Become a Creator today!Start creating today - Share your story with the world!
Start for free
00:00:00
00:00:01
The Role of JAK Inhibitors in IBD
114 Plays1 year ago
Dr. Yvette Leung speaks with Dr. Neeraj Narula and Dr. Jesse Siffledeen about the role of JAK inhibitors in the treatment and management of inflammatory bowel disease.
This episode of Science for the Real World is part of Canadian IBD Today, an open access scientific journal for the gastroenterology community.
Recommended
Transcript
Introduction to the Podcast
00:00:01
Speaker
Welcome to Science for the Real World, conversations with Canadian clinicians. This episode, part of Canadian IBD Today, is about the role of JAK inhibitors in the treatment and management of inflammatory bowel disease and is sponsored by AVI.
Meet the Panelists
00:00:16
Speaker
Our moderator, Dr. Yvette Leung, is joined by Dr. Naraj Narula and Dr. Jesse Sivilden.
00:00:24
Speaker
Hi,
JAK Inhibitors in IBD - Current Challenges
00:00:25
Speaker
everyone. My name is Yvette Leung. I'm a gastroenterologist with UBC at St. Paul's Hospital, and I'm delighted to be joined by two of my colleagues.
00:00:34
Speaker
from the IBD community. Dr. Neeraj Narula is joining us from McMaster University at Hamilton Health Sciences and Dr. Jesse Ciffledon from the University of Alberta Grey Nuns Hospital. Tonight we're going to talk about the role of Jack Inhibitors in the treatment and management of IBD. So let's get started right off the bat with our first question for Neeraj. I had the pleasure of reading your most recent article as part of that special supplement for Canadian IBD today. I really like the way you outline the
00:01:02
Speaker
many significant challenges and unmet needs when we're treating our patients with IBD. Can you just briefly take us through these challenges and really help us identify what needs to change to overcome these challenges? Certainly. Thanks for the invite to be a part of this podcast, Yvette. I think it's a great time for us to be health care practitioners who manage inflammatory bowel disease. Certainly, there's been a boom of treatment options that have come to market
00:01:31
Speaker
And we're still expecting more options to come in the coming couple of years. But the problem is the therapies that are still available to us today, they're pretty limited in terms of what they can do. Generally, we see 50% rates of clinical remission, 30% ish rates of endoscopic improvement. And even further, when patients are on treatment, not all of these patients are really optimally controlled. And some of them will still need intermittent courses of corticosteroids to get them under better control.
00:01:59
Speaker
And really the result of this is partially uncontrolled or sometimes fully uncontrolled disease. And some of these patients will still have progression of the disease despite being on advanced therapy. And that can lead to bad things down the line, whether that's surgery or bowel cancer and these kinds of poor outcomes. However, as more therapies have come to market, we are starting to see higher efficacy rates and higher deltas compared to placebo. And that certainly gives me hope that we're heading in the right direction.
RINVOC's Impact on IBD Treatment
00:02:29
Speaker
So what I'm hearing is as treatments have evolved and efficacy has gone up and hopefully endoscopic improvement rates have gone up, hopefully that will overcome a lot of these challenges. So with these changes in mind, we're going to focus a little bit more than on RINVOC, which is our selective Jack inhibitor. We know it's been recently approved in Canada. When you look at the data, particularly the phase three data that's recently come out for both the Crohn's disease and UC phenotypes,
00:02:55
Speaker
How do you anticipate this new option based on this data? How is it going to really able to change your approach to these patients knowing from where you're coming from, right? When you've only had 50% clinical response or improvement and still unfortunately a lot of patients with, you know, chronic symptoms. Yeah, it's a great question. And you know, to, to go to this new treatment option we have available written book, I think, you know, certainly will offer some advantage to a lot of our patients.
00:03:24
Speaker
You know, just to perhaps inform our audience a little bit about Rinn-Bokes, since probably some people haven't had much experience with it. It's a Selective Jack-1 inhibitor, and I think this theoretically does confer some additional anti-inflammatory benefit without the unwanted consequence that can occur if you have some off-target binding of things like Jack-2, Jack-3, for example. And that is an advantage compared to Pan-Jack inhibitors.
