Episode Transcript
[00:00:00] Speaker A: You join us today on Tuesday of the bsg, and I'm delighted to say I'm joined by Professor Florian Rieder, who is the vice chair of the Department of Gastroenterology at the Cleveland Clinic and the global director for IBD for the whole of the Cleveland Clinic project, as well as the section. My boss, the section chief for the IBD section with the bsg, Shahid Ad Din. And we've had a fantastic session this morning which has really focused in about fibrosis. And we've got this opportunity to go even deeper behind the scenes and chat with Flo today about fibrosis and Crohn's and inflammatory bowel disease in general.
It's something you've been championing for a long time. Part of the STAR set up the STAR Consortium and really we're beginning to feel like, you know, all the hard work in setting up the ground rules and, you know, endpoints and trial design and everything else is beginning to bear fruit. And we're beginning to see the first kind of novel agents in this area. Really exciting. So I'm going to dive down. I've mentioned trial design. It's quite different from our traditional trials. We're very used to phase two, phase three. It's the same sort of group of patients. We know what they look like. What are we looking for in these trials?
[00:01:16] Speaker B: Yeah. Thank you so much for having me. And thank you, Shahida, for highlighting fibrosis as an area of unmet need, which it still is. But we are, in fact at the starting line of big things happening with now randomized controlled trials with endofibrotic restriction disease. Your point is well taken because when the first trial started, there was in fact a lot of adaption necessary to the population that is eligible. That's very different from luminal disease in strict chain. Crohn's disease. We largely recruit through imaging and most of the screening happens in the radiology department based on criteria. We call them the constrict criteria, wall thickening, luminal narrowing and then the pre stricture dilation. So the ballooning up of the bowel upstream of the stricture. And once this patient is identified in the radiology department, you make sure the patient is symptomatic, which is another criterion.
And then usually the gastroenterologist gets involved at that stage. Rather than starting through endoscopy identifying moderate to severe disease patients in the trial, we do it through imaging. This took quite a while for centers to get adjusted to, but I think now we're In a good space.
[00:02:21] Speaker A: Yeah. Fantastic. And I think it's going to mean that teams globally for us here in the UK are going to need to be working really closely with our radiology departments. And we saw that today in the session that we had and how we can work together to identify these patients because that pre screening is quite stressful. We used to centrally read colonoscopies, but now we're going to have centrally read MRIs, is that correct?
[00:02:45] Speaker B: So for eligibility you will have a central eligibility Mr. Read and then the endpoints are either endoscopy based or imaging based as an objective marker for change in stricture morphology.
[00:02:59] Speaker A: Okay, fantastic.
[00:03:01] Speaker C: If I can maybe ask a question. One of the things that really interested me this morning listening to the talks was that there's talking about dynamic function of the bowel. So how will that be incorporated into your trial design with eligibility? Or is it just going to be static two dimensional images?
[00:03:15] Speaker B: Yeah. So very exciting what Gaurang Vatnagar presented about motility of strict chain disease. So this is still in the early stages and experimental.
The approach we took in the STAR consortium is what matters to the patient is how narrow the lumen is. If the stool doesn't pass through your symptoms, you're doing poorly. So the morphology of the stricture is what matters for clinical trials. And actually then the endpoints are simple measurements, simple quote unquote, which is stricture length, the degree of pre stricture dilation. As a starting point, we do think that motility may explain symptoms and may predict outcomes. But to establish this as a regulator accepted endpoint, you have to go through multiple steps, you have to show reliability of the measurements, you have to link it to a clinically meaningful change for the patient and then you have to establish what change in motility actually constitutes a meaningful change for the future of the patient.
These are quite high bars for a novel technique. Not impossible, but we are actually working with gorung on doing exactly that.
[00:04:22] Speaker A: But it will take some time if I come back.
In the last 30 years, we've seen massive strides forward in our ability to target inflammation across the board.
And we are now in a situation where we've got what, six, seven licensed classes with a huge diverse pipeline, more diverse than we've ever seen before.
So my question is, why has fibrosis been so far behind this, you know, pulmonary fibrosis, cirrhosis of the liver. Fibrosis is a systemic problem brain.
Why has it lagged so far behind? Could you just for the kind of audience, say what are those issues?
And is safety a sort of major kind of player in this?
[00:05:08] Speaker B: Yeah, very good question. So we have now three drugs approved for idiopathic pulmonary fibrosis. We have one drug approved for liver fibrosis. And there will be more coming. The pipeline across liver, lung, heart or skin is very rich. So we'll see more happening in that space. The challenge in the gut was everyone sees the problem.
