SESCD score with a clinical endpoint. So it's really improved things tremendously. Now the question of comparison.
00:12:58
Speaker
I guess I'm not the greatest proponent of network meta-analysis for this reason. One of the fundamental premises of network meta-analysis is that you can integrate placebo controls from trials that were performed a decade ago to current contemporaneous control groups. That's a really challenging assumption given what we just talked about regarding the evolution of endpoints.
00:13:26
Speaker
It does create an issue there. Yeah, Devil's definitely in the details and some of these NMA's around transitivity and whether or not that's truly preserved.
00:13:36
Speaker
Alan, as someone who is a trialist and Brian talked about endoscopy in both Crohn's disease and ulcerative colitis, you've seen some of these therapies achieve mucosal healing in the trial setting.
Mucosal Healing: The New Standard
00:13:48
Speaker
Is that your new clinical standard of care? And how do you see that being integrated in terms of your clinical practice, both for induction and maintenance therapy?
00:14:00
Speaker
I think that as any gastroenterologist who's heavily invested in the care of their IBD patients, our treatment targets have evolved over time. If you look at the current stride guidelines with the ultimate treat to target goal of precosal healing or improvement, I think that's the goal that we're all aiming for.
00:14:19
Speaker
For most of my IBD patients, we would typically assess their disease from mucosal healing at six to nine months. Realistically, it's probably more like nine to 12 months given the resource and time constraints. So I think we've always looked for mucosal healing or improvement in all of our IBD patients in the last couple of years. What was really nice about being a part of the trial was that we have endoscopic data as early as week 12. So it was really
00:14:46
Speaker
great to be able to correlate the clinical responses at week 12 to what I was seeing endoscopically for a lot of the patients. It would probably change my practice in the sense that if you have a patient where you're questioning whether or not Rizakizumab or one of the newer therapies was working for them, knowing that you have data at week 12 showing response in a certain number of the patients, then you could probably reassess them sooner and switch their therapies if they're not responding.
00:15:13
Speaker
Yeah, that would be a total paradigm shift in how we've managed Crohn's disease up to now. So Brian, we now have multiple therapeutic options available in Canada.
Choosing the Right Crohn's Therapy
00:15:23
Speaker
More are coming. How do clinicians decide which therapy to use first? You know, there's probably two schools of thought. One would be to say, I have these newer therapies, they show mucosal healing even in treatment failure populations. So should I save that for last or should I go with
00:15:41
Speaker
hit me with your best shot first kind of approach. Yeah, there's a lot of balls in the air about deciding the initial choice of therapy and it's a balance between
00:15:51
Speaker
therapeutic index, availability, root of administration, number of things. So that could be 40 minutes. But I'll get to the point. Patients like safe drugs. And as I started out by saying that one of the biggest changes in therapeutics in the last 20 years has been classes of drugs that are safe. And so Beto, Usta, the 23s are all really quite safe drugs.
00:16:16
Speaker
So, in most patients, they're going to be preferable choices to TNF antagonists. Now, there are notable exceptions. If you have a patient, if you're wearing a white coat, or if a patient may be in an environment where they're going to be around white coats, TNF antagonists are still very valuable induction drugs. And so, we shouldn't forget that.
00:16:37
Speaker
And overlap syndromes are common inflammatory diseases like psoriasis, ankylosing spondylitis are going to change your approach on an individual patient basis. But the safer drugs are becoming dominant.
00:16:53
Speaker
Now the notion of reserving your best quotation marks drug for last, I think that's an antiquated idea. And it comes from an era where we didn't have many choices and the kind of naive notion that if you didn't preserve that drug, you wouldn't have it when you needed it.
00:17:11
Speaker
Remember though that with biologic drugs, there's a drop off with every agent to use of about 10 to 15% in relative efficacy. And so if you start off with a low number using your less efficacious drug, you get to a very low likelihood of response early. Whereas starting with an effective drug is probably the way to go, especially if it's a safer drug.
00:17:39
Speaker
Alan, I've saved the toughest question for you at the end. In terms of bio-experienced, bio-naive patients, you know, we have a mix of those patients going through clinical trials. Now in your practice, how do you position our currently available therapies for both of those groups for bio-naive and for bio-experienced Crohn's disease?
Strategies for Bio-Naive and Bio-Experienced Patients
00:18:02
Speaker
Yeah, that's a tough one. I think for my bio-naive patients, I agree that the first biologic you use is probably the one that's got the highest chance of being the most effective. So you want to pick a therapy that's got a high efficiency rate and low side effect or infection risk.
00:18:21
Speaker
I think more than ever, your history is really important at this point in time because you really need to hammer down whether or not they have other extra intestinal manifestations, you know, psoriasis or uveitis, angspon, RA, things that may push you towards using an NTTNF versus an NTIL-23 versus vitalizumab. For your bio-failure patients,
00:18:47
Speaker
You know, as you fail more drugs, your options become more and more limited. So you may not have a lot of therapeutic options left to choose from. I think a lot of these patients for me end up in clinical trials. And if you look at the trials that we've been a part of, for example, the Rizakizmab trial, if you look at the Motov8 data,
00:19:04
Speaker
over 50% of the patients in that induction trial had failed more than one biologic before enrolling into the study. So you're talking about a really drug resistant patient population. And they were still able to achieve, you know, a very high clinical and endoscopic response of around 30% by week 12. So I'm a big fan of Rizakizmab based on that data and what I saw in the trial. Awesome.
Conclusion and Thanks
00:19:29
Speaker
Well, that's all the time that we have for tonight. I just want to take a moment to thank Brian and thank Alan for joining us tonight. You know, I think you can easily appreciate that as we get more therapies for Crohn's disease, the decision making potentially gets more complex, but also hopefully the opportunities for our patients to get better also proves. So Brian, Alan, thank you so much for your time and for your expertise. This is really great and much appreciated.
00:19:54
Speaker
Thank you for joining us for this episode of Science for the Real World, sponsored by Advi and produced by Catalytic Health.