00:03:49
Speaker
And by selectively targeting JAK1, which is the primary JAK signaling molecule that's implicated in the signaling pathways for cytokines that basically lead to ongoing inflammation, and avoiding JAK2 and JAK3, which are involved in things like hematopoiesis and immune cell development, it allows you to potentially have higher efficacy and more benefit without that additional risk.
00:04:15
Speaker
Now, the trials of Renvoke are actually fairly unique, and I think they basically raised the bar for IBD trials moving forward. Particularly in Crohn's disease, we observed for the first time ever that a steroid ween occurred after only four weeks of therapy during induction, and significantly more patients achieved steroid-free remission after induction compared to patients that were receiving placebo during induction. To me, that shows a lot of confidence that this drug works, and it works quickly.
00:04:43
Speaker
We also observed a post-induction endoscopic response in patients who are treated with Rimboc. And this is actually only the second phase three trial for Crohn's disease that's demonstrated endoscopic response. And even though probably in clinical practice, we're not going to be scoping our patients to check for improvement after three months. For me, it's more of a proof of concept that this drug works and it works well.
00:05:04
Speaker
For UC, we see the highest clinical response and endoscopic improvement rates, and Delta is the placebo that we've seen to date. And as a result, I think it's a welcome option for us in the clinic, and it'll help us overcome some of these challenges that we face with patients who do need, you know, repeated course of steroids or have partially controlled disease.
Efficacy and Safety of RINVOC
00:05:23
Speaker
I really like the way you outlined that, Niraj, and I think
00:05:26
Speaker
Truthfully, I always love hearing you speak for data because you always find this really, really lovely way of us being able to organize really complicated data and think of it clinically. I really like the way you pointed out, really not that we're going to be assessing early on, but it really is a proof of concept that you have such a mechanism of action that can really, really induce healing and hopefully much earlier on in the disease course.
00:05:52
Speaker
So I know Jesse's been on the sideline, excited to jump in. So I really do have a bunch of really good questions for you, Jesse. Maybe a lot of people don't know this, but you're one of the highest enrolling sites in the world. They're in Edmonton for the Renvoke-based retrial. Certainly here in Vancouver, I was really jealous, but always a fan, Jesse. So how does a neurologist description of that benefit risk profile of Renvoke align with your experience then during these very important clinical trials?
00:06:21
Speaker
Hi. Thank you very much, Yvette, for inviting me to speak today on RENVOKE. We had a very, very good clinical trial experience, as you've already mentioned, being able to enroll 43 patients in the ulcerative colitis program and 26 patients in the Crohn's disease program in the phase 3 trials for both indications. And our experience with RENVOKE, if I could speak on the ulcerative colitis aspect,
00:06:51
Speaker
was quite phenomenal and our early patient experience in the trial, having such a quick clinical and endoscopic response, gave us a lot of confidence in being able to use this medication and actually offer to other patients who were coming into our clinics needing advanced therapies for both indications. So that was very much
00:07:21
Speaker
something that stuck in my mind early on was a very quick onset of action of Rindwolk. And I think it speaks volumes when 41 out of 43 patients in the ulcerative colitis program, for example, and I believe 19 out of 26 patients in the Crohn's disease program were able to have a response and then enter into the maintenance phase
00:07:44
Speaker
And really in both programs, 80 to 88% of those patients continued in the long-term studies. So there was a clear benefit, not just for the ability to show that clinical response, but patients demonstrated an enduring response and remission to these, to our invoke in both disease indications.
00:08:11
Speaker
So again, given the long-term extension, you feel very comfortable and confident that there's not any sort of signals anyways in terms of safety risks that you've observed and actually a very large cohort of patients.
00:08:25
Speaker
So, I mean, great question. And I think this is always going to be front and center whenever physicians are considering these treatment options. Our adverse events, I can tell you, again, three patients with shingles, three patients who developed Clostridium difficile infection. There was a
00:08:47
Speaker
non-relevant elevation in creatine possible kinase levels. And again, with regards to lymphopenia, there was a signal initially, but interestingly occurred in a lot of patients who already had demonstrated lymphopenia prior to entering the trial. And so I'm very confident in being able to say that this is a safe treatment option.