Strictures have been described with the first description of Crohn's disease about 100 years ago.
But the industry refrains from engaging in the absence of regulator accepted endpoints. And how do you achieve an endpoint if you don't have an anti fibrotic? So you need an antifibrotic to develop an endpoint because you need a treatment of non efficacy. You need an endpoint to develop an anti fibrotic because you need regular accepted endpoint. And so what took so long is I think there was no group until we started that actually does all the groundwork to establish what a stricture is, justify the definitions, define what constitutes improvement, justify why it constitutes improvement, and then build the endpoints layered onto that which is a symptom, instrument and an objective marker like endoscopy or imaging.
The safety is a concern. It's always a concern for novel drugs. I don't think there was a big holdup, but the questions always come up in our space. A lot of these drugs are influencing remodeling naturally because fibrosis is part of remodeling.
Will patients develop internal penetrating disease because there's a higher association of strictures with internal penetrating disease.
If you have internal penetrating disease, 85% of the patients have strictures. At the same time, we have not seen that. We have not seen that in Stenova, the first anti fibrotic trial. We have not seen that in observational studies. So we followed patients with imaging, confirmed strictures for many, many years.
We have not seen that as a problem, but we closely monitor it.
Then the other safety considerations, depending on drug class. But as example for an anti TGF beta approach, there were concerns about systemic immune activation, heart valves, cancer. There's another drug class coming, the ROC inhibitors. These are active on the vasculature, hypotension, tachycardia are concerns. I think there are safety concerns in relation to the drug class.
But the big benefit of the gut is it allows local delivery and you can design the drug to be either metabolized in the circulation or undergo first pass to the liver.
And that's actually quite unique for a fibrotic Disease you can locally deliver in high concentrations without systemic exposure.
[00:07:48] Speaker C: I was going to ask a question just related to that. My understanding of pathophysiology was the reason you get fistulisation is due to the pre stenotic pressures you have.
Because I was just thinking, as you were speaking, I'm not sure I've seen fistulising disease without luminal narrowing.
So if you improve luminal narrowing, surely just a mechanical process that means that you have less visualizing disease. Do you think that's a reasonable conclusion or.
[00:08:14] Speaker B: I have an unproven hypothesis about that. So humans tend to try to explain everything they find in a context that they know and that they can relate to. So this high pressure hypothesis makes intuitive sense.
And you have a wall that's weakened by inflammation, then develop a fistula tract.
I'm not sure if that's the case because if that were to be the case and you have an abscess, for instance, the abscess would be massive because if there's high pressure and everything gets diverted through the tract into the abscess, you would have these massive abscesses.
And the other observation we made, and I don't know if you relate to that, but in our consortium I have hardly seen a stricture progress to internal penetrating disease. What we've seen a lot is patients present either with a stricture or with a stricture and internal penetrating disease. Even when we go back, they're inflammatory and then they either go to stricture and IP or stricture only. We rarely ever see IP only and we rarely see stricture Image confirmed, progressing turn offending disease. So what I'm wondering is, are these two different phenotypes all together rather than one progressing into the other? It's an hypothesis. We haven't seen enough data to support that.
But that's also one reason why I'm less worried in the trials, that this may be a big problem.
[00:09:47] Speaker C: Sometimes when I think about these trials, I was wondering, maybe it doesn't matter if they do develop penetrating disease, because the only outcome for these patients is eventually they will need surgery.
So if you precipitate that time point happening sooner, where you're trying to help improve that disease process, maybe that's not
[00:10:06] Speaker B: a bad trade off in the setting of a clinical trial. I agree with you. I think in clinical practice it would be a challenge because these patients technically will be on therapy for years to prevent progression of fibrosis or even achieve regression. And if that internal penetrating disease would be a significant concern, they would not be able to prevent surgery in the clinical trial setting. You're right, I'm not so worried because the setting is controlled and they would otherwise go to surgery anyway once approved, I think it would be.
But I'm not so worried about it at the moment. I think we need to be vigilant. I don't want to sound negligent, but I'm not so concerned about it.
[00:10:49] Speaker A: When we had the talks this morning, Shahida, you sort of introduced with these two images looking quite similar looking strictures and both had ulceration in there.
One advantage of this trial design which I think is going to make it really acceptable to patients is they're going to often stay on their existing drug. So they're staying, you know, maybe they're on an anti interleukin, so they're going to stay on that drug. No washout period, no concern around that. It's that they've got symptoms from obstruction. We now need to deal with that. That's fine. So if we go in there and we find a dry fibrotic looking endoscopic stricture and everything sort of lines up.