00:09:14
Speaker
And Jesse, having that experience with both bio-naive and bio-experienced patients, you know, for your very, very large and busy clinical IBD practice, where do you see the Renvoke
Practical Use and Broader Implications of RINVOC
00:09:27
Speaker
fitting in? And I know that's always the million dollar question and you can kind of take different angles, but where do you find yourself reaching for it? Like we've had UC availability now. You know, I'd really love to know what you do day to day.
00:09:41
Speaker
So great question again. And yes, since Revoke was approved at the end of July, I think I've already prescribed it eight times. So in our clinical trial program, patients ranged from 18 to 74. They were bio-naive to bio-experienced. We did have about two thirds of patients who had prior biologic exposure.
00:10:10
Speaker
But that also means a third of our patients were biologic naive. And across the spectrum, patients were responding and robustly responding to medical therapy. Patients who were on prednisone and baseline, that pretty much mirrored the rest of the clinical trial program. And so, I could say confidently that at least at our site, and again taking into account almost 70 patients on hepatic sitting during that time,
00:10:39
Speaker
It didn't matter how many biologics they were on. And frankly, it didn't matter if they were bioinnaive. There's always going to be a question, I think, when it comes to young women who are of childbearing age who are considering having a family. But other than that, and even in that situation, we do have a very good conversation about what options are available. And so far as our experience is,
00:11:08
Speaker
Rainbok appears to provide the best opportunity for success.
00:11:13
Speaker
Thank you for that, Jesse. Neeraj, there are many other immune media conditions that Renvoke's been around for. I mean, it's the sixth approved drug for UC, the seventh for Crohn's, but we know that we've had it for other disease states. Is your impression of the safety data quite consistent across other indications for Renvoke? And the second question to that would be also because it's been around for other disease states,
00:11:41
Speaker
Does that in any way in your mind make it feel almost more safe? Because at least you can tell your patients, well, hey, it's been approved for all these other indications.
00:11:51
Speaker
Well, Yvette, from a safety standpoint, as Jesse had alluded to, we did see an increased risk for herpes zoster with RIN-VOC. And that's a class effect. We've seen this with other JAK inhibitors as well. The good thing about this is we can mitigate this risk with vaccination. And when you look at the clinical trials for RIN-VOC, actually less than 10% of the patients in all of these programs had previously been vaccinated.
00:12:16
Speaker
I do expect in the real world when we vaccinate these patients proactively, whether it's before we actually start the JAK inhibitor or early in the disease course, that we'll actually have much lower rates of zoster.
00:12:29
Speaker
With regards to other safety concerns, there is a black box warning issued by the FDA for JAK inhibitors in the US, and that's largely because of the oral surveillance study, which suggested an association of Tofacidinib with malignancy, major burst cardiovascular events, and VTEs.
00:12:47
Speaker
But from the safety profile we've seen with RINVOLG specifically across numerous other diseases, as you alluded to, including psoriasis, rheumatoid arthritis, ankylosing spondylitis, apoptic dermatitis, we've not actually seen similar risks for major vascular events or VTE. And in fact, when you look at some of these studies, particularly the RA and psoriatic arthritis studies with our active comparators like anti-TNF and methotrexate,
00:13:15
Speaker
we actually see that the rates of VTE, MACE, and malignancy are actually pretty similar with RINVOC as it is in patients who are treated with these other well-established therapies. With that said, we don't have a similar study to oral surveillance with RINVOC, which was a study that was enriched with high-risk patients for cardiovascular outcomes like oral surveillance was. But ultimately, the choice of medical therapy is always a benefit-risk evaluation. And I think with RINVOC, the benefits are quite clear
00:13:45
Speaker
Right. So then when you're talking Jesse, then about benefit, benefit, risk ratios, do you really think it's any different than how we've always discussed benefit, risk ratios? Jesse, because, you know, we've been doing this for a long time.