But what if we find lots of ulceration and the drug they're currently on is clearly not controlling the inflammation plus they've got a stricture, are you going to include those patients into the study? Are you going to say, well hold on, we need to take a, you know, this patient needs both things potentially. They need a new, this drug's not working. They're going to need their anti inflammatory component changed and they need, and how do you control for that?
[00:11:51] Speaker B: So it's a very good point.
In my mind I separate anti fibrotic drugs into two buckets.
One only antifibrotic, potentially antifibrotic, and one anti inflammatory and antifibrotic combined.
So you're referring to a scenario where you have an anti fibrotic only you add it on, you keep the background therapy stable and you assess stricter morphology as an endpoint.
When a patient has very severe inflammation, there's a high risk they're going to obstruct anyway.
The way this was so far handled in the trials was with a clause saying patient should have a non critical stenosis that is likely not to obstruct within 12 or 24 weeks of the trial or go to surgery or balloon dilation during the time frame. So at the moment a lot is left to clinical judgment. And you're a very experienced clinician and clinical trialist.
So if you see a patient like this, you would then Say I don't think that's going to work for this patient.
It's not going to be in the trial. The other approach we have taken is to capture the ileal SCSCD inflammation part of the score, not the narrowing subscore. Because narrowing subscore patient has a stricture. But look at the inflammation score and cap it at a max.
We don't really know what is the optimal max, which patients are going to do bad. I think leaving it up to the clinicians may be a good idea.
Instanova has turned out to be the right choice. We did not have a problem with patients going in with too severe inflammation. Obstructing the other bucket is anti inflammatory and anti fibrotic. And in these instances you would wash out the existing biologic and start a drug that treats both.
And then you need to worry about the placebo arm that needs to have something and they are potentially a steroid lead in for both groups could be reasonable. And then they get randomized to the anti fibrotic, anti placebo.
[00:13:51] Speaker C: So that's really interesting. I'm just going to come back to placebo. Is that in that context because we know our current drugs don't work so well. You might be more comfortable, you know, putting because you know data is that the drugs don't work so well with Al disease as compared to clonic disease. And in that situation then a placebo arm might be appropriate.
[00:14:10] Speaker B: So I think it's, it's. So I agree with you, definitely appropriate when you continue background medication.
I feel very comfortable with that. When inflammation activity is not through the roof like what you had mentioned.
Where it becomes challenging is if you start with patients with a higher inflammatory activity in the stricture that are symptomatic and you randomize them to placebo for let's say a 48 week treat through design, that's a tougher one and there I think we need to find rules to treat them.
And this is where this lead in steroids could be one option. Or you randomize if it's a 48 week trial to an anti inflammatory versus anti inflammatory and fibrotic and you start everything new. So combo therapy approach, essentially there are options I think to tackle that given that it's a new indication.
I don't think the FDA will approve drugs without a placebo arm. And I think we as a community then just need to be creative to create one that's ethically acceptable to the patient. But I was surprised in stenova was a 12 week study.
The dropout within 12 weeks was about 10% really not, not bad at all. And the dropout was not due to obstruction and patients cannot make it because of their stricture. There were other reasons for it. So I'm actually quite comfortable that, that we will be able to use placebo arms.
[00:15:42] Speaker A: Holding that patient on a consistent therapy really help we're getting towards the end of this. Can I just.
So we've talked about the strictures in the. In the lumen. Obviously fibrosis is a multi system event or happens everywhere in the body.
Psc, is there a possibility that these drugs could work there? High first pass metabolism. So they're arriving in the portal vein in quite high concentration concentrations. Could there be a role for this in PSC or even fistulizing?
[00:16:10] Speaker B: Crohn's could be really interesting for drugs with local delivery first pass metabolism in the liver. As long as the drug arrives at the parts of the liver where it's supposed to work is an active form and not as the inactive metabolite. So I would love to look at onto Nisertib from Agomab Stenova and now Novera for IBD associated PSC because that would could be a game changer in that there was an anti inflammatory signal. So you could treat this mild UC patients that is milder when they have associated PSC than without and you may actually have reasonable concentrations of the drug in the liver and pac. Fibrosis is a really tough one to treat and that would be interesting. You should suggest it and run the trial.
[00:17:01] Speaker A: We could. We'll have to make a trip to Antwerp together.
Well, I just wanted to say a huge thank you, thank you for flying all this way, getting up to Liverpool. It's not super easy and straightforward and for the time you've given us today and for a really excellent talk and for all this work in an area where, you know, there's been so little up until now. Huge thank you, thank you for the
[00:17:25] Speaker B: invitation and the amazing confidence you put together.
[00:17:27] Speaker A: Great, thank you. Thank you very much.