00:13:59
Speaker
Yeah, yeah, I guess we have been doing it for a very long time. I could almost echo word for word everything that Neeraj has said so far when it comes to the, you know, the risks of infections of serious infections. I think we've become comfortable in having that discussion on other therapies. And I do think that with, you know, with our foreknowledge of vaccination, particularly with Zoster,
00:14:29
Speaker
it becomes a lot easier to have that discussion and to be comfortable with using RINVOC in these patients. And I should also, it's always on the top of my mind that patients with inflammatory bowel disease already have an increased risk of things like deep vein thrombosis, pulmonary embolisms, they have a higher
00:14:55
Speaker
risk, at least when you look at large population studies, they have a higher risk of cardiac events. And so it's reassuring to me when I look at the data, not just with the IBD studies, but also across the other indications, that there really isn't a higher risk of these occurrences in those patient populations with measuring block use.
00:15:22
Speaker
So that just makes me feel more comfortable. And I mean, the three of us have talked on, you know, other panels and have discussed, you know, many times at different
Strategizing RINVOC Use in Treatment Plans
00:15:32
Speaker
sort of settings. The reality is what we always have to tell patients is also the risk of untreated disease, right? I mean, we started off our podcast talking about, you know, potentially these are disabling diseases if we don't give them drugs with good efficacy.
00:15:47
Speaker
So I'm going to off-script a little bit. I know you guys had a little bit of a hint about what I was going to ask, but you know me, I'd like to surprise you guys. So this is actually a general sort of question statement, and I'd like both of you to comment a little bit more about it. And we've kind of alluded to this because we've been talking about benefits and benefit-risk ratios. I mean, the reality is there's no doubt Ren Vogue has showed us that we can be very stringent with our outcomes and have very high rates of mucosal healing.
00:16:17
Speaker
not only in our naive by our prior bio failures. So this comes up all the time, guys. And again, it doesn't matter who wants to jump in first, but knowing that and also knowing what one of you said a few minutes ago that even though it works well in bio failure, it always looks better in that bio naive chart. Should we save the best drug for last or adopt an approach of hit me with your best shot first? So this is open for both of you. And in fact, I'd love to hear from both of you.
00:16:47
Speaker
Sure, I can take that first. Now, I can't confidently say what the best drug for IBD is, but I don't think we should save the best for last by any means, particularly in Crohn's disease, given the progressive nature of the condition. And what we have certainly learned in the last decade is that more time with uncontrolled disease means more time to accumulate bowel damage and disease progression.
00:17:14
Speaker
And we've also seen from almost every clinical trial program that Crohn's patients that have lesser disease duration have higher rates of clinical remission and higher rates of endoscopic healing. So I think trying to get these patients under good control earlier with our most efficacious therapies is sensible and will lead to the best chance for patients to have good long-term prognosis without disease progression. Your turn, Jesse. Oh, hard to follow that one up.
00:17:40
Speaker
So if I was to consider the two diseases separately, for Crohn's disease, definitely I think you want to hit the patient with the best treatment option right off the bat. Try to change that natural progression so that they're not experiencing the complications of strictures and perforations and what have you. When it comes to ulcerative colitis, and then really, whether it's Crohn's or colitis, it's really hard.
00:18:08
Speaker
not to put RINVOC at the top of the list when you see just how dramatic that efficacy can be and what it's been shown in our clinical trial programs. So, yeah, I mean, I think it's always worth considering at first line.
00:18:30
Speaker
So for the purposes of time, you guys know me, I could talk about this all night, but we do have to wrap it up.
Conclusion and Closing Remarks
00:18:37
Speaker
I just want to thank you guys for coming out and doing this podcast. As always, it's just so wonderful to, you know, share experience and information. And I love always hearing the two of you present data in a way that's always very helpful and clinically focused. So thank you again, Neeraj and Jesse. Thank you, Yvette. Thank you very much, Yvette.
00:18:59
Speaker
Thank you for joining us for this episode of Science for the Real World, sponsored by Abby and produced by Catalytic Health